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Hereditary gastric cancer
Best Practice & Research Clinical Gastroenterology 23 (2009) 147–157
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Best Practice & Research Clinical Gastroenterology
2
Hereditary gastric cancer Carla Oliveira, PhD, Professor a, b, Raquel Seruca, MD, PhD, Professor a, b, Fa´tima Carneiro, MD, PhD, Professor a, b, c, * a
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Medical Faculty of the University of Porto, Porto, Portugal c ˜o, Porto, Portugal Department of Pathology, Hospital S. Joa b
Keywords: familial gastric cancer hereditary gastric cancer E-cadherin CDH1 germline mutations in situ carcinoma pagetoid spread prophylactic gastrectomy surveillance endoscopy
Gastric cancer is a heterogeneous and highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer associated death worldwide. Most cases are sporadic and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases (1–3%) and a single hereditary syndrome – Hereditary Diffuse Gastric Cancer (HDGC) – has been characterised. Among families that fulfil the clinical criteria for HDGC, about 40% carry CDH1 germline mutations, the genetic cause of the others being unknown. The management options for CDH1 asymptomatic germline carriers are intensive endoscopic surveillance and prophylactic gastrectomy. In this chapter we review the pathophysiology and clinicopathological features of HDGC and discuss issues related with genetic testing and management of family members. Ó 2009 Elsevier Ltd. All rights reserved.
Definition Carcinomas of the stomach are very heterogeneous from the morphologic standpoint [1]. There are two main types of gastric carcinoma – intestinal and diffuse – which display different clinicopathologic profiles and often occur in distinct epidemiologic settings [2]. Intestinal carcinoma is more prevalent in elderly persons, of the masculine gender, whereas diffuse carcinoma tends to occur in younger individuals, mainly females, and frequently depicts hereditary conditioning. The incidence of intestinal carcinomas is steadily decreasing in most countries, in contrast to diffuse carcinomas whose incidence
* Corresponding author at: IPATIMUP, Rua Dr. Roberto Frias S/N, 4200-465 Porto, Portugal. Tel.: þ351 225570700; Fax: þ351 225570799. E-mail addresses: [email protected] (C. Oliveira), [email protected] (R. Seruca), [email protected] (F. Carneiro). 1521-6918/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.02.003
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is quite stable or even increasing [3]. The classification proposed by Carneiro et al [4] highlights the heterogeneity of gastric carcinoma, individualising isolated cell type carcinomas and glandular carcinomas (roughly corresponding to diffuse and intestinal carcinomas, respectively) as well as mixed and solid carcinomas [1,4]. Most cases of gastric cancer are sporadic, although descriptions of clustering of multiple gastric cancer cases in the same family are also present in the literature [5,6]. In 1999, Guilford et al [7] reported three Maori kindred with early onset, multigenerational, diffuse gastric cancer, in which germline mutations of the E-cadherin (CDH1) gene were identified by genetic linkage analysis and mutation screening. These findings led to the identification of a new inherited cancer syndrome designated as Hereditary Diffuse Gastric Cancer (HDGC) [7]. Soon afterwards, families from other ethnicities were identified sharing similar features [8–10]. Later, in 1999, the inaugural meeting of the International Gastric Cancer Linkage Consortium (IGCLC) was held to determine the diagnostic criteria and to provide guidelines for the clinical management of families with familial gastric cancer. The IGCLC defined the syndrome of Hereditary Diffuse Gastric Cancer (HDGC) (OMIM #137215) as any family fulfilling one of the following criteria: (1) two or more documented cases of diffuse gastric cancer in first/second degree relatives, with at least one diagnosed before the age of 50; or (2) three or more cases of documented diffuse gastric cancer in first/second degree relatives, independently of age [11]. Families with aggregation of gastric cancer and an index case with diffuse gastric cancer, but not fulfilling the IGCLC criteria for HDGC, were coined as familial diffuse gastric cancer (FDGC) [11]. According to the criteria of the IGCLC, the designation of familial gastric cancer (FGC) should be used for cases with familial aggregation of gastric cancer in which the histopathology of the tumors is unknown. Additionally, families with aggregation of intestinal carcinomas should be designated familial intestinal gastric cancer (FIGC) (for a review see Refs [11,12]). From the above descriptions it is clear that the definition of HDCG is based mainly in clinical features (according to the IGCLC) while, according to the criteria adopted by the New Zealand group, the designation of HDGC should be restricted to cases in which CDH1 gene germline mutations have been identified [7,10]. An updated definition of the different syndromes is expected to be provided soon by the members of the International Gastric Cancer Linkage Consortium.
Prevalence Gastric cancer is a highly prevalent disease, the fourth most common cancer and the second leading cause of cancer associated death worldwide (10% of the cancer deaths) [13]. Most cases of gastric cancer are sporadic in nature, but approximately 10% display familial clustering [5]. Of these, only 1–3% is predicted to be hereditary [6]. Comparative studies between Asian and Western countries demonstrate striking differences in the incidence and overall survival of gastric cancer, which suggest ethnic origin as a possible risk factor [14,15]. Incidence is highest in Japan (>40 per 100,000), Eastern Asia, South America, and Eastern and Southern Europe, and contrasts with Canada (10 per 100,000), Northern Europe, Africa, and the United States with the lowest incidences [16]. Although rare before the age of 40, gastric cancer incidence steadily climbs thereafter and peaks in the seventh decade of life, independently of the population [17]. Epidemiology data supports family history as an important risk factor, with a 1.5–3.0-fold increase in the risk of the disease among first-degree relatives of gastric cancer patients [15]. Nevertheless, this risk may well be associated with life-style, environmental associated disease and low susceptibly gene variations, rather than with high penetrance inherited genetic factors. The assessment of the overall prevalence of HDGC is difficult and has not been done so far, due both to the recent identification of this syndrome and to the bias in the study of familial gastric cancer, mainly focused on families with diffuse gastric cancer. We have recently performed a review of 439 families with aggregation of gastric cancer: 118 fulfilled the HDGC criteria (IGCLC), 104 were classified as FDGC, 38 as FIGC and 179 as FGC [18]. In the same report, the frequency of CDH1 mutations was analysed and CDH1 mutations were preferentially observed in families classified as HDGC (36.4%). In FDGC, the frequency of CDH1 germline mutations was much lower (12.5%). Neither FIGC nor FGC
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families harboured CDH1 germline mutations. Importantly, isolated cases of diffuse gastric cancer in individuals younger than 35 years were also found to have CDH1 germline mutations [18]. From the data collected in this study [18] and taking into consideration that familial aggregation of gastric cancer accounts for about 10% of the whole burden of gastric cancer, the frequency of families with HDGC according to the criteria defined by the IGCLC would be about 2.7%. However, according to the criteria proposed by the New Zealand group, requiring the detection of presence of CDH1 germline mutations for the identification of HDGC, the frequency of this syndrome would be about 1.3%. It is important to stress that the striking differences in the incidence of gastric cancer in general, also apply for the fraction of families in which gastric cancer clustering is observed. To illustrate this, we analysed the CDH1 mutation frequency in families fulfilling the IGCLC criteria for HDGC, from regions with low, moderate and high incidence of gastric cancer and found that in low gastric cancer incidence countries, the frequency of germline CDH1 alterations was higher than 40% in HDGC families and was 20% in isolated patients with diffuse gastric cancer under the age of 35, whilst in moderate and high incidence countries the frequency of CDH1 alterations was not higher than 20% both in HDGC families and isolated patients with diffuse