Origins based clinical and molecular complexities of epithelial ovarian cancer

Accepted Manuscript Origins based clinical and molecular complexities of epithelial ovarian cancer

Thingreila Muinao, Mintu Pal, Hari Prasanna Deka Boruah PII: DOI: Reference:

S0141-8130(18)31436-3 doi:10.1016/j.ijbiomac.2018.06.036 BIOMAC 9876

To appear in:

International Journal of Biological Macromolecules

Received date: Revised date: Accepted date:

27 March 2018 6 June 2018 7 June 2018

Please cite this article as: Thingreila Muinao, Mintu Pal, Hari Prasanna Deka Boruah , Origins based clinical and molecular complexities of epithelial ovarian cancer. Biomac (2017), doi:10.1016/j.ijbiomac.2018.06.036

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ACCEPTED MANUSCRIPT Origins based Clinical and Molecular Complexities of Epithelial Ovarian Cancer Thingreila Muinao1, Mintu Pal1,* and Hari Prasanna Deka Boruah1

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Biological Sciences and Technology Division, CSIR-North East Institute of Science and

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Technology, Jorhat, Assam-785006, India; Academy of Scientific & Innovative

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Research, Jorhat Campus, Assam-785006, India.

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* Corresponding author: Mintu Pal, PhD

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SERB-DST Ramanujan Fellow

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Assistant Professor, Academy of Scientific & Innovative Research (AcSIR) Biological Sciences and Technology Division

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CSIR-North East Institute of Science and Technology

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Jorhat, Assam-785006, INDIA

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Electronic address: [email protected]

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ACCEPTED MANUSCRIPT Abstract Ovarian cancer is the most lethal of all common gynaecological malignancies in women worldwide. Ovarian cancer comprises of more than 15 distinct tumour types and subtypes characterized by histopathological features, environmental and genetic risk factors,

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precursor lesions and molecular events during oncogenesis. Recent studies on gene signatures profiling of different subtypes of ovarian cancer have revealed significant

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genetic heterogeneity between and within each ovarian cancer histological subtype. Thus,

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an immense interest have shown towards a more personalized medicine for understanding the clinical and molecular complexities of four major types of epithelial

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ovarian cancer (serous, endometrioid, clear cell, and mucinous). As such, further in depth studies are needed for identification of molecular signalling network complexities

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associated with effective prognostication and targeted therapies to prevent or treat metastasis. Therefore, understanding the metastatic potential of primary ovarian cancer

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and therapeutic interventions against lethal ovarian cancer for the development of personalised therapies is very much indispensable. Consequently, in this review we have updated the key dysregulated genes of four major subtypes of epithelial carcinomas. We

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have also highlighted the recent advances and current challenges in unravelling the

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complexities of the origin of tumour as well as genetic heterogeneity of ovarian cancer. Key Words: Ovarian cancer; Genetic heterogeneity; Clinical and Molecular Complexities.

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ACCEPTED MANUSCRIPT 1. Introduction Ovarian cancer is a heterogeneous disease comprising of more than 15 distinct tumor types and subtypes according to histological appearance [1]; where two-thirds of cases are of high-grade serous types. An ovary is an ovum producing reproductive organ, and it

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consists of distinct components enveloped by mesothelium or the surface epithelium beneath which contains the germ cells and the primordial follicular cells, which are

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spread out in the stromal region. In the domain of gynaecological malignancy, ovarian

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cancer stands as the most lethal because of the high death to diseased ratio [2]. The American Cancer Society estimated that around 1.3 percent of women are diagnosed with

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ovarian cancer during their lifetime [3]. In addition, it is estimated that about 22,240 new cases of ovarian cancer will be diagnosed and 14,070 deaths from this disease in 2018 Epidemiology,

and

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(Survellience,

End

Results,

SEER,

2018,

(https://seer.cancer.gov/statfacts/html/ovary.html), making it the fifth leading cause of

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cancer death. Most of this tumors originate from one of the three major ovarian cell types-the germ cell or the oocyte; the sex cord stroma including the granulosa, thecal layer or the hilus cells, and the surface epithelial cells [4]. The statistical structures of the



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ovarian cancer are represented in Figure 1.

The germ cell tumours arise most frequently in age group of 20 and 30 years and account for 3–5 % of ovarian malignancy. The sex-cord-stromal tumors arise from the ovarian connective tissue, often secrete hormones, and can occur in women of all ages, and comprise approximately 6 % of all ovarian malignancies [5, 6]. The epithelial ovarian cancers (EOC) generally develop after age 40 and constitute approximately 90 % of 3

ACCEPTED MANUSCRIPT primary malignant ovarian tumors [7]. Borderline tumours (intermediate between benign and malignant categories) are highly proliferative but with low-malignant potential that does not invade the underlying stroma and are partially transformed in their morphology and molecular features. Approximately 10 - 20 % of epithelial ovarian neoplasms are borderline and about 10 % of borderline tumors can recur after resection that could be

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lethal. Of the invasive epithelial ovarian cancers, about 55–60 % are serous, 15 %

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endometrioid, 5–10 % clear cell and < 5 % are mucinous [8] as shown in Figure 2.

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Moreover, there are a number of socio-demographic variables are categorized to

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investigate the clinical characteristics on invasive epithelial ovarian cancer as shown in Figure 3, according to the Kaiser Permanente Research on Ovarian Cancer Survival

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(KPROCS) Study. Another related cohort study of KPROCS on epithelial ovarian cancer

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in Kaiser Permanente Northern California (KPNC) health care have accounted for prognostic variables including age at diagnosis, race, grade, histologic type, cancer

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antigen 125 levels and body mass index (BMI) at diagnosis [9]. The study was conducted on the basis of patients registered for primary invasive EOC in KPNC Cancer Registry

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from January 2000 and May 2013. Only those patients with 21 years and above were eligible for the study. The number of patients in the overall cohort was 1157 and overall this study suggests that body size should not be a major factor for influencing the dose reduction decisions in women with ovarian cancer [9, 10]. Different subtypes of epithelial ovarian cancer are diverse in their epidemiology, gene expression, genetic abnormalities, expression of tumor markers, or responsiveness to 4

ACCEPTED MANUSCRIPT therapy [11]. The origin and pathogenesis of these tumors have been difficult to interpret for years. One of the key complications in explaining the pathogenesis of ovarian cancer is because of its heterogeneity in clinicopathological features and behaviour. Whole genome profiling proved a wide range of genomic variability associated with the different histological subtypes of epithelial ovarian cancer. Subsequent differences in

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their genetic instability had been recognized resulting from chromosomal mutations,

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deregulations or alteration in their chromosome copy number. Serous borderline tumors

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(SBT) or low-grade serous ovarian carcinoma (LGSOC) is identified by its high frequency mutations of KRAS or BRAF [12, 13]. Mucinous types of tumors show KRAS

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mutations [14, 15] while endometrioid tumors demonstrate PTEN mutations [16]. In addition to this, serous, endometrioid, clear cell, and mucinous ovarian cancer do not

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bear resemblance in their morphology to ovary; rather their histology and genetic features identified them respectively to fallopian tube, endometrium, endocervical or the

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nest within the vagina. Moreover, mucinous cancers and clear-cell cancers often fail to

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respond to platinum- and taxane-based chemotherapeutic treatment unlike those of the serous and endometrioid cancers. Use of oral contraceptives, parity or breastfeeding has

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been associated with decreased risk of epithelial ovarian cancer [17-20], but not for

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mucinous cancers whose risk is rather associated with smoking cigarette[21]. An estimation of approximately 70 % of ovarian cancers is identified at advanced stage with peritoneal propagation and substantial ascites. Out of these only 30.6 % of women, succeed to survive for 5 years [22]. If the tumor is diagnosed prior to its metastasis, the 5year survival rate would exceed 90 % with conventional therapy alone, but less than 20 % of such diagnosis is observed. With the progress in the methods of treating this disease, the 5-year survival rate has improved but there is still a room for improvement. One of the ovarian cancer biomarker, CA125, is widely used for the diagnosis of ovarian 5

ACCEPTED MANUSCRIPT cancer [23, 24] and more commonly in serous cancers when compared to mucinous cancers [25]. However, the cost effectiveness of screening ovarian cancer by traditional techniques, as well as low sensitivity and specificity of detection of the commonly used biomarkers remained a great challenged. Understanding the molecular and clinical complexities of ovarian cancer will facilitate in ideal treatment strategies to combat

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against this deadly disease. In this review, we focus on the major subtypes of epithelial

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ovarian cancer, the variation in the tumorigenesis of the subtypes and the heterogeneity

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2. Subtypes of epithelial ovarian cancer

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contributed from the molecular perspective.

Epithelial ovarian carcinomas are heterogeneous in entity. The four major subtypes of

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serous, endometrioid, clear cell or mucinous are classified based on the morphology of tumor cell. The epithelial ovarian cancers may be present within the ovarian surface

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epithelium as neoplastic cyst larger than one cm [26] lined by epithelium derived from different extra ovarian tissues such as the fallopian tube, endometrium, or endocervix. These represent the benign form of the serous, endometrioid and mucinous ovarian

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carcinomas respectively. Another category connects the benign with the carcinomatous

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forms known as atypical proliferative tumours, tumours of low malignant potential, and tumors of borderline malignancy. Borderline carcinomas of low potential malignancy are the cystadenomas with epithelial cells demonstrating rapid proliferation and abnormalities in the nucleus, but with no damaging growth in the stromal areas [27]. Clinicopathologic and molecular characteristics simply classify the major histological types of epithelial ovarian carcinomas as type I and type II tumours (Table 1). Distinct genetic features identify each of these types during tumor development [28]. Type Itumors follow slow course and comprises of low-grade serous, low-grade endometrioid, 6

ACCEPTED MANUSCRIPT mucinous and clear cell carcinomas. In Type I tumors, mutations of KRAS, BRAF, PTEN, PIK3CA, CTNNB1, ARID1A and PPP2R1A genes can be found [29, 30]. Type II tumors are aggressive and typically detected at an advanced stage [31]. High-grade serous, high grade endometrioid, undifferentiated carcinomas and malignant-mixed mesodermal tumors constitute this type. Moreover, Type II tumors initially display marked

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chromosomal irregularities but tend to remain relatively stable over the course of the

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disease. In addition, early stage carcinomas are mostly of non-serous carcinomas

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subtypes [32] while the advanced stage carcinomas are predominantly of serous subtype.

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Studies based on whole-genome sequencing had provided insights of intrinsic and

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extrinsic mutational processes high grade serous ovarian cancer [33, 34].Complementary

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examinations were also attempted for structural variation (SV) pattern that would indicate the functional double-strand break repair mechanisms in various tumor types

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with genomic instability. Recent study on ab initio hierarchical clustering of ovarian cancer reported seven major subgroups based on 20 genomic features, six of which are

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epithelial subtype of ovarian cancer (Table 2). The 20 genomic features are contribution from somatic single-nucleotide variants (SNVs) and its features, indels and its properties, copy number alterations (CNAs) with its properties, and structural variations (SVs) including 32 mutation signatures [35]. Distinct biological subgroups were also identified within HGSC, separated by mutational processes. H-FBI subgroup exhibits overrepresentation of focal copy number amplification of CCNE1 (19q21); while HRD subgroup demonstrated over-represented focal copy number amplification of MECOM 7

ACCEPTED MANUSCRIPT (3q26.2), MYC (8q24.21), and CCND1 (11q13.3). In addition, they are differentiated by relatively poor prognosis in comparison to that of H-HRD subgroup. Extensive intratumoural variation in mutation, copy number and gene expression profiles of HGSC reflect the intra-tumoural diversity on evolutionary selection, raising the questions as

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how the advanced tumours might be optimally controlled [36].

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3. Major risk factors

Approximately 15 % of ovarian cancers are familial and 85 % are sporadic. Major risk

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factors for ovarian cancer include advancing age, number of ovulatory cycles; early menarche, late menopause and first pregnancy at age older than 30 years; and a positive

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family history of ovarian, breast, uterine, or colon cancer; whereas early menopause,

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pregnancy, breast feeding or the use of oral contraceptive use decreases the risk of ovarian cancer as shown in Table 3. Women harboring BRCA1 or BRCA2 mutations are

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at increased risk of developing ovarian cancer [37, 38] and correspond respectively to 40 - 60 % and 11 -27 % chance of developing high grade type of serous carcinomas [39-41]

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Chronic inflammation caused by talc has been considered as a risk [42].



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ACCEPTED MANUSCRIPT 4. Complexities in Ovarian Cancer Ovarian cancer is a heterogeneous disease with respect to its subtypes, diversity in their origin and the genomic differences associated with each of the subtypes of epithelial ovarian cancer. Origin of the epithelial ovarian cancers, such as high-grade serous

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ovarian carcinoma, clear cell carcinoma and endometrioid carcinoma are primarily not from the tissues of ovary [43]. Understanding the tumorigenesis of each subtypes and

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molecular characteristics will contribute in unravelling the complexities of this lethal

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disease and the current understanding on these areas are discussed below.

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4.1 Based on origin of tumour

Microscopic cysts are frequently observed within ovaries. Typically almost all mucinous

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and all benign serous ovarian tumors are cystic [26]. Epithelial ovarian tumors considered neoplastic are commonly enclosed as cysts with no normal ovarian

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counterpart. A cell layer resembling the coelomic epithelium of the ovary often lines

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ovarian cysts. Such cortical invaginations entrapped within the ovarian parenchyma are commonly identified as inclusion cysts. Metaplastic cysts are proposed as those cortical

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inclusion cysts which may have differentiated through the process of metaplasia. Such metaplastic cyst may subsequently become neoplastic, and epithelial ovarian carcinomas

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may originate from inclusion cyst in the ovary that undergoes malignancy [44]. 4.1.1. Serous ovarian carcinoma Prior to the onset of menarche epithelial inclusions, cysts are lined by mesothelial cells of the ovarian surface epithelium (OSE). While, approximately 41 % of the cyst after post menarche are lined by endosalpingeal cells, a ciliated tubal phenotype [45]. These mesothelial cells or endosalpingeal cells are distinct in their expression of protein markers and hormones [46]. During ovulation exposure of the ovarian surface epithelium 9

ACCEPTED MANUSCRIPT to repeated stress and to follicular fluid that are rich in estrogen may perhaps have contributed in increase cell proliferation, deleterious mutations and epithelial metaplasia to a Mullerian phenotype that consequently led to ovarian tumorigenesis [47]. However, Cheng and group have stressed that a large mass-forming, tubal-type cystic lesions are the potential precursors for the serous borderline tumour and the low-grade serous

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carcinoma [48]. Tubal type epithelium are known to be ectopically stationed and create a

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condition known as endosalpingiosis [49]. In ovary, this is identified as a microscopic or

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small macroscopic tubal-type cortical inclusion cysts (CICs) filled with serous fluid. Small serous carcinomas and large benign-like cystadenomas are found within this same

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cyst. In view of this, mutations such as p53 must have triggered the ovarian cystadenomas to develop into malignant serous carcinomas [50]. Moreover, it is unlikely

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that CICs are the sole precursors for ovarian epithelial tumors, or at least for high grade serous carcinomas.

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Malignant tumors with histological and clinical features similar to ovarian carcinomas are found in extra ovarian tissue in patients where ovaries have been removed several years prior to the development of tumour for causes other than cancer [51, 52]. In

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addition, high risk women for type II ovarian carcinomas showed increased chance of

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acquiring serous extra-ovarian carcinomas post prophylactic salpingo-oophorectomies [53]. Such high risk women associate with occult carcinomas in the fallopian tubes particularly in the fimbria [54, 55]. Histological studies complement the tissues of ovaries and fallopian tubes and cite fimbriae as the site of origin for many high grade serous ovarian carcinomas [56] and the precursor lesion in the fallopian tube is termed as STIC. Most of the tumor-specific changes were present in STICs such as those of the TP53, BRCA1, BRCA2 or PTEN [57, 58]. The occult tubal carcinomas might have spread the malignant cells to ovary during ovulation or through peri-ovarian adhesions and 10

ACCEPTED MANUSCRIPT induce the primary ovarian tumorigenesis. This may probably be linked to the high proliferative capacity of STICs, and several other studies add up the importance of fallopian tube in the derivation of majority of ovarian HGSCs [59-63]. STIC may have originated from a histologically normal site in the fallopian tube that acquire mutation in TP53 which is known as the p53 signature [64]. Though some reported the absence of

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such lesions in the ovarian surface epithelium [65], yet, rare microscopic cancer with

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STIC-like lesions are also found in CICs [66] which suggest that some of the HGSCs

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may have originated from the CIC. Alternatively, recent study report the non STIC associated lesion within the same biological origin assumed to be the distal portion of the

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4.1.2. Endometroid ovarian carcinoma

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fallopian tube which may contribute in the origin of the HGSC subtype [67].

Other than endosalpingiosis, microscopic structures lined by Mullerian epithelium are

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observed in the para-tubal and para-ovarian areas, ovarian medulla or the ovarian cortex.

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The ectopic presence of endometrium (epithelium and stroma) is termed as endometriosis, and is usually blood filled. In ovary, it is identified as endometrial cyst or

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endometriomas [68]. Several studies provide evidence for endometriosis as the origin of endometrioid ovarian carcinoma [69-71]. A meta-analysis of women with endometriosis

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had been reported [72]. The ovary has a high oxidative environment that induces the epithelial cells lining the endometriotic cyst to tumorigenesis [73]. Few proposals like retrograde or vascular dissemination during menstrual flow, metaplasia or Mullerian developmental remnants such as stem-like cells may account for endometriosis [74]. In addition,

histopathological,

epidemiological

and

molecular

evidences

suggest

endometriosis as the precursor of ovarian endometrial carcinomas [75]. Loss of heterozygosityis present in ovarian endometrioid carcinoma and in the corresponding endometrial cyst of the ovary. Somatic mutation of PTEN is an early event in the 11

ACCEPTED MANUSCRIPT development of these carcinomas in the ovary [76]. Mutation in ARIDA1 is also known in endometrioid cancers and in the adjacent endometriosis [77]. A recent study identified somatic mutations of cancer driver genes such as KRAS, ARID1A, PIK3CA, or PPP2R1A [78, 79] in the epithelial compartment of majority of

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benign non-ovarian deep infiltrating endometriosis lesions [80]. These driver genes are also frequently mutated in endometriosis-related ovarian neoplasms and in clonally

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related adjacent and distant endometriotic lesions from patients with endometriosis-

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related ovarian neoplasms [77, 81]. However, a low estimated rate of malignant transformation of endometriosis may suggest the insufficiency of the driver mutations

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alone to drive the transformation. In addition, not all of the lesions harbour a detectable mutation of the driver genes and the mutation-harboring endometriosis may therefore

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represents a distinct pathology [80]. These findings also support the potential coexistence of multiple endometriosis lineages in a single patient and introduce new prospects for a

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thorough analysis of all forms of endometriosis. 4.1.3. Clear cell ovarian carcinoma

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Clear-cell EOC are non-hormone dependent, heterogeneous group of tumors with a low growth index [82]. This carcinoma is exclusive in that it has a high percentage

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of PIK3CA activating mutations [83]. Like other EOC, the origin of CCC is poorly described. Studies associate the origin of ovarian CCCs with endometriosis [71, 84]. This is supported by the study on tumor suppressor gene ARID1A [81]. Mutations of ARID1A are expected to have initiated in the early transformation of endometriosis. The chromatin remodeling function of ARID1A [81, 85] or its collaboration with PRKCI are involved in the initiation ofthe pathogenesis [86, 87]. Zhao and group have however drawn two pathways for the derivation of ovarian CCC from endometriosis, the cystic and non-

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ACCEPTED MANUSCRIPT cyctic pathway [88]. For cystic pathway, epithelial atypia in the endometriotic cyst causes the development of carcinoma. Former studies substantiated the progression of endometriosis to clear cell carcinoma [84, 89], where atypical endometriosis may sandwiched in between the two. This must have mediated through large number of molecular changes [90-94] such as mutations which drive the endometriotic lesions with

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low malignant state to transform into clear cell carcinomas [77]. In non-cystic pathway,

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endometriosis induced fibromatosis produce adenofibroma. This adenofibroma

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developed into atypical adenofibroma which eventually give rise to clear cell carcinoma [95]. Therefore, two distinctive forms of clear cell carcinoma exist, one that has an

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adenofibromatous background and the other without adenofibromatous background [96, 97]. Cystic pathway derived ovarian CCC is more common and is predominantly of

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lower stage. While, clear cell carcinomas with adenofibromatous background are less frequent and they are primarily identified by low grade, low mitotic index, tubulocystic

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architecture and better overall survival [97]. The adenofibromatous derived clear cell

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neoplasm including the benign adenofibroma, atypical proliferative and carcinoma of clear cell show progressive increase in the mitotic index [97] and exhibit loss of

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heterozygosity [97] that become more common as the neoplasm shift from benign state to carcinomatous state supporting the tumorigenic relationship of adenofibroma, atypical

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proliferative tumor and clear cell carcinoma of adenofibromatous background. Patient with endometriosis also report the development of clear cell adenocarcinoma from benign and borderline adenofibromas of endometrioid and clear cell subtype [98]. Both clear cell and endometrioid carcinomas are derivatives of endometriosis [69] and show overlapping molecular genetics features, yet they are individually distinct in their morphologic phenotype and clinical behaviour [91].

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ACCEPTED MANUSCRIPT 4.1.4. Mucinous ovarian carcinoma The origin of mucinous carcinoma is not well defined. Most of the mucinous carcinomas of the ovary are due to metastases from extra ovarian origin [99]. Most advanced mucinous cancers are prospective metastatic gastrointestinal and pancreaticobiliary

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cancers that invade the ovary and peritoneum making the difficulties of clinical and molecular analyses of ovarian mucinous adenocarcinomas [100]. Consequently, true

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primary ovarian mucinous carcinomas are rare contributing to only 3 % of ovarian

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carcinomas. Recently mucinous metaplasia of Brenner (transitional cell) tumors has been introduced [101]. Unlike the other epithelial ovarian carcinomas, transitional cell tumors

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and mucinous tumors do not typically have Mullerian features, yet their development from cortical inclusion cysts and Walthard cell nests had been proposed [102]. Walthard

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cell nests are recognized as benign transitional-type epithelium that is commonly found in paraovarian and paratubal locations. In a study on mucinous cystadenomas and

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Brenner tumors, mucinous cystadenomas containing foci of Brenner tumor were observed in 18 % of cases [103]. The association of mucinous tumours with Walthard cell nests drew the possibility of similar histogenesis between Brenner tumors and

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mucinous carcinomas where the latter could have developed from transitional cell nests

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at the tubal peritoneal junction [104]. A few of mucinous tumors exhibited Mullerian (endocervical) characteristic [105]. Ectopic presence of such Mullerian-like group expressed homeobox genes Hoxa11 that in vitro study demonstrated the differentiation of immortalized OSE cells along Mullerian lineages. Subsequent intraperitoneal inoculation of these transformed cells generated tumours resembling mucinous epithelial carcinomas [106].

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ACCEPTED MANUSCRIPT 4.2. Based on Genetic Heterogeneity Microarray and other molecular biology experiments demonstrated that the different types of EOCs are distinct diseases where each resembles their respective extra-ovarian cancers. Among the common ovarian cancer histotypes, only high-grade endometrioid

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cancers and high-grade serous cancers display similarity supported by their gene expression profiling and high grade endometrioid cancers therefore may not be a distinct

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entity [107]. However, endometriotic cysts are the proposed origin of low grade

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endometrioid tumours with frequent activating mutations in the Wnt–β-catenin pathway [108]. Biomarker expression profile of different subtypes revealed significant difference

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in the expression [109] and support the heterogeneity of the disease.

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4.2.1. Serous ovarian carcinoma

Low grade serous or their putative precursor lesion, SBT exhibit only few sub-

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chromosomal losses. Apart from that LGSOC display many allelic disparities on

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different chromosomal arms including chromosomes 1p, 5q, 8q, 18p, 22q, and Xp. Heterozygous loss of chromosome 1p identifies several low-grade serous carcinomas but

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seldom SBTs. However, SBTs are closely associated with low-grade but not with the high grade serous carcinomas presenting their close interactions with low grade but

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divergence from the high grade serous carcinomas. Expression of WT1 is more frequent in serous ovarian carcinomas than the other types of ovarian carcinoma [110]. Ovarian tumour progression is associated with dysregulation of several enlisted genes as shown in Table 4. Attenuation of the local immune response within the tumour microenvironment may be responsible for the pathogenesis of ovarian cancer [111] and the aggressive behaviour of high-grade serous carcinoma. 15

ACCEPTED MANUSCRIPT 4.2.2. Endometroid ovarian carcinoma There are differences in the expression profile between the low grade and high grade endometroid carcinomas with overlapping molecular alterations. KRAS and PTEN mutations, oestrogen- and progesterone receptors expression, microsatellite instability are recognizable features of low grade endometroid carcinomas [112]. β-catenin-mediated

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canonical Wnt (Wnt/β-catenin/Tcf or Wnt/β-cat) signaling pathway is involved in various

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cellular processes of endometroid carcinomas. CTNNB1 encode for β-catenin and

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mutation of CTNNB1 deregulate the Wnt/β-cat pathway in ovarian endometrioid carcinomas. In addition, inactivation of PTEN and activating mutations of PIK3CA are

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identified in ovarian endometrioid carcinomas and promote the PI3K signalling pathway. Mutations that suppress the PI3K/PTEN signalling correspond to mutational defects in

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canonical Wnt signalling pathway [113]. Type II categories are characterized by altered expression of p53, p16, loss of hormone receptor and aneuploidy and are without

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mutations in either Wnt/β-cat and/or PI3K/PTEN signalling pathways that is otherwise prevalent in low-grade endometrioid carcinoma. Increase in the DNA copy gains of ESR, KRAS2,MYCN, JUNB ,and CCND2 loci [114] and other chromosomal changes of

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endometrioid are listed in Table 5.





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ACCEPTED MANUSCRIPT 4.2.3. Mucinous ovarian carcinoma Mucinous ovarian carcinomas exhibit distinct gene expression pattern [115] which include expressions of caudal type homeobox transcription factorsCDX1 and CDX2. LGALS4 is not detectable in normal OSE but is expressed at high levels in different

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forms of mucinous tumour. Changes in MAP Kinase signalling pathway are the most common. Increase in DNA copy number of HER2 and mutations of KRAS occur at

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separate events and only 5.6 % revealed simultaneous expressions of the two genes in

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mucinous carcinomas. Changes in mTOR pathway related to PIK3CA and PTEN are less observed. Moreover, we have enlisted the major signalling pathways related dysregulated

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key signalling molecules linked to mucinous ovarian cancer as shown in Table 6.



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4.2.4. Clear cell ovarian carcinoma Clear cell carcinomas (CCC) demonstrated the most distinguishing gene expression profile. They are commonly p53 wild type with low frequency mutations of breast cancer 1 (BRCA1) and BRCA2 [116] BRAF, KRAS and TP53 [117]. Mutations in AT rich interactive domain 1A (ARID1A) and phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) [81, 83, 118]are significant in CCC. ARID1A mutations may be associated with the tumorigenesis of CCCs [87]. The high frequency mutations of PI3KCA and ARID1A, the low rate of mutations in KRAS and the negligible mutations in 17

ACCEPTED MANUSCRIPT BRAF identifies the molecular features of ovarian clear cell carcinomas as shown in Table 7.

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In the absence of gene amplification, deletions of chromosomes were evident in 1p, 11q,

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and 10q (PTEN locus is at 10q23.3). Deletion of chromosome 9p21 region was most evident [119] and that deletion accounts for about 41 % of ovarian cancers across all

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histological grades [120]. Tumor suppressor genes identified on 9p include the cyclindependent kinase inhibitor 2 genes [121]. Numerous genetic changes qualify the

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heterogenous entity of clear cell carcinoma.

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5. Molecular pathways oriented target inhibitors of ovarian carcinoma

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In view of the distinct molecular aberrations associated with the different histological subtypes of epithelial ovarian carcinoma, it is vital in understanding the different molecular pathways associated with each genetic alternations for advanced therapeutic approach. Development of surgical techniques and chemotherapy processing through several clinical phases has advanced over the years [122-125]. One monoclonal antibody that has received clinical approval for ovarian cancer is bevacizumab, which is an antiangiogenic agent targeting vascular epithelial growth factor [126, 127]. Antiangiogenic agents are currently moving from Phase II to Phase III clinical trials in 18

ACCEPTED MANUSCRIPT ovarian cancer. The Phase II trial of bevacizumab exhibited promising output [128]. Bevacizumab exhibited significant improvement in progression free survival (PFS) in high risk categories and in recurrent ovarian cancer [129]. In addition, inhibitors targeting poly-ADP-ribose polymerase (PARP), mammalian target of rapamycin (mTOR) or EGFR pathway are other targets in clinical research. Ovarian cancer exhibit

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70 % over-expression of EGFR and are commonly associated with chemo-resistance and

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advanced stage at diagnosis [130, 131]. Targeting this receptor showed preclinical

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significance [132, 133]. On the contrary, EGFR inhibitors such as erlotinib and gefitinib exhibited poor response rates in platinum pre-treated ovarian cancer [134]. The phase III

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clinical trial of Erlotinib did not show improvement in either progression-free survival or the overall survival [135]. The poor outcome may be due to the effect of alternate

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pathways involved in ovarian carcinogenesis. Moreover, advanced stage platinumrefractory ovarian cancers demonstrate poor response to therapy stressing the need for a

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more effective therapeutic approach. Molecular therapeutic strategies targeting most

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common and important signalling pathways are associated with few of the mutated genes of ovarian carcinoma and the mutational impact of these genes are highlighted below

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with a scope to improve the studies on advanced ovarian cancer therapy.

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5.1. KRAS and BRAF Mutations Lead to the Activation of the MAPK/ERK Pathway KRAS and BRAF are frequently mutated in type I ovarian carcinomas [12]. Oncogenic KRAS drive half of this low grade category which are resistant to chemotherapeutic approach and deathly when metastasized to peritoneal cavity [136]. KRAS and BRAF are signalling molecules of MAPK pathway [137, 138]. RAS/RAF/MEK/ERK cascade or the MAPK pathway is an important intracellular signalling pathway involved in the transduction of several cytokines, growth factors and proto-oncogenes [138]. Activation of KRAS by extracellular mitogen subsequently lead to sequential activation of BRAF, 19

ACCEPTED MANUSCRIPT MEK and ERK and transcription factors and further activate the transcription of several genes of cellular growth, survival, angiogenesis and others [139]. Mutations of KRAS or BRAF lead to constitutive activation of ERK and the subsequent downstream transcription factors and kinases and promote to oncogenic role of MAPK [140, 141]. The importance of this pathway is realised even in the more aggressive type 2 ovarian tumor

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where the common HGSOC showed ~25 % activation of RAS pathway thus drawing the

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significance of this pathway in both subtypes of ovarian carcinoma [142, 143]. Targeting

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the mutated MAPK pathway could be an alternate approach to control tumor growth in the chemotherapy insensitive low-grade ovarian carcinoma. Several attempts are in the

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process for inhibitors of MAPKs as potential inhibitor therapy in ovarian cancer and

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those which have reached the clinical trials are underlined in Table 8.

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5.2. BRCA

Germline mutations in BRCA1/2 are comparatively common in ovarian carcinoma and

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are exhibited in serous type of ovarian cancer [144-146]. BRCA mutations demonstrated a higher occurrence of peritoneal spread than the wild genotype [147]. BRCA1 and

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BRCA2 are important DNA double strand (DSB) break repair proteins that functions through homologous recombination repair mechanism and protect the genomic stability [148]. DSBs are responsible for disturbance in both the DNA reading frames. This causes the repair mechanism to be more demanding since the reading frame is disturbed leading to higher error susceptibility. In healthy cells, DNA DSBs are efficiently repaired via homologous recombination mechanisms. Both BRCA1 and BRCA2 genes participate effectively in the repair. In cases of aberrations of either BRCA1 or BRCA2 different 20

ACCEPTED MANUSCRIPT route of DNA repair pathways can be achieved through non-homologous end joining where open ends of DNA invite binding of proteins to stabilize and reconnect the sides of the DNA however without consideration for the DNA reading frame [149, 150]. This attracts errors in DNA resulting in chromosomal instability and cell death [151]. PARP inhibitor in BRCA lacking cells causes remarkable cell death [152, 153]. Poly (ADP-

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ribose) polymerase (PARP) is known for DNA single strand break repair through base

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excision repair mechanism [154, 155]. In its absence, SSB gets accumulated leading to

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DSB [151]. PARP inhibitors applied this concept of synthetic lethality in BRCA mutation carrier whereby the combined effect of base excision repair inhibition and

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defective homologous recombination DNA repair pathway is speculated [156]. The consequences produce DNA SSBs unrepaired, increase in DSBs, failed replication fork

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and subsequently cell death [152, 153]. Current PARP inhibitors in preclinical studies of ovarian cancers include Olaparib, Rucaparib and Niraparib [157-159]. BRCA lacking

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cells exhibit around 1,000 fold higher sensitivity to the inhibitor like olaparib than those

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of the wild type [152] or heterozygous mutation with functional BRCA mutations [151, 152, 160]. The potential of PARP inhibitors in ovarian cancer therapy are highlighted in

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Table 9 underlining their current progress in the clinical trials.



5.3. PI3KCA-AKT pathway PI3K pathway is activated occur in around 30 % of ovarian cancers primarily due to mutation or amplification of PIK3CA or AKT [161, 162]. PTEN deregulation occurs because of loss of heterozygosity in endometrioid subtype [162]. Inactivation of the key 21

ACCEPTED MANUSCRIPT molecules of PI3K–Akt pathway leads to gain of function or activation of downstream signaling pathways, which drive oncogenesis [163]. mTORC1 is one of the downstream molecules activated by AKT which could be a potential therapeutic target [164]. Akt has anti-apoptotic function and upregulation in cancer cells may also cause chemoresistance or resistance towards therapeutic radiation [165]. Akt are hyperactivated in response to

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dysregulation of PI3K or PTEN and causes resistance to paclitaxel [166] and cisplatin

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[167] in ovarian cancer. However, inhibition of PI3K through its inhibitor LY294002 has

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caused the paclitaxel induced apoptosis in ovarian cancer in human [168]. The combined therapy of inhibitors and chemotherapy exposure will be effective in treating ovarian

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cancer. Few of the inhibitors targeting the molecules of PIK3CA pathway or in

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combinations with other pathway are highlighted below in Table 10.

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6. Challenges

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Based on the existing literature on the complexity and heterogeneity of ovarian cancer, it

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is very important to understand the genomic aberrations for each of the subtypes of ovarian cancer. Although significant advances have been made in advanced research on

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ovarian cancer, many questions still need to be addressed and further pursued in research to combat this disease and some are highlighted here. 

Gene expression profiling is largely based on tumour cells with respect to that of the normal coelomic epithelium. However with the understanding of the involvement of extra-ovarian precursors of epithelial ovarian cancer, it is required to take initiatives to compare the gene profile of ovarian tumours cells with that of the normal Mullerian epithelium. In addition, the precise origin for each of the 22

ACCEPTED MANUSCRIPT subtypes of ovarian cancer is crucial for proper diagnosis and treatment of the disease. 

DNA microarray technologies or sequenced-based techniques such as serial analysis of gene expression (SAGE) are largely used for gene expression

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profiling. However, the reliability and reproducibility of the results is limited by sample size and lack of independent validation and thus the clinical application of

Many genomic alterations related to DNA mutations, gene amplifications or other

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

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gene profiling becomes a challenge.

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gene anomalies associated with the different subtypes of epithelial ovarian cancer have been discussed. But, it is important to recognize how the several bio-

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molecules associated are interacting in the environmental niche to initiate and favour the pathogenesis and metastasis of this disease. Recently ovarian cancer stem cells involved in initiation and chemotherapeutic

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

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resistance of ovarian cancers have been studied and many markers associated with ovarian cancer stem cells are identified. More in-depth studies of cancer

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stem cells in the area of ovarian cancer are necessary to unravel the cellular and molecular signalling pathways controlling cancer stem cells maintenance and



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survival, in order to develop more effective anticancer therapies. One of the biggest concerns of epithelial ovarian cancer is to develop biomarker which can diagnose the disease at an early stage with high sensitivity and specificity. Preferably, it will be ideal to develop a panel of signature biomarkers to screen the ovarian cancer using clinical samples.



Technological development need to improve on fast-track. Genetically engineered mouse models of each subtypes of ovarian cancer is in need for understanding the 23

ACCEPTED MANUSCRIPT complex mechanisms underlying cancer biology in context to genetic composition, tumour cells interactions with microenvironment, drug response and resistance and also for development of new therapeutic strategies for overall

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improvement of the survival of cancer patients.

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7. Conclusions

Despite the low occurrence of new cases ovarian cancer 11.6 per 100,000 women in

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United State from 2011-2015, the annual death report about 7.2 per 100,000 women

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according to National Cancer Institute in 2018 [300], focusing that the severity of this disease has not receded. This could be accounted due to the diagnosis at the late stage of

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the disease and the complex nature of the disease. Reliable techniques and protocols for early diagnosis of ovarian cancer have to be advanced. Progressive research efforts on

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pathogenesis have surfaced the complexities and the involvement of heterogeneous

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population of extra-ovarian tissues associated with the origin of different subtypes of epithelial ovarian carcinoma. It is critical and a great challenge to identify the originating

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tissues of each subtype clearly as this would not only enhance the pathological concept of the disease but the need to improve in management of the disease including prevention.

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Therefore, it is very much decisive for robust research on targeted therapy to eliminate the root of the disease. Several therapy associated inhibitors either individually or in combinations has advanced in different phases of clinical trials. This will provide an additional advantage in the treatment strategy of ovarian cancer. However, it should be mindful of the resistance and recurrence of the disease which are commonly seen in ovarian cancer therapy. Moreover, no single treatment strategy is suitable to all cases or health care settings, andresearch needs additional miles in screening the suitable patients

24

ACCEPTED MANUSCRIPT or the right time to realise the practical applications of the therapy. In summary, further studies in advanced diagnostic approach, rational preclinical studies, subtype-and patient specific target therapies through interdisciplinary studies including molecular biology, immunology, chemical and bioinformatics approaches would help in understanding the molecular basis of this disease for advancing in personalized treatment and in overall

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management of ovarian cancer. Moreover, since the percentage of occurrence of ovarian

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cancer is low, stronger collaboration of different research association will be required to

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achieve these goals.

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Conflict of interest- The authors confirm that this article content has no conflicts of

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interest.

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Acknowledgements- The authors are thankful to the Director, CSIR-NEIST, Jorhat for

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his support. This work is financially supported by SERB-Department of Science & Technology (SERB-DST), Government of India for providing the Ramanujan Fellowship

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(SB/S2/RJN-087/2014) to Dr. Mintu Pal; and CSIR/UGC JRF (21/06/2015(i) EU-V to

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Thingreila Muinao.

Figure Legends:

Figure 1.Percentage of ovarian cancer based on occurrence, malignancy and age group affected. Figure 2.Major morphological subtypes of ovarian carcinomas. Figure 3. Selected demographic representation of invasive epithelial ovarian carcinoma

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ACCEPTED MANUSCRIPT Figure 4. Analysis of specific interaction network of genes expressed in serous ovarian carcinoma STRING network database. Figure 5. The gene names of identified proteins associated with endometrioid ovarian carcinoma were used as input to build a functional network using STRING analysis.

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Figure 6. Network showing the functional interactions of genes associated with mucinous subtype of ovarian cancer based on the STRING database interaction

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probability.

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Figure 7. Network showing the functional interactions of genes associated with clear cell

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subtypes of ovarian cancer based on the STRING database interaction probability.

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Oncology 26(15_suppl) (2008) 5510-5510. [280] J. Ledermann, P. Harter, C. Gourley, M. Friedlander, I. Vergote, G. Rustin, C.L.

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J. Korach, T. Huzarski, A. Poveda, S. Pignata, M. Friedlander, N. Colombo, P. Harter, K. Fujiwara, I. Ray-Coquard, S. Banerjee, J. Liu, E.S. Lowe, R. Bloomfield, P. Pautier, Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial, The Lancet. Oncology 18(9) (2017) 12741284.

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PT

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PT E

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PT

resistance in ovarian cancer: modulation of p53 action on caspase-dependent mitochondrial death pathway, Cancer research 66(6) (2006) 3126-36.

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D

Liu, L.C. Cantley, E. Winer, Phase I dose escalation study of the PI3kinase pathway

PT E

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Schilder, K.Q. Cai, A.K. Godwin, R.K. Alpaugh, Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent

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PT E

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CE

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AC

Hendrickson, A. Jatoi, M.S. Block, T.A. Dinh, M.W. Robertson, J.A. Copland, Phase 2 trial of everolimus and letrozole in relapsed estrogen receptor-positive high-grade ovarian cancers, Gynecologic oncology 146(1) (2017) 64-68. [299] H.S. Chon, S. Kang, J.K. Lee, S.M. Apte, M.M. Shahzad, I. Williams-Elson, R.M. Wenham, Phase I study of oral ridaforolimus in combination with paclitaxel and carboplatin in patients with solid tumor cancers, BMC cancer 17(1) (2017) 407.

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ACCEPTED MANUSCRIPT [300] National Cancer Institute. SEER cancer statistics review (CSR) 2013–

AC

CE

PT E

D

MA

NU

SC

RI

PT

2015.https://seer.cancer.gov/statfacts/html/ovary.html. 2018. Accessed June, 2018.

77

ACCEPTED MANUSCRIPT Table 1. Characteristics of ovarian cancer based on histopathological, molecular and genetic studies. Type I Subtypes

low

Type II grade

and

serous High grade serous, high grade undifferentiated

PT

borderline tumour , low grade endometrioid, endometrioid, mucinous, clear carcinomas,

mesodermal, carcinosarcomas

RI

cell

malignant-mixed

SC

Characteristics slow growth of development, Clinically aggressive; typically

MA

cystic masses in ovary

NU

generally present as large present at advance stage Marked

chromosomal

instability; yet stable over the course of disease.

mutations in KRAS, BRAF, high mutation in TP-53

behaviour

PTEN, PIK3CA, CTNNB1,

PT E

D

Chromosomal

group

show

of the

BRCA1/BRCA2

mutation,

AC

CE

ARID1A and PPP2R1A

Approximately half

78

ACCEPTED MANUSCRIPT Table 2. Seven subgroups of ovarian cancer identified between and within histotypes based on ab initio clustering of integrated point mutation and structural variation signatures. Subgroup

adult granulosa cell tumors with mutation signature S.BC (associated with

PT

G-BC

Comment

RI

breast cancer and medulloblastoma

microsatellite instability (MSI) endometrioid tumors characterized by

SC

E-MSI

High grade serous, clear cell, and endometrioid cases without obvious discriminant features

MA

Mixture

NU

mutation signature S.MMR (reflective of mismatch-repair deficiency)

clear cell cases characterized by mutation signature S.APOBEC (attributed

APOBEC

to activity of the AID/APOBEC family of cytidine deaminases)

C-AGE

clear cell cases characterized by mutation signature S.AGE (associated

CE

PT E

D

C-

H-FBI

AC

with age at diagnosis)

H-HRD

High grade serous cases with high prevalence of fold back inversion SVs.

High grade serous with prevalence of duplications or deletion rearrangements and mutation signature S.HRD (reflective of homologous recombination deficiency).

79

ACCEPTED MANUSCRIPT Table 3. Major risk factors of ovarian cancer. Risk of ovarian Characteristics

References

cancer Women under 40 age group show [37, 43]

Age

age

group

PT

lower risk while 80 to 84 year-old show

maximum

SC

Women who had family history of [44-46]

NU

Family history

RI

incidence.

MA

ovarian, breast, uterine, or colon cancer increase the risk. Ovulation

increases

risk

with [47]

D

Ovulatory cycle

PT E

ovulation in different age periods showing different contribution to

AC

CE

risk rate; maximum risk of 20 %

Parity

per ovulation for one year in the age group of 20-29 years. Childbearing significantly reduces [48-50] the risk of ovarian cancer. Comparison between nulliparous and

parous

decrease

in

women

show

the

relative

risk

with

80

ACCEPTED MANUSCRIPT number of births in women with 5 or

more

births.

Every

birth

conferred added 20% reduction in risk.

PT

Women with first birth at 35 years of age or older were at 39% lower

RI

risk compared to women who gave

SC

birth at age earlier than 20 years of

NU

age.

Women with unexplained infertility [51]

Infertility

MA

were associated with increased risk of ovarian cancer.

Obese women with a body mass [52]

D

Obesity

PT E

index of 30 or more in accordance to World Health Organization's

AC

CE

criteria show increased risk of

Smoking

ovarian cancer. Increase risk in mucinous ovarian [53-55] carcinoma

Oral

Women with oral contraceptive use [56, 57]

contraceptive use

for 10 or more years decrease the risk. Reduction persisted for more than 81

ACCEPTED MANUSCRIPT 30 years after oral contraceptive use had ceased Hormone

Increases risk.

[58]

replacement

AC

CE

PT E

D

MA

NU

SC

RI

PT

therapy

82

ACCEPTED MANUSCRIPT Table 4. Genes expression profiles of serous subtypes of ovarian cancer. Genes

Features/effects

TP 53

> 96% mutation in ovarian high [128, 129] grade serous carcinoma.

[130, 131]

RI

Missense or nonsense mutations.

PT

(Tumour protein 53)

References

Overexpression of mutant p53 was

SC

associated with better progression

NU

free survival and overall survival Low frequency mutations

[132]

MA

BRCA1/2

mechanism of mutation other than [133]

D

point mutation

PT E

Hypermethylation of the BRCA1 [134] promoter reduce Brca1 protein

CE

expression by 15-31%

AC

No

direct

association

to

p53 [135]

signature Epigenetic

mutation

defective recombination

cause [136]

homologous of

DNA

repair

pathway in HGSC

83

ACCEPTED MANUSCRIPT Loss of heterozygosity (LOH) at [137, 138] BRCA

locus

reduces

BRCA1

expression Mutation associated with improved

PT

overall survival and progression free survival copy

number

change [139]

RI

DNA

Notch3

SC

associated with apoptosis

MA

poor survival

NU

Higher expression associated with [140-142]

Higher resistance to paclitaxel and observed

in

sphere

D

cisplatin

PT E

forming cells of primary serous ovarian cancer.

CE

Upregulation

c-Myc

AC

relationship

showed with

inverse

cisplatinum

response. Serous papillary ovarian carcinoma [143] had significantly higher expression. Highly amplified in > 20% of high [128] grade serous ovarian carcinomas.

84

ACCEPTED MANUSCRIPT DNA

RSF1

copy

number

change [99, 128]

observed Rsf-1 protein is a member of a chromatin-remodeling complex

PT

Regulate gene expression and cell

DNA copy number change seen

[128, 144]

SC

CCNE1(cyclin E1)

RI

proliferation

Knockdown arrest G1/S phase, cell

and

MA

apoptosis

viability

NU

decreased

18.2 % amplifications observed in [145, 146]

AKT2

D

high-grade carcinomas.

PT E

Along with BCAM, it may be involved in AKT2 kinase activation

AC

CDKN2A/B

CE

in HGSC.

Absence of gene expression is 27 % [147-149] at mRNA level and 21% at protein level in serous papillary ovarian cancer Homozygous deletion of 6.4 % in serous borderline tumors, lowgrade serous carcinomas and high-

85

ACCEPTED MANUSCRIPT grade serous carcinomas CCKN2A

along

with

TP53

expression can be used as marker for diagnosis of low grade serous

PT

tumors. Overexpression of 64 % was [150, 151]

(high-mobility group

observed in high-grade papillary

RI

HMGA

SC

serous carcinoma

AT-hook)

NU

Expression significantly higher in

high grade papillary serous over

MA

other histological types ofovarian

D

carcinomas.

PT E

Silencing of the gene cause growth inhibition and enhances apoptosis All mutations associated with loss [152, 153]

CE

CDK12(cyclin

AC

dependent kinase 12) of heterozygosity in the gene locus Downregulation impaired

associated

expression

of

with DNA

damage repair genes p21(WAF1/CIP1)

High

level

expressions [154-156]

preferentially expressed in low grade serous carcinoma and SBT

86

ACCEPTED MANUSCRIPT increases the overall survival Higher expression tendency in low [157-159]

Cyclin D1

grade than high grade serous High expression is prognostic for a

KRAS/BRAF/MAPK

RI

Follow

PT

shorter progression-free interval

SC

signalling pathway.

Expression is associated with poor

NU

prognosis.

sarcoma

2

MA

KRAS (Kirsten rat Mutations in over half of low-grade [160, 161] viral serous carcinomas and SBTs Mutations might be an early event.

PT E

D

oncogene homolog)

Mutation alteration such as copy

CE

number loss.

BRAF(v-raf murine Mutations vary from 23 % to 48 [162, 163] viral %in

AC

sarcoma

oncogene B)

serous

borderline

tumour

homolog andwhereas zero to 33 % mutations in low grade serous carcinoma Mutation may be a good prognostic factor in low grade serous cancer

DOCK4(Dictator of Homozygously deletion of 4.3% of [164]

87

ACCEPTED MANUSCRIPT cytokinesis 4)

high grade serous carcinomas

CSMD1(CUB sushi

and Homozygous deletion of 6.4% in [148]

multiple high-grade serous carcinomas

domains 1)

multiple serous ovarian carcinomas

RI

sushi

and Recurrently mutated in high grade [128]

PT

CSMD3(CUB

SC

domains 3 )

Mutation observed in low grade [145, 165, 166]

ERBB2

encoding

HER2/neu

MA

Mutations

NU

serous ovarian cancer.

activate an upstream regulator of

D

KRAS

PT E

Activation

is

through

Ras/Raf/MEK/MAPK

CE

signallingpathway

AC

MAPK(Mitogen activated

protein low-grade serous carcinomas and

kinase) BTG-2

Hyperactivation seen in 80 % of [167]

78 % of serous borderline tumour

(B-cell Expressed

translocation gene 2)

in

low

malignant [168, 169]

potential and grade 1 serous tumor

88

ACCEPTED MANUSCRIPT Participated in growth arrest RB1

About 2 % tumor suppressor genes [128, 161]

(Retinoblastoma 1)

present in regions of homozygous deletions

(Neurofibromatosis

Significantly

mutated in

high

grades serous ovarian carcinomas.

RI

1)

PT

and NF1

loss.

and

DNA potential

damage-inducible)

in

low

malignant [168]

NU

arrest

(growth Expressed

and low grade serous

MA

gadd34

SC

Both the gene show copy number

tumor

D

Involvement in tumor suppression, [170]

PT E

cell proliferation and in apoptosis Deletion in low grade and SBT; [99, 171]

miR-34

CE

identified within chromosome1p36

AC

Low levels related to worse overall

HLA-G

survival Overexpression frequent in high [172, 173] grade serous and rarely in

low

grade or SBT mRNA and protein levels greater in

89

ACCEPTED MANUSCRIPT advanced stages than early stages or normal state Role

intumorigenesis

and

AC

CE

PT E

D

MA

NU

SC

RI

PT

progression

90

ACCEPTED MANUSCRIPT Table 5. Gene expression profiles in endometrioid subtypes of ovarian cancer.

Features

KRAS

Low frequency mutation of <7 [177, 178] %

References

identified

in

ovarian

copy

number

SC

Gene

RI

endometrioid carcinomas.

PT

Genes

amplification of 3 % in primary

NU

endometrial carcinomasand 18

MA

% in metastatic lesions.

This change is associated with prognosis

of

5-year

D

poor

PT E

survival of 46 %. Microsatellite instability of 13-

AC

CTNNB1

CE

20 % found.

tensin homolog)

ovarian [89, 161]

endometrioid

carcinomas

showed over 50 % mutations.

PTEN (Phosphatase

Low-grade

Inactivating mutations and

%-21

%

in

of 14 [16, 89, 179] ovarian

endometrioid adenocarcinomas

Mutations

correspond

to [175, 180]

91

ACCEPTED MANUSCRIPT CTNNB1

mutations,

coordination catenin

with

Wnt/β-

signaling

andPI3K

signalling activation 30

%

of

endometrioid [97, 161]

carcinomas show mutations

SWI–SNF

chromatin

SC

the

RI

Encodes a key component of

Mutations

are

clustered

MA

exons 9 and 20

NU

remodeling complex PIK3CA

Mutations

PT

ARID1A

associated

in [175]

with

PT E

D

adverse prognostic indicators p53

63.0 % mutations

[161, 181]

JUNB

AC

CE

Absence of p53 overexpression associated

with

a

poorer

survival 83% showed gain in DNA copy [176, 182] number. Expression higher in invasive ovarian cancer than in benign tumors

92

ACCEPTED MANUSCRIPT CCND2

Amplification of 50% observed

[176]

ESR

Expression positive in about [183] 50%

(Estrogen receptor)

Increase in copy number of50 [176, 184] %

targets

AC

CE

PT E

D

MA

NU

serous ovarian cancer

in

SC

downstream

RI

Deregulation of MYC-N and

PT

MYCN

93

ACCEPTED MANUSCRIPT Table 6. Gene expression profiles in the progression and metastasis of mucinous subtype of ovarian cancer. Genes

Features

References

MUC genes

62 % of MUC1 expressed in [186-188]

in

RI

Low MUC2 expression mucinous

adenocarcinoma

correlated

with

Mucinous

better

SC

NU

survival rate

a

PT

mucinous carcinomas

adenoma

and

MA

mucinous borderline tumor

D

show positive MUC5

PT E

MUC13 has higher

significantly

expression

AC

CE

mucinous

LGALS4 (galectin 40)

and

Brennerstumors comparison

in

in to

other

histological types of ovarian cancer samples High expression in mucinous [185] cystadenomas,

borderline

tumors, and carcinomas Expression occurs in early

94

ACCEPTED MANUSCRIPT stage CDX1 and CDX2 (caudal

CDX1

type homeobox

transcriptions factors)

upregulated

in [185, 189]

mucinous carcinoma 79 % CDX2 prevalent in

borderline

of

benign,

and

malignant

SC

majority

RI

CDX2 is detectable in the

PT

primary mucinous tumors

CK20 (Cytokeratin 20)

NU

ovarian mucinous tumors Primary

ovarian

tumour [190]

Mutations of 40 % -50 %

[161, 191]

BRAF

3.5 % of mutations

[192]

PT E

KRAS

D

MA

expressed 83 %

CDKN2A

Approximately

HER2

AC

CE

mucinous

21

%

of [193]

tumour showed

mutation Amplification in 19 % in [194] invasive mucinous ovarian cancers

and

borderline

6

%

in

ovarian

carcinomas CEACAM6

Expression upregulated in [195, 196]

95

ACCEPTED MANUSCRIPT (Carcinoembryonic

mucinous ovarian tumours

antigen-related

cell

adhesion molecule 6

Expression correlated with apoptosis in normal colonic epithelial cells Mutations found in 35 % of [192]

PT

p53

RNF43

RI

cases Recurrent

mutations [193, 197]

SC

observed.

NU

Mutation of 9 % in mucinous

ovarian borderline tumors

MA

and 21 % in mucinous ovarian

carcinomas

PT E

D

identified Immunoreaction for p53 was

AC

CE

present

in

37.7

%

of

mucinous carcinomas Along with Ki67, act as important depicting

markers the

in

aggressive

nature of mucinous tumors cMET

Expression found in 42.9 % [198, 199] in mucinous ovarian tumour

96

ACCEPTED MANUSCRIPT EGFR

50 % of gene gain

[192]

whole EGFR over expression

AC

CE

PT E

D

MA

NU

SC

RI

PT

accounts for 57 %

97

ACCEPTED MANUSCRIPT Table 7. Gene expression profiles of clear cell ovarian carcinoma.

Gene

Features

References

c-Myc

High incidence of c-Myc [203]

Sequence mutations of 15 % [164, 204]

RI

p53

PT

overexpression

SC

found in ovarian clear cell carcinoma

is

mainly

NU

Overexpression

MA

observed only in a stage III clear cell carcinoma due to

D

missense point mutation higher

in [135]

PT E

HIF-1α (hypoxia-inducible Significantly factor 1)

ovarian clear cell carcinoma

AC

CE

than in other histological types Correlation between mRNA and protein expression level was not observed

BRCA1/2

Low frequency of BRCA1/2 [200] mutations

KRAS

Mutation detected in 13 %- [181, 205]

98

ACCEPTED MANUSCRIPT 16.2

%

of

clear

cell

adenocarcinoma BRAF

Varying mutation from non [164, 205] to low sequence mutations of

PT

1 % detected in ovarian clear cell carcinoma

found. is

an

early

event

NU

This

SC

1A (ARID1A)

RI

AT rich interactive domain Over 46 % gene mutations [97, 103, 202]

in tumorigenesis

MA

Mutations very common and often harbour phosphatase

D

and tensin homolog (PTEN)

PT E

or PIK3CA mutations

Phosphatidylinositol-4,

subunit

AC

catalytic

3-kinase frequency

CE

bisphosphate

(PIK3CA)

PTEN P27

5- Ovarian CCCs have a high [164, 205] of

α activating mutations. Mutations

in

32

%

of

tumours Mutations in 8 % of tumours

[206]

(cyclin-dependent Encode the proteins p15, p16 [207-210]

kinase inhibitor 2 genes)

and p14

99

ACCEPTED MANUSCRIPT Low

CDK2

activity

correlated with high p27 protein expression Function

in

tumour

PT

suppression to regulate Rb

dependent kinase inhibitor WAF1) 1A, p21)

regulator

p21 that

(Cip1

function

of

or [211]

SC

(cyclin- Encodes

NU

CDKN1A

RI

and p53 related pathways

cell

as

cycle

MA

progression in G1 phase STAT3

Activated

STAT3

was [212]

D

constitutively expressed in

PT E

ovarian clear cell carcinoma

CE

Inhibition of STAT3 lead to

AC

HNF-1β(Hepatocyte

nuclear factor-1 beta)

induction of apoptosis Upregulated at the mRNA [213-215] and protein level Downregulation of HNF-1β expression in ovarian cancer cells increased cisplatin- or paclitaxel-mediated

100

ACCEPTED MANUSCRIPT cytotoxicity represses

HNF-1β

cell

growth and its suppression increases proliferations Overexpression explains the [216]

peroxidase 3)

chemoresistance of clear cell

Encodes

the

protein [217, 218]

SC

PPM1D

RI

carcinomas

PT

GPX3(Glutathione

Function

NU

phosphatase Wip 1 as

negative

MA

feedback regulator of p53

D

Role in the expression of cell regulatory

proteins

PT E

cycle

including CCND1

AC

CE

significantly higher levels of mRNA

expression

in

ovarian clear cell carcinoma cell

lines

harboring

gains/amplifications

of

17q23.2 IL-6 (interleukin-6)

High level expression

[219]

This may relate with the

101

ACCEPTED MANUSCRIPT frequent

occurrence

of

hypercalcemia

and

thromboembolic events in ovarian clear cell carcinoma Up-regulated in clear cell [220]

PT

ANXA4(annexin A4)

carcinoma domain-containing Up-regulated in

epithelial [221]

RI

FXYD

ovarian clear cell carcinoma

VCAN(versican)

Up-regulated

primary [222]

NU

in

SC

ion transport regulator 2

ovarian clear cell carcinoma

MA

MAP3K5/ASK1 (Mitogen- Expressed in ovarian clear [223]

apoptosis signal-regulating

PT E

kinase 1)

D

activated protein kinase 5/ cell carcinoma

AC

CE

Activates c-Jun N-terminal [224]

complementing)

to

a

different

stresses

including oxidative stress

ERCC1/XPB(Excision repair

kinase and p38 in response

mRNA

levels [225]

cross- of ERCC1 and XPB appeared to be more in clear cell tumors in comparison to other

epithelial

ovarian

102

ACCEPTED MANUSCRIPT cancer Included in DNA damage [226] excision activity, linkage of repair

transcription

with

DNA

and

gene-

PT

DNA

specific repair

Expression is increased in [227]

RI

OPN (osteopontin)

SC

clear cell ovarian carcinomas

expression

NU

Down regulation of OPN [228] decreased

MA

extracellular matrix invasion TFPI2(tissue

factor differentially expressed in [229] both ovary and endometrium

D

pathway inhibitor 2)

AC

CE

PT E

clear cell tumours

103

ACCEPTED MANUSCRIPT TABLE 8. Clinical trials on MAPK pathway inhibitors in ovarian cancer.RECIST: Response Evaluation Criteria in Solid Tumors. Type

Inhibitors

Sample type

Phase Consequences

MEK1/2

Selumetinib

recurrent

II

(AZD6244)

On

oral [254, 255]

LGSC,

administration of 50

≥18 years

mg drug twice daily, out

RI

one

PT

inhibitor

of

PT E

D

MA

NU

completely

CE

52

response

SC

patients

AC

References

while

seven showed partial response. Grade 3 toxicities were most common and

include

gastrointestinal, dermatological, metabolic,

fatigue,

anaemia,

pain,

constitutional

and

cardiac events. No death reported due

to

this

treatment.

104

ACCEPTED MANUSCRIPT Trametinib

recurrent or III

Rash,

diarrhea, [256]

progressive

central

LGSC

retinopathy

serous

observed in phase I

Pimasertib

II

LFT

elevation, [257] vein

RI

retinal

PT

study

SC

occlusion, skin rash,

rash,

serous

retinal

LGS

PT E

Binimetinib

D

MA

NU

pharyngitis,

III

carcinoma

detachment, macular oedema in phase I Binimetinib

is [258]

administered 45 mg is

BID orally. Patients

recurrent or

receive therapy until

persistent

disease progression

AC

CE

that

acneiform

or

unacceptable

toxicity. The will

enroll

study 300

patients from round the globe. BRAF

vemurafenib LGSC

II

Oneovarian

cancer [259]

105

ACCEPTED MANUSCRIPT inhibitors

patient

studied

which showed 70% reduction in the total sum of the baseline

AC

CE

PT E

D

MA

NU

SC

RI

PT

target lesions.

106

ACCEPTED MANUSCRIPT Table 9: Important events of PARP inhibitors as a potential ovarian cancer therapy. EMA: European Medicines Agency; TRR: tumor response rate; OS: Overall survival; PFS: progression free survival ; HRD: homologous recombination deficiency; HGSOC: High grade serous ovarian carcinoma. gBRCAmut: germlineBRCA mutation.

inhibitors PARP

Drug

Patient type

Consequences

gBRCAmut

Single-agent

name I

Olaparib

witholaparib

SC

inhibitors

Reference

PT

Phase

RI

Target

showed

benefit

a

63%

(including

NU

clinical

treatment [276]

disease stabilization).

IB

Olaparib

nausea,

Platinum

anorexia and fatigue.

PT E

refractory, platinum-

CE

resistant,

AC

Grade 1–2 toxicities such as [272,

mutation,

D

inhibitors

BRCA

MA

PARP

platinum-

No

vomiting,

dysgeusia, 279]

significant

differences

observed between BRCA and non-BRCA patients in toxicities response.

sensitive Platinum

sensitive

patient

group showed overall response rate of 40%.

IIA

Recurrent

PFS was 8.4 months and 4.8 [280]

patients

months for olaparib and placebo

with

or respectively

with

no

BRCA

107

277-

ACCEPTED MANUSCRIPT without

status known.

germline

PFS was 11.2 months and4.3

BRCA

months for olaparib and placebo

mutation.

respectively.

Platinum sensitive.

RI

When drug dose of 400 mg taken [281]

resistant

was twice daily, TRR was 31%

patient

and stable disease rate of 40%.

SC

Platinum

NU

IIB

from EMA

PT

Olaparib received grant approval

MA

PFS showed 7 months and OS of

18 years or At 150 mg tablets intake two [282]

D

III

16.6 months.

times

AC

CE

PT E

older,

a

day,

significant

platinum-

progression-free

sensitive,

observed

relapsed

patient at 19.1 months compared

ovarian

to placebo at 5.5 months.

cancer

olaparib

was

treated

Anaemia, fatigue or asthenia,

patients with

in

survival

neutropenia a

were

the

most

common adverse effect.

BRCA1/2 mutation ARIE

Rucaparib

Recurrent,

PFS was 12.8 months versus 5.2 [283]

108

ACCEPTED MANUSCRIPT L2

platinum-

months

Part 1

sensitive,

mutation and BRCA wildtype

germline

low-LOH score.

BRCA

comparing

BRCA

Rucaparib approved as the first PARP

inhibitor

germline

for

use

PT

mutation

or

somatic

in

BRCA

RI

mutation patients who have had

Niraparib

Recurrent

PFS

for

patients

with

a [274]

NU

III

SC

⩾2 lines of therapy

gBRCAmut was 21 months and

platinum

5.5 months for drug and placebo

MA

HGSOC,

AC

CE

PT E

D

sensitive.

respectively. A significant improvement in PFS among high HRD score patient without gBRCAmut. Low HRD score patient without germline/somatic

BRCA

mutation also had a significant PFS advantage. Niraparib received approval for use in the maintenance setting for platinum-sensitive HGSOC, regardless of BRCA status.

109

ACCEPTED MANUSCRIPT Table 10. Important events on clinical trials ofPRKCI/AKT pathway inhibitors in ovarian cancer.DLT(s): Dose-limiting toxicities, MTD: Maximum tolerated dose, PFS: progression free survival.

Phase

s target

Patient

consequences

sample BKM1

I

and

+olaparib

Recurrent

MTD was established at [292] 50 mg daily for BKM120

SC

PI3K

References

PT

Drug

RI

Inhibitor

and 300 mg twice daily

NU

PARP

for

olaparib.

D

MA

BothgBRCAm

+ I

demonstrated

clinical benefits. DLTs included

PT E CE

Afuresertib

grade

depression

3 and

transaminitis. Recurrent

125

mg

carboplatin

established

and paclitaxel

afuresertib.

AC

AKT

gBRCAwt

and

One

was MTD

patients

the [293] of

showed

DLTs among the 125 mg cohort with grade 3 rash while 2 patients from the

110

ACCEPTED MANUSCRIPT 150 mg cohort exhibit DTL with grade 3 rash in both

the

patients

concurrent

G2

and

febrile

neutropenia and G2 lip

Platinum

Adverse Grade 3/4 effects [293]

carboplatin

resistant

are

and paclitaxel

and

diarrhoea,

rash,

fatigue,

vomiting

and

nausea.

NU

platinum

RI

+ II

SC

Afuresertib

PT

swelling in one of them.

PT E

D

MA

refractory

AC

CE

Ipatasertib

I

Overall response rate was 32.1%

according

RECIST

while

to

median

PFS showed 7.1 months in resistant patients. Patients

MTD at 600 mg showed [294]

without

stable

anticancer

incomplete response in

disease

or

therapy for ovarian patient four months before the treatment.

111

ACCEPTED MANUSCRIPT Temsirolimus

II

Platinum-

9.3% out of 54 patients [287, 295]

refractory

showed partial response.

ovarian

Fatigue,

carcinoma

and metabolic alterations,

gastrointestinal

renal failure and grade 4

PT

pulmonary

the

RI

embolism were

Everolimus

II

Ovarian

Initiated from September [296]

cell 2014

NU

clear

SC

adverse effects.

MA

carcinoma and

+ I

Advanced

12.5% out of 34 patients [297]

panitumumab

ovarian

resulted

+ bevacizumab

cancer

ovarian cancer.

CE

PT E

Everolimus

D

recurrent

AC

mTOR

Three

to

of

the

recurrent

patients

response to the treatment that last for around 6 months. Electrolytic

disorders,

blood hypertension, skin rush and mucositis were the common grade 3 – 4 112

ACCEPTED MANUSCRIPT toxicities. II

and letrozole

Relapsed

Among 19 patients, nine [298]

estrogen

were

receptor-

evaluation

positive

Median

high grade months.

s

I

paclitaxel

and

PT E CE AC

3.9

Twelve patients had at least one grade 3 or worse

Advanced

Two out of 22 showed [299]

solid

grade 4 dose limiting

tumor

toxicity of neutropenia.

cancers

D

carboplatin

was

adverse events.

MA

+

PFS

point.

NU

Ridaforolimus

time

the

SC

carcinoma

at

RI

ovarian

alive

PT

Everolimus

Median tumor decrease of 25%

was

observed

evaluable patients selected (n=18), of which 50 % were

partial

response

group, 33% showed stable disease and 17% were progressive diseased.

113

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7