gastric cancer under the age of 35 (Oliveira, unpublished data). These observations are most probably related with an increased number of families, in moderate and high incidence countries, in which clustering of gastric cancer cases occurs due to environmental (life-style, diet) risk factors and/or low susceptibly gene variations. Pathophysiology The diminished or absent E-cadherin immunoreactivity observed in neoplastic cells from primary gastric tumours (hereditary and sporadic) harbouring CDH1 mutations, is consistent with biallelic inactivation of the CDH1 gene by a 2nd hit mechanism. Both alterations are expected to lead to CDH1 complete inactivation which determines initiation of diffuse gastric cancer [19–25]. In sporadic diffuse gastric carcinomas harbouring somatic CDH1 mutation, promoter methylation has been described to be the 2nd hit inactivation mechanism in more than half of the cases [21]. Loss of heterozigosity (LOH) at the CDH1 locus, as well as a second CDH1 mutation has been less frequently described [21]. In the setting of HDGC, few tumors were analysed for 2nd hit inactivation mechanisms. Although somatic structural alterations of CDH1 seem uncommon mechanisms of CDH1 inactivation [22], promoter hypermethylation was shown to be the most frequent 2nd hit mechanism in this setting [20,24,25]. Alterations in other tumor suppressor genes and oncogenes are expected to play a role in the pathophysiology of diffuse gastric cancer, although this issue has rarely been explored in the literature. Humar et al [26] have described that diffuse gastric cancer initiation seems to occur at the proliferative zone of the gastric epithelium and correlates with absent or reduced expression of junctional proteins. Moreover, these authors claim that these lesions are associated with poor differentiation, increased proliferation, activation of the c-Src system, and epithelial-mesenchymal transition [26]. Clinicopathological features of hereditary diffuse gastric cancer Histopathological features of hereditary diffuse gastric cancer (HDGC) At initial diagnosis, most GC patients present an advanced disease stage with a high risk of relapse after surgical treatment. Various multimodal therapy regimens are used to improve the patient prognosis, with limited success and the diffuse type of gastric cancer is not an exception. For this reason, carriers of germline CDH1 deleterious mutations are offered the possibility to be submitted to total prophylactic gastrectomy, with the aim of preventing the development of a lethal cancer. Stomachs removed from germline CDH1 deleterious mutation carriers have constituted an extremely useful tool to understand disease initiation as well as to identify markers for early diagnosis. Therefore, the current knowledge on the morphologic steps underlying the development of HDGC stems from detailed studies performed in stomachs that were totally mapped, encompassing prophylactic gastrectomy specimens and total gastrectomies performed in patients referred from chromoendoscopic surveillance programs. Currently, there is a information available from 96 total gastrectomies in the setting of HDGC, corresponding to published reports [27–43] and unpublished observations.
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Seventy-three of these gastrectomies were systematically studied and 70 (96%) displayed one or multiple foci of intramucosal diffuse (signet-ring cell) carcinoma (number of foci varying from 1 to 318). In two out of the three cases in which early invasive carcinoma was not identified, tiny foci of in situ signet-ring cell carcinoma were observed (unpublished observations). Additionally, three other publications reported prophylactic gastrectomies performed in CDH1 germline mutation carriers in which cancer was not identified [37,41,44]. Two of these publications did not provide detailed data on the protocol used for the study of the surgical specimens [37,41]. The case reported in the third study [44] was later submitted to a detailed analysis according to a research protocol and shown to be positive for early invasive carcinoma (four foci) [42]. Similar findings had been previously reported by Lewis et al [28]. In our experience, unless total sampling of the whole stomach is performed, the diagnosis of early invasive cancers cannot be excluded. Actually, one of us (FC) had the opportunity to see in consultation several prophylactic gastrectomies, originally reported as negative for cancer, in which the detailed microscopic study of the whole length of gastric mucosa (after complete embedding of the whole stomach) revealed the presence of foci of early invasive signet-ring cell carcinomas in all cases (data not published). In North American and European families, early invasive carcinoma was not restricted to any topographic region in the stomach: foci were identified from cardia to pre-pyloric region, without evidence of antral clustering [27–29,31,42]. In a series of eight cases reported by Rogers et al [40], 70% of the total foci were localised in the proximal 1/3 of the stomach. In another series from United Kingdom [42] the highest number of foci was observed in the fundus (44.7%) followed by the body (40.2%). In New Zealand Maori families, a predilection was observed for the occurrence of early invasive carcinomas for the distal stomach and the body-antral transitional zone [30,35]. Reasons for the different anatomical localisation of the cancer foci in the aforementioned studies remain to be clarified, probably encompassing genetic susceptibility and/or environmental factors. As precursors of the invasive cancers, two distinct types of lesions were identified in prophylactic gastrectomies: (i) in situ signet-ring cell carcinoma, corresponding to the presence of signet-ring cells within basal membrane, generally with hyperchromatic and depolarised nuclei (Fig. 1A); (ii) pagetoid spread of signet-ring cells below the preserved epithelium of glands/foveolae (Fig. 1B) [31]. Model of development of hereditary diffuse gastric cancer On the basis of the findings in prophylactic gastrectomies, a model for the development of diffuse gastric cancer in germline CDH1 deleterious mutations carriers was proposed [12,31] encompassing the following lesions: mild non-atrophic gastritis, in situ signet-ring cell carcinoma, pagetoid spread of signet-ring cells and invasive carcinoma. E-cadherin immunoexpression was shown to be reduced or absent in early invasive gastric carcinomas, contrasting with the normal membranous E-cadherin expression in adjacent non-neoplastic mucosa, in keeping with a clonal origin of the cancer foci. However, one should be aware that E-cadherin may be expressed at the cell membrane of neoplastic cells (reduced intensity and/or dotted pattern) as well as in the cytoplasm [22]. Most probably, the cytoplasmic expression is due to the temporary accumulation of truncated protein in the endoplasmic reticulum (cytoplasm) on its way to degradation [45,46]. In pagetoid spread lesions and in situ carcinomas E-cadherin immunoexpression was also shown to be reduced or absent (Fig. 1C and D) [31]. It is accepted that the gastric mucosa in CDH1 germline mutation carriers is quite normal until the second CDH1 allele is inactivated. It is postulated that this downregulation occurs in multiple cells in the gastric mucosa, accounting for the multifocal tumor lesions. Background changes in the gastric mucosa of prophylactic gastrectomy specimen encompass mild chronic gastritis, foveolar hyperplasia and tufting of surface epithelium [18]. Occasionally, an inflammatory granulomatous reaction is observed. In almost all prophylactic gastrectomies studied so far, intestinal metaplasia and Helicobacter pylori infection are absent, namely in families from North America and Europe. Gastric cancer in other inherited cancer syndromes Gastric cancer may be seen as part of the tumour spectrum in other inherited cancer predisposition syndromes, such as HNPCC, FAP and Li-Fraumeni syndromes [47–49]. Stomach cancer can also occur in
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Fig. 1. In situ carcinoma and pagetoid spread of signet-ring cells. (A) In situ signet-ring cell carcinoma: gland with intact basement membrane lined by signet-ring cells (arrow heads) (H&E, original magnification 100); (B) Pagetoid spread of signet-ring cells below the preserved epithelium of one gland (arrows) (H&E, original magnification 100); (C) In situ carcinoma: loss of E-cadherin immunoexpression (arrow heads) (IHC, original magnification 200); (D) Pagetoid spread: loss of E-cadherin immunoexpression in signet-ring cells spreading below the preserved epithelium of one gland (arrows) (IHC, original magnification 200).
breast and ovarian cancer families. In two studies [50,51] germline TP53 mutations were found in families with heavy history of gastric cancer and lacking CDH1 germline mutations (3.2% and 2.9%) [50,51]. It was also shown that 20.7% of families harbouring both gastric and breast malignancies displayed germline mutations in BRCA2 [52]. Moreover, a BRCA2 mutation was found in 23.5% of women with ovarian cancer and a family history of stomach cancer [53].
Other cancer types clustering in HDGC families In HDGC families several types of malignancies have been described other than diffuse gastric cancer. Specifically, lobular breast cancer has been diagnosed in several HDGC families [39,54–56] and 40% of CDH1 germline mutation female carriers are at risk to develop this type of cancer [57].
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Colorectal carcinoma has also been identified in patients belonging to CDH1 positive families. Signet-ring cell carcinoma of the colon, a rare subtype of colon cancer, was found in two families with CDH1 germline mutations, one of them not meeting the HDGC criteria [55,58]. Moreover, a screening of germline CDH1 mutations in Korean gastric and colorectal cancer patients, with and without family history, demonstrated that the pathogenic T340A mutation in CDH1 gene was identified in one patient from an HNPCC family that was negative for hMLH1 and hMSH2 germline mutations as well as in one colorectal cancer patient without family history [59]. Although prostate and ovarian carcinomas have been observed in HDGC families carrying CDH1 mutations [11,60], no deleterious germline CDH1 mutations have been identified in families with both gastric and prostate carcinomas [61,62], and no studies have addressed the role of germline CDH1 mutations in ovarian carcinoma families. HDGC segregates with middle line malformations An interesting observation was reported describing the association of E-cadherin germline mutations with cleft lip, with or without cleft palate (CLP), in two HDGC families [63]. In these families, the underlying CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing extracellular cadherin repeat domains involved in cell–cell adhesion. Since an association of CDH1 mutations with syndromic CLP has not been reported so far, Frebourg et al suggested that these two previously not described mutations in CDH1 have a specific effect [63]. Role of genetic testing Genetic counselling is an essential component of any cancer genetic testing and management program and it is mandatory that occurs before a blood sample is collected, and the search for a pathogenic mutation starts. Guidelines for genetic testing are common to the majority of hereditary disorders. Recently the European Society of Human Genetics led an initiative to harmonise the genetic testing across Europe. Taking advantage of the information available at http://www.eurogentest.org/ news/info/public/unit6/patients.xhtml, herein we present our view on guidelines and the role of genetic testing in HDGC syndrome. Any patient at high risk of developing a genetic disorder must have given informed consent, known that the protection of confidentiality will be secure and, be fully informed about the multifaceted issues that relate to genetic testing, namely in relation to the laboratory and clinical meaning of a positive and a negative result. In the case of HDGC, the patient must fully apprehend the fact that failure to identify a germline CDH1 mutation, in the family, does not exclude the presence of a hereditary factor, as only about 40% of HDGC families fulfilling the IGCLC criteria have been found to harbour a CDH1 germline pathogenic mutation. Therefore, disease in the remainder apparently negative HDGC families is likely caused by yet-to-be-identified germline alterations either within CDH1 gene or in alternative genes. High-risk patients must also appreciate the fact that there are very few reports in which CDH1 mutations are not fully penetrant. Moreover, in the genetic counselling session, it is mandatory to discuss the limitations in clinical management of carriers of CDH1 germline pathogenic mutations, as discussed below. Management According to the recommendations of the IGCLC, asymptomatic carriers of pathogenic (truncating) CDH1 mutations should be offered intensive endoscopic surveillance (twice a year) and/or prophylactic gastrectomy. In the setting of HDGC, Pharoah et al [57] estimated that the cumulative risk of clinically detected gastric cancer is 67% for men and 83% for woman, at the age of 80. Increased penetrance in females was also observed by Kaurah et al [64]. Early invasive diffuse carcinoma has been identified in the large majority of total gastrectomies performed in carriers of germline CDH1 mutations. These observations show that although CDH1 mutation carriers may develop early diffuse gastric cancer in relative young ages, not all mutation carriers will have clinically expressed disease during their lives. These
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observations suggest that a proportion of in situ/early invasive lesions may remain indolent and will not progress into clinically significant cancer. Genetic testing and commencement of screening in the late teens or early 20s have been recommended [64,65] and a surveillance program for asymptomatic CDH1 mutation carriers was proposed by Fitzgerald and Caldas [66,67]. The approach of the Stanford group for individuals in known HDGC families is to recommend genetic counselling and testing for CDH1 carriage by the early 20s, and biannual chromoendoscopy and biopsies by the age of 25 or at least 10 years earlier than the youngest family member affected by cancer [40]. Furthermore, for women with CDH1 mutations, the Stanford group recommends a similar approach to screening as for other hereditary breast cancer syndromes, including annual mammography and breast MRI starting at the age of 25 years [40]. In what concerns endoscopic screening, one should be aware of the limitations for the detection of early lesions of HDGC in asymptomatic CDH1 mutation carriers. The likelihood of detecting foci preoperatively was shown to be positively correlated with the number of biopsies taken and the number of lesions in the gastrectomy specimen [42]. Endoscopic surveillance has the benefit of preserving the stomach until lesions are identified. However, there are a number of issues which have made the use of endoscopy in this context questionable, including patient compliance and the sensitivity and specificity of the technique [27,29,68]. Chromoendoscopy with congo red/methylene blue has been pointed as an improved surveillance technique in comparison to white light gastroscopy for the intensive endoscopic surveillance of CDH1 germline mutation carriers [30,35,36]. Moreover, van Kouwen et al [32] suggested that [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scanning may facilitate early detection of HDGC. The role of this technique as a screening modality in HDGC deserves further investigation. Despite the advances in screening procedures for early (curable) gastric cancer, large scale studies need to be performed to confirm the usefulness of the aforementioned methods in clinical practice. Importantly, it should be taken into consideration that surveillance using endoscopy (with chromoendoscopy in some cases) and multiple mucosal biopsies had failed to identify intramucosal carcinoma in many CDH1 germline mutation carriers submitted to prophylactic gastrectomy [27,29,33,38,40–42,64]. These findings suggest that prophylactic (total) gastrectomy should be considered as a valid approach for management of asymptomatic carriers of CDH1 germline mutations in well-characterised HDGC families [27,40,55]. Prophylactic gastrectomy should be considered in the early 20s in male mutation carriers whereas female mutation carriers may wish to delay the procedure taking into consideration the dietary consequences of total gastrectomy during pregnancy [55]. Alternatively, it has been suggested that total gastrectomy should be considered in CDH1 mutation carriers at an age five years younger than the youngest family member who developed gastric cancer [69]. Specific recommendations were also proposed by the New Zealand HDGC group regarding age dependent guidelines for genetic testing, surveillance gastroscopy and prophylactic gastrectomy [35]. Revised guidelines for clinical management are expected to be published in the near future, reflecting the consensus achieved in the Workshop organised by the IGCLC on Hereditary Diffuse Gastric Cancer, with the participation of experts from different geographic regions. An unsolved issue in HDGC is the management of carriers of CDH1 germline missense variants. Fitzgerald and Caldas [66] suggested that the significance of CDH1 germline missense variants should be assessed in at least four affected members in combination with functional and transcript analysis (to look for activation of cryptic splice sites). However, in some cases this type of analysis is impossible to accomplish due to the lethality of this disease. To circumvent this limitation, our group developed a procedure for selection of high-risk individuals for HDGC within carriers of CDH1 germline missense variants, based on the information collected on co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, functional in vitro studies (aggregation and invasion assays) and in silico data [70]. The in silico model estimates the degree of conservation within species of the mutated site, the impact of the mutation on the protein structure and its effect on splicing. To date, most missense variants studied have a clear functional impact on E-cadherin function, hampering cell–cell adhesion and increasing cell invasion, when compared with wild-type expressing E-cadherin cells, supporting their pathogenic nature. The integration of the functional in vitro and in silico analysis of CDH1 germline missense variants, along with segregation of
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the missense mutations with disease within pedigrees, frequency in controls, and recurrence could be used as an adjunct for the counselling of mutation carriers. In the absence of clear clinical observations, we believe that this multidisciplinary approach improves the clinical utility of the genetic tests offered to the patients, helping to clarify the potential pathogenic nature of each CDH1 germline missense variant.
Genotype–phenotype correlations Very little is known about a putative genotype–phenotype correlation between the type (truncating versus missense) or position (localisation in the different domains of protein) of CDH1 germline mutations and the clinical parameters of disease (age of onset, disease penetrance, tumour spectrum or disease severity). The majority (80%) of CDH1 germline mutations, reported to date in HDGC families, is truncating and predicted to generate transcripts with premature termination codons (PTCs) [18,64]. Such transcripts are usually degraded by the nonsense mediated decay (NMD), an RNA surveillance pathway and a quality control system, when the PTC is located upstream from at least exon–exon junction [71]. Recently, we examined the role of NMD in the downregulation of several CDH1 PTC-containing transcripts in normal gastric mucosa from CDH1 germline mutation carriers. We found that while PTC-containing transcripts localised in the NMD-competent region are degraded by the NMD system, PTC-containing transcripts located in the NMD incompetent region are not. Moreover, the analysis of medical data from 264 carriers of truncating germline mutations revealed that patients carrying PTCs in the NMD-competent region developed cancer earlier and had a higher cumulative risk of developing gastric cancer than patients carrying PTCs in the NMD incompetent region [18,64]. These findings suggest that NMD may have a detrimental effect in the clinical progression of HDGC because it potentially degrades PTC-containing transcripts (especially those with PTC at the final portion of CDH1) that probably encode mutated proteins with residual function and tumour suppressor activity [71]. Another line of evidence of a genotype–phenotype correlation is the aforementioned report of two families, with co-existence of HDGC and midline malformations, carrying CDH1 splice-site mutations [63]. Each of these mutations generates at least one in-frame mutant transcript that would escape NMD downregulation and would be potentially responsible for the clustering of these phenotypes [63]. Nevertheless, available evidence is insufficient to claim for a definitive genotype–phenotype correlation. Evidence from in vitro studies points to a putative genotype–phenotype relation between the E-cadherin domain affected, the associated cellular effects, and the signaling pathways involved, but validation in patient material has not been performed yet [72].
Practice points Most gastric cancer cases (90%) are sporadic in nature, familial clustering occurs in 10% of the cases and, out of these, 1–3% is hereditary. Hereditary Diffuse Gastric Cancer (HDGC) is an autosomal dominant inherited gastric cancer syndrome caused by germline mutations of E-cadherin gene (CDH1). Among families that fulfil the clinical criteria for HDGC, about 40% carry CDH1 germline mutations, the genetic cause of the others being unknown. At the moment genetic testing for mutations in CDH1 gene should be considered in families fulfilling the criteria for HDGC. In countries with low prevalence of gastric cancer, genetic testing can be offered also to isolated cases of DGC in individuals younger than 35 years. The management options for CDH1 asymptomatic germline carriers are intensive endoscopic surveillance and prophylactic gastrectomy.
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Prophylactic gastrectomy is currently offered as a curative strategy to carriers of germline CDH1 pathogenic mutations aiming to prevent the development of a lethal disease. A model of development of HDGC was proposed on the basis histopathological lesions observed in the study of prophylactic gastrectomies.
Research agenda A thorough analysis of the mechanisms responsible for the 2nd hit inactivation of CDH1 in the very early lesions of HDGC is necessary to define strategies for chemoprevention. Identification of the molecular mechanisms underlying disease progression is mandatory to explain why some early intramucosal carcinomas remain indolent for undefined periods of time, while others progress to widely invasive gastric cancer. Significance of CDH1 germline missense mutations needs to be assessed by a multidisciplinary approach to elucidate pathogenicity, penetrance and impact on disease progression. Meta-analysis of available data on type and location of CDH1 mutations and clinical presentations of the disease is necessary to elucidate putative genotype–phenotype correlations. Genetic cause of HDGC not associated with CDH1 germline mutations needs to be identified.
Acknowledgements Fa´tima Carneiro, Carla Oliveira and Raquel Seruca are members of the International Gastric Cancer Linkage Consortium (IGCLC). The work herein reported from the IPATIMUP team was partly funded by the Sixth Framework Programme from EU-FP6 (LSHC-CT-2005-018754) and the Portuguese Science Foundation (POCTI/SAU-OBS/58111/2004 and PTDC/SAU-GMG/72168/2006). Carla Oliveira receives salary support from the Program Cieˆncia 2007, FCT, Portugal.
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A women with a family history of gastric and breast cancer. N Engl J Med 2007;357: 283–91. *[40] Rogers WM, Dobo E, Norton JA, et al. Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic findings with clinical implications. Am J Surg Pathol 2008;32:799–809. *[41] Lynch HT, Kaurah P, Wirtzfeld D, et al. Hereditary diffuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy. Cancer 2008;112:2655–63. [42] Barber M, Save V, Carneiro F, et al. Histopathological and molecular analysis of gastrectomy specimens from hereditary diffuse gastric cancer patients has implications for endoscopic surveillance of individuals at risk. J Pathol 2008;216: 286–94. [43] Caron O, Schielke A, Svrcek M, et al. A usefulness of prophylactic gastrectomy in a novel large hereditary diffuse gastric cancer (HDGC) family. Am J Gastroenterol 2008;103:2160–1. [44] Gaya DR, Stuart RC, McKee RF, et al. E-cadherin mutation-associated diffuse gastric adenocarcinoma: penetrance and non-penetrance. Eur J Gastroenterol Hepatol 2005;17:1425–8. [45] Chen YT, Stewart DB, Nelson WJ. Coupling assembly of the E-cadherin/beta-catenin complex to efficient endoplasmic reticulum exit and basal-lateral membrane targeting of E-cadherin in polarized MDCK cells. J Cell Biol 1999;144:687–99. [46] Huber AH, Stewart DB, Laurents DV, et al. The cadherin cytoplasmic domain is unstructured in the absence of betacatenin. A possible mechanism for regulating cadherin turnover. J Biol Chem 2001;276:12301–9. [47] Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer: an updated review. Gastroenterology 1993;104:1535–49. [48] Giardiello FM, Welsh SB, Hamilton SR, et al. Increased risk of cancer in the Peutz–Jeghers syndrome. N Engl J Med 1987; 316:1511–4. [49] Varley JM, McGowan G, Thorncroft M, et al. An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53. J Med Genet 1995;32:942–5. [50] Oliveira C, Ferreira P, Nabais S, et al. E-Cadherin (CDH1) and TP53 rather than SMAD4 and Caspase-10 germline mutations contribute to genetic predisposition in Portuguese gastric cancer patients. Eur J Cancer 2004;40:1897–903. [51] Keller G, Vogelsang H, Becker I, et al. Germline mutations of the E-cadherin (CDH1) and TP53 genes, rather than of RUNX3 and HPP1, contribute to genetic predisposition in German gastric cancer patients. J Med Genet 2004;41:e89.
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Contents lists available at ScienceDirect
Best Practice & Research Clinical Gastroenterology
2
Hereditary gastric cancer Carla Oliveira, PhD, Professor a, b, Raquel Seruca, MD, PhD, Professor a, b, Fa´tima Carneiro, MD, PhD, Professor a, b, c, * a
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal Medical Faculty of the University of Porto, Porto, Portugal c ˜o, Porto, Portugal Department of Pathology, Hospital S. Joa b
Keywords: familial gastric cancer hereditary gastric cancer E-cadherin CDH1 germline mutations in situ carcinoma pagetoid spread prophylactic gastrectomy surveillance endoscopy
Gastric cancer is a heterogeneous and highly prevalent disease, being the fourth most common cancer and the second leading cause of cancer associated death worldwide. Most cases are sporadic and familial clustering is observed in about 10% of the cases. Hereditary gastric cancer accounts for a very low percentage of cases (1–3%) and a single hereditary syndrome – Hereditary Diffuse Gastric Cancer (HDGC) – has been characterised. Among families that fulfil the clinical criteria for HDGC, about 40% carry CDH1 germline mutations, the genetic cause of the others being unknown. The management options for CDH1 asymptomatic germline carriers are intensive endoscopic surveillance and prophylactic gastrectomy. In this chapter we review the pathophysiology and clinicopathological features of HDGC and discuss issues related with genetic testing and management of family members. Ó 2009 Elsevier Ltd. All rights reserved.
Definition Carcinomas of the stomach are very heterogeneous from the morphologic standpoint [1]. There are two main types of gastric carcinoma – intestinal and diffuse – which display different clinicopathologic profiles and often occur in distinct epidemiologic settings [2]. Intestinal carcinoma is more prevalent in elderly persons, of the masculine gender, whereas diffuse carcinoma tends to occur in younger individuals, mainly females, and frequently depicts hereditary conditioning. The incidence of intestinal carcinomas is steadily decreasing in most countries, in contrast to diffuse carcinomas whose incidence
* Corresponding author at: IPATIMUP, Rua Dr. Roberto Frias S/N, 4200-465 Porto, Portugal. Tel.: þ351 225570700; Fax: þ351 225570799. E-mail addresses: [email protected] (C. Oliveira), [email protected] (R. Seruca), [email protected] (F. Carneiro). 1521-6918/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bpg.2009.02.003
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is quite stable or even increasing [3]. The classification proposed by Carneiro et al [4] highlights the heterogeneity of gastric carcinoma, individualising isolated cell type carcinomas and glandular carcinomas (roughly corresponding to diffuse and intestinal carcinomas, respectively) as well as mixed and solid carcinomas [1,4]. Most cases of gastric cancer are sporadic, although descriptions of clustering of multiple gastric cancer cases in the same family are also present in the literature [5,6]. In 1999, Guilford et al [7] reported three Maori kindred with early onset, multigenerational, diffuse gastric cancer, in which germline mutations of the E-cadherin (CDH1) gene were identified by genetic linkage analysis and mutation screening. These findings led to the identification of a new inherited cancer syndrome designated as Hereditary Diffuse Gastric Cancer (HDGC) [7]. Soon afterwards, families from other ethnicities were identified sharing similar features [8–10]. Later, in 1999, the inaugural meeting of the International Gastric Cancer Linkage Consortium (IGCLC) was held to determine the diagnostic criteria and to provide guidelines for the clinical management of families with familial gastric cancer. The IGCLC defined the syndrome of Hereditary Diffuse Gastric Cancer (HDGC) (OMIM #137215) as any family fulfilling one of the following criteria: (1) two or more documented cases of diffuse gastric cancer in first/second degree relatives, with at least one diagnosed before the age of 50; or (2) three or more cases of documented diffuse gastric cancer in first/second degree relatives, independently of age [11]. Families with aggregation of gastric cancer and an index case with diffuse gastric cancer, but not fulfilling the IGCLC criteria for HDGC, were coined as familial diffuse gastric cancer (FDGC) [11]. According to the criteria of the IGCLC, the designation of familial gastric cancer (FGC) should be used for cases with familial aggregation of gastric cancer in which the histopathology of the tumors is unknown. Additionally, families with aggregation of intestinal carcinomas should be designated familial intestinal gastric cancer (FIGC) (for a review see Refs [11,12]). From the above descriptions it is clear that the definition of HDCG is based mainly in clinical features (according to the IGCLC) while, according to the criteria adopted by the New Zealand group, the designation of HDGC should be restricted to cases in which CDH1 gene germline mutations have been identified [7,10]. An updated definition of the different syndromes is expected to be provided soon by the members of the International Gastric Cancer Linkage Consortium.
Prevalence Gastric cancer is a highly prevalent disease, the fourth most common cancer and the second leading cause of cancer associated death worldwide (10% of the cancer deaths) [13]. Most cases of gastric cancer are sporadic in nature, but approximately 10% display familial clustering [5]. Of these, only 1–3% is predicted to be hereditary [6]. Comparative studies between Asian and Western countries demonstrate striking differences in the incidence and overall survival of gastric cancer, which suggest ethnic origin as a possible risk factor [14,15]. Incidence is highest in Japan (>40 per 100,000), Eastern Asia, South America, and Eastern and Southern Europe, and contrasts with Canada (10 per 100,000), Northern Europe, Africa, and the United States with the lowest incidences [16]. Although rare before the age of 40, gastric cancer incidence steadily climbs thereafter and peaks in the seventh decade of life, independently of the population [17]. Epidemiology data supports family history as an important risk factor, with a 1.5–3.0-fold increase in the risk of the disease among first-degree relatives of gastric cancer patients [15]. Nevertheless, this risk may well be associated with life-style, environmental associated disease and low susceptibly gene variations, rather than with high penetrance inherited genetic factors. The assessment of the overall prevalence of HDGC is difficult and has not been done so far, due both to the recent identification of this syndrome and to the bias in the study of familial gastric cancer, mainly focused on families with diffuse gastric cancer. We have recently performed a review of 439 families with aggregation of gastric cancer: 118 fulfilled the HDGC criteria (IGCLC), 104 were classified as FDGC, 38 as FIGC and 179 as FGC [18]. In the same report, the frequency of CDH1 mutations was analysed and CDH1 mutations were preferentially observed in families classified as HDGC (36.4%). In FDGC, the frequency of CDH1 germline mutations was much lower (12.5%). Neither FIGC nor FGC
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families harboured CDH1 germline mutations. Importantly, isolated cases of diffuse gastric cancer in individuals younger than 35 years were also found to have CDH1 germline mutations [18]. From the data collected in this study [18] and taking into consideration that familial aggregation of gastric cancer accounts for about 10% of the whole burden of gastric cancer, the frequency of families with HDGC according to the criteria defined by the IGCLC would be about 2.7%. However, according to the criteria proposed by the New Zealand group, requiring the detection of presence of CDH1 germline mutations for the identification of HDGC, the frequency of this syndrome would be about 1.3%. It is important to stress that the striking differences in the incidence of gastric cancer in general, also apply for the fraction of families in which gastric cancer clustering is observed. To illustrate this, we analysed the CDH1 mutation frequency in families fulfilling the IGCLC criteria for HDGC, from regions with low, moderate and high incidence of gastric cancer and found that in low gastric cancer incidence countries, the frequency of germline CDH1 alterations was higher than 40% in HDGC families and was 20% in isolated patients with diffuse gastric cancer under the age of 35, whilst in moderate and high incidence countries the frequency of CDH1 alterations was not higher than 20% both in HDGC families and isolated patients with diffuse gastric cancer under the age of 35 (Oliveira, unpublished data). These observations are most probably related with an increased number of families, in moderate and high incidence countries, in which clustering of gastric cancer cases occurs due to environmental (life-style, diet) risk factors and/or low susceptibly gene variations. Pathophysiology The diminished or absent E-cadherin immunoreactivity observed in neoplastic cells from primary gastric tumours (hereditary and sporadic) harbouring CDH1 mutations, is consistent with biallelic inactivation of the CDH1 gene by a 2nd hit mechanism. Both alterations are expected to lead to CDH1 complete inactivation which determines initiation of diffuse gastric cancer [19–25]. In sporadic diffuse gastric carcinomas harbouring somatic CDH1 mutation, promoter methylation has been described to be the 2nd hit inactivation mechanism in more than half of the cases [21]. Loss of heterozigosity (LOH) at the CDH1 locus, as well as a second CDH1 mutation has been less frequently described [21]. In the setting of HDGC, few tumors were analysed for 2nd hit inactivation mechanisms. Although somatic structural alterations of CDH1 seem uncommon mechanisms of CDH1 inactivation [22], promoter hypermethylation was shown to be the most frequent 2nd hit mechanism in this setting [20,24,25]. Alterations in other tumor suppressor genes and oncogenes are expected to play a role in the pathophysiology of diffuse gastric cancer, although this issue has rarely been explored in the literature. Humar et al [26] have described that diffuse gastric cancer initiation seems to occur at the proliferative zone of the gastric epithelium and correlates with absent or reduced expression of junctional proteins. Moreover, these authors claim that these lesions are associated with poor differentiation, increased proliferation, activation of the c-Src system, and epithelial-mesenchymal transition [26]. Clinicopathological features of hereditary diffuse gastric cancer Histopathological features of hereditary diffuse gastric cancer (HDGC) At initial diagnosis, most GC patients present an advanced disease stage with a high risk of relapse after surgical treatment. Various multimodal therapy regimens are used to improve the patient prognosis, with limited success and the diffuse type of gastric cancer is not an exception. For this reason, carriers of germline CDH1 deleterious mutations are offered the possibility to be submitted to total prophylactic gastrectomy, with the aim of preventing the development of a lethal cancer. Stomachs removed from germline CDH1 deleterious mutation carriers have constituted an extremely useful tool to understand disease initiation as well as to identify markers for early diagnosis. Therefore, the current knowledge on the morphologic steps underlying the development of HDGC stems from detailed studies performed in stomachs that were totally mapped, encompassing prophylactic gastrectomy specimens and total gastrectomies performed in patients referred from chromoendoscopic surveillance programs. Currently, there is a information available from 96 total gastrectomies in the setting of HDGC, corresponding to published reports [27–43] and unpublished observations.
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Seventy-three of these gastrectomies were systematically studied and 70 (96%) displayed one or multiple foci of intramucosal diffuse (signet-ring cell) carcinoma (number of foci varying from 1 to 318). In two out of the three cases in which early invasive carcinoma was not identified, tiny foci of in situ signet-ring cell carcinoma were observed (unpublished observations). Additionally, three other publications reported prophylactic gastrectomies performed in CDH1 germline mutation carriers in which cancer was not identified [37,41,44]. Two of these publications did not provide detailed data on the protocol used for the study of the surgical specimens [37,41]. The case reported in the third study [44] was later submitted to a detailed analysis according to a research protocol and shown to be positive for early invasive carcinoma (four foci) [42]. Similar findings had been previously reported by Lewis et al [28]. In our experience, unless total sampling of the whole stomach is performed, the diagnosis of early invasive cancers cannot be excluded. Actually, one of us (FC) had the opportunity to see in consultation several prophylactic gastrectomies, originally reported as negative for cancer, in which the detailed microscopic study of the whole length of gastric mucosa (after complete embedding of the whole stomach) revealed the presence of foci of early invasive signet-ring cell carcinomas in all cases (data not published). In North American and European families, early invasive carcinoma was not restricted to any topographic region in the stomach: foci were identified from cardia to pre-pyloric region, without evidence of antral clustering [27–29,31,42]. In a series of eight cases reported by Rogers et al [40], 70% of the total foci were localised in the proximal 1/3 of the stomach. In another series from United Kingdom [42] the highest number of foci was observed in the fundus (44.7%) followed by the body (40.2%). In New Zealand Maori families, a predilection was observed for the occurrence of early invasive carcinomas for the distal stomach and the body-antral transitional zone [30,35]. Reasons for the different anatomical localisation of the cancer foci in the aforementioned studies remain to be clarified, probably encompassing genetic susceptibility and/or environmental factors. As precursors of the invasive cancers, two distinct types of lesions were identified in prophylactic gastrectomies: (i) in situ signet-ring cell carcinoma, corresponding to the presence of signet-ring cells within basal membrane, generally with hyperchromatic and depolarised nuclei (Fig. 1A); (ii) pagetoid spread of signet-ring cells below the preserved epithelium of glands/foveolae (Fig. 1B) [31]. Model of development of hereditary diffuse gastric cancer On the basis of the findings in prophylactic gastrectomies, a model for the development of diffuse gastric cancer in germline CDH1 deleterious mutations carriers was proposed [12,31] encompassing the following lesions: mild non-atrophic gastritis, in situ signet-ring cell carcinoma, pagetoid spread of signet-ring cells and invasive carcinoma. E-cadherin immunoexpression was shown to be reduced or absent in early invasive gastric carcinomas, contrasting with the normal membranous E-cadherin expression in adjacent non-neoplastic mucosa, in keeping with a clonal origin of the cancer foci. However, one should be aware that E-cadherin may be expressed at the cell membrane of neoplastic cells (reduced intensity and/or dotted pattern) as well as in the cytoplasm [22]. Most probably, the cytoplasmic expression is due to the temporary accumulation of truncated protein in the endoplasmic reticulum (cytoplasm) on its way to degradation [45,46]. In pagetoid spread lesions and in situ carcinomas E-cadherin immunoexpression was also shown to be reduced or absent (Fig. 1C and D) [31]. It is accepted that the gastric mucosa in CDH1 germline mutation carriers is quite normal until the second CDH1 allele is inactivated. It is postulated that this downregulation occurs in multiple cells in the gastric mucosa, accounting for the multifocal tumor lesions. Background changes in the gastric mucosa of prophylactic gastrectomy specimen encompass mild chronic gastritis, foveolar hyperplasia and tufting of surface epithelium [18]. Occasionally, an inflammatory granulomatous reaction is observed. In almost all prophylactic gastrectomies studied so far, intestinal metaplasia and Helicobacter pylori infection are absent, namely in families from North America and Europe. Gastric cancer in other inherited cancer syndromes Gastric cancer may be seen as part of the tumour spectrum in other inherited cancer predisposition syndromes, such as HNPCC, FAP and Li-Fraumeni syndromes [47–49]. Stomach cancer can also occur in
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Fig. 1. In situ carcinoma and pagetoid spread of signet-ring cells. (A) In situ signet-ring cell carcinoma: gland with intact basement membrane lined by signet-ring cells (arrow heads) (H&E, original magnification 100); (B) Pagetoid spread of signet-ring cells below the preserved epithelium of one gland (arrows) (H&E, original magnification 100); (C) In situ carcinoma: loss of E-cadherin immunoexpression (arrow heads) (IHC, original magnification 200); (D) Pagetoid spread: loss of E-cadherin immunoexpression in signet-ring cells spreading below the preserved epithelium of one gland (arrows) (IHC, original magnification 200).
breast and ovarian cancer families. In two studies [50,51] germline TP53 mutations were found in families with heavy history of gastric cancer and lacking CDH1 germline mutations (3.2% and 2.9%) [50,51]. It was also shown that 20.7% of families harbouring both gastric and breast malignancies displayed germline mutations in BRCA2 [52]. Moreover, a BRCA2 mutation was found in 23.5% of women with ovarian cancer and a family history of stomach cancer [53].
Other cancer types clustering in HDGC families In HDGC families several types of malignancies have been described other than diffuse gastric cancer. Specifically, lobular breast cancer has been diagnosed in several HDGC families [39,54–56] and 40% of CDH1 germline mutation female carriers are at risk to develop this type of cancer [57].
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Colorectal carcinoma has also been identified in patients belonging to CDH1 positive families. Signet-ring cell carcinoma of the colon, a rare subtype of colon cancer, was found in two families with CDH1 germline mutations, one of them not meeting the HDGC criteria [55,58]. Moreover, a screening of germline CDH1 mutations in Korean gastric and colorectal cancer patients, with and without family history, demonstrated that the pathogenic T340A mutation in CDH1 gene was identified in one patient from an HNPCC family that was negative for hMLH1 and hMSH2 germline mutations as well as in one colorectal cancer patient without family history [59]. Although prostate and ovarian carcinomas have been observed in HDGC families carrying CDH1 mutations [11,60], no deleterious germline CDH1 mutations have been identified in families with both gastric and prostate carcinomas [61,62], and no studies have addressed the role of germline CDH1 mutations in ovarian carcinoma families. HDGC segregates with middle line malformations An interesting observation was reported describing the association of E-cadherin germline mutations with cleft lip, with or without cleft palate (CLP), in two HDGC families [63]. In these families, the underlying CDH1 mutation was a splicing mutation generating aberrant transcripts with an in-frame deletion, removing extracellular cadherin repeat domains involved in cell–cell adhesion. Since an association of CDH1 mutations with syndromic CLP has not been reported so far, Frebourg et al suggested that these two previously not described mutations in CDH1 have a specific effect [63]. Role of genetic testing Genetic counselling is an essential component of any cancer genetic testing and management program and it is mandatory that occurs before a blood sample is collected, and the search for a pathogenic mutation starts. Guidelines for genetic testing are common to the majority of hereditary disorders. Recently the European Society of Human Genetics led an initiative to harmonise the genetic testing across Europe. Taking advantage of the information available at http://www.eurogentest.org/ news/info/public/unit6/patients.xhtml, herein we present our view on guidelines and the role of genetic testing in HDGC syndrome. Any patient at high risk of developing a genetic disorder must have given informed consent, known that the protection of confidentiality will be secure and, be fully informed about the multifaceted issues that relate to genetic testing, namely in relation to the laboratory and clinical meaning of a positive and a negative result. In the case of HDGC, the patient must fully apprehend the fact that failure to identify a germline CDH1 mutation, in the family, does not exclude the presence of a hereditary factor, as only about 40% of HDGC families fulfilling the IGCLC criteria have been found to harbour a CDH1 germline pathogenic mutation. Therefore, disease in the remainder apparently negative HDGC families is likely caused by yet-to-be-identified germline alterations either within CDH1 gene or in alternative genes. High-risk patients must also appreciate the fact that there are very few reports in which CDH1 mutations are not fully penetrant. Moreover, in the genetic counselling session, it is mandatory to discuss the limitations in clinical management of carriers of CDH1 germline pathogenic mutations, as discussed below. Management According to the recommendations of the IGCLC, asymptomatic carriers of pathogenic (truncating) CDH1 mutations should be offered intensive endoscopic surveillance (twice a year) and/or prophylactic gastrectomy. In the setting of HDGC, Pharoah et al [57] estimated that the cumulative risk of clinically detected gastric cancer is 67% for men and 83% for woman, at the age of 80. Increased penetrance in females was also observed by Kaurah et al [64]. Early invasive diffuse carcinoma has been identified in the large majority of total gastrectomies performed in carriers of germline CDH1 mutations. These observations show that although CDH1 mutation carriers may develop early diffuse gastric cancer in relative young ages, not all mutation carriers will have clinically expressed disease during their lives. These
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observations suggest that a proportion of in situ/early invasive lesions may remain indolent and will not progress into clinically significant cancer. Genetic testing and commencement of screening in the late teens or early 20s have been recommended [64,65] and a surveillance program for asymptomatic CDH1 mutation carriers was proposed by Fitzgerald and Caldas [66,67]. The approach of the Stanford group for individuals in known HDGC families is to recommend genetic counselling and testing for CDH1 carriage by the early 20s, and biannual chromoendoscopy and biopsies by the age of 25 or at least 10 years earlier than the youngest family member affected by cancer [40]. Furthermore, for women with CDH1 mutations, the Stanford group recommends a similar approach to screening as for other hereditary breast cancer syndromes, including annual mammography and breast MRI starting at the age of 25 years [40]. In what concerns endoscopic screening, one should be aware of the limitations for the detection of early lesions of HDGC in asymptomatic CDH1 mutation carriers. The likelihood of detecting foci preoperatively was shown to be positively correlated with the number of biopsies taken and the number of lesions in the gastrectomy specimen [42]. Endoscopic surveillance has the benefit of preserving the stomach until lesions are identified. However, there are a number of issues which have made the use of endoscopy in this context questionable, including patient compliance and the sensitivity and specificity of the technique [27,29,68]. Chromoendoscopy with congo red/methylene blue has been pointed as an improved surveillance technique in comparison to white light gastroscopy for the intensive endoscopic surveillance of CDH1 germline mutation carriers [30,35,36]. Moreover, van Kouwen et al [32] suggested that [18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scanning may facilitate early detection of HDGC. The role of this technique as a screening modality in HDGC deserves further investigation. Despite the advances in screening procedures for early (curable) gastric cancer, large scale studies need to be performed to confirm the usefulness of the aforementioned methods in clinical practice. Importantly, it should be taken into consideration that surveillance using endoscopy (with chromoendoscopy in some cases) and multiple mucosal biopsies had failed to identify intramucosal carcinoma in many CDH1 germline mutation carriers submitted to prophylactic gastrectomy [27,29,33,38,40–42,64]. These findings suggest that prophylactic (total) gastrectomy should be considered as a valid approach for management of asymptomatic carriers of CDH1 germline mutations in well-characterised HDGC families [27,40,55]. Prophylactic gastrectomy should be considered in the early 20s in male mutation carriers whereas female mutation carriers may wish to delay the procedure taking into consideration the dietary consequences of total gastrectomy during pregnancy [55]. Alternatively, it has been suggested that total gastrectomy should be considered in CDH1 mutation carriers at an age five years younger than the youngest family member who developed gastric cancer [69]. Specific recommendations were also proposed by the New Zealand HDGC group regarding age dependent guidelines for genetic testing, surveillance gastroscopy and prophylactic gastrectomy [35]. Revised guidelines for clinical management are expected to be published in the near future, reflecting the consensus achieved in the Workshop organised by the IGCLC on Hereditary Diffuse Gastric Cancer, with the participation of experts from different geographic regions. An unsolved issue in HDGC is the management of carriers of CDH1 germline missense variants. Fitzgerald and Caldas [66] suggested that the significance of CDH1 germline missense variants should be assessed in at least four affected members in combination with functional and transcript analysis (to look for activation of cryptic splice sites). However, in some cases this type of analysis is impossible to accomplish due to the lethality of this disease. To circumvent this limitation, our group developed a procedure for selection of high-risk individuals for HDGC within carriers of CDH1 germline missense variants, based on the information collected on co-segregation of the mutation within pedigrees, frequency in healthy population control, recurrence in independent families, functional in vitro studies (aggregation and invasion assays) and in silico data [70]. The in silico model estimates the degree of conservation within species of the mutated site, the impact of the mutation on the protein structure and its effect on splicing. To date, most missense variants studied have a clear functional impact on E-cadherin function, hampering cell–cell adhesion and increasing cell invasion, when compared with wild-type expressing E-cadherin cells, supporting their pathogenic nature. The integration of the functional in vitro and in silico analysis of CDH1 germline missense variants, along with segregation of
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the missense mutations with disease within pedigrees, frequency in controls, and recurrence could be used as an adjunct for the counselling of mutation carriers. In the absence of clear clinical observations, we believe that this multidisciplinary approach improves the clinical utility of the genetic tests offered to the patients, helping to clarify the potential pathogenic nature of each CDH1 germline missense variant.
Genotype–phenotype correlations Very little is known about a putative genotype–phenotype correlation between the type (truncating versus missense) or position (localisation in the different domains of protein) of CDH1 germline mutations and the clinical parameters of disease (age of onset, disease penetrance, tumour spectrum or disease severity). The majority (80%) of CDH1 germline mutations, reported to date in HDGC families, is truncating and predicted to generate transcripts with premature termination codons (PTCs) [18,64]. Such transcripts are usually degraded by the nonsense mediated decay (NMD), an RNA surveillance pathway and a quality control system, when the PTC is located upstream from at least exon–exon junction [71]. Recently, we examined the role of NMD in the downregulation of several CDH1 PTC-containing transcripts in normal gastric mucosa from CDH1 germline mutation carriers. We found that while PTC-containing transcripts localised in the NMD-competent region are degraded by the NMD system, PTC-containing transcripts located in the NMD incompetent region are not. Moreover, the analysis of medical data from 264 carriers of truncating germline mutations revealed that patients carrying PTCs in the NMD-competent region developed cancer earlier and had a higher cumulative risk of developing gastric cancer than patients carrying PTCs in the NMD incompetent region [18,64]. These findings suggest that NMD may have a detrimental effect in the clinical progression of HDGC because it potentially degrades PTC-containing transcripts (especially those with PTC at the final portion of CDH1) that probably encode mutated proteins with residual function and tumour suppressor activity [71]. Another line of evidence of a genotype–phenotype correlation is the aforementioned report of two families, with co-existence of HDGC and midline malformations, carrying CDH1 splice-site mutations [63]. Each of these mutations generates at least one in-frame mutant transcript that would escape NMD downregulation and would be potentially responsible for the clustering of these phenotypes [63]. Nevertheless, available evidence is insufficient to claim for a definitive genotype–phenotype correlation. Evidence from in vitro studies points to a putative genotype–phenotype relation between the E-cadherin domain affected, the associated cellular effects, and the signaling pathways involved, but validation in patient material has not been performed yet [72].
Practice points Most gastric cancer cases (90%) are sporadic in nature, familial clustering occurs in 10% of the cases and, out of these, 1–3% is hereditary. Hereditary Diffuse Gastric Cancer (HDGC) is an autosomal dominant inherited gastric cancer syndrome caused by germline mutations of E-cadherin gene (CDH1). Among families that fulfil the clinical criteria for HDGC, about 40% carry CDH1 germline mutations, the genetic cause of the others being unknown. At the moment genetic testing for mutations in CDH1 gene should be considered in families fulfilling the criteria for HDGC. In countries with low prevalence of gastric cancer, genetic testing can be offered also to isolated cases of DGC in individuals younger than 35 years. The management options for CDH1 asymptomatic germline carriers are intensive endoscopic surveillance and prophylactic gastrectomy.
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Prophylactic gastrectomy is currently offered as a curative strategy to carriers of germline CDH1 pathogenic mutations aiming to prevent the development of a lethal disease. A model of development of HDGC was proposed on the basis histopathological lesions observed in the study of prophylactic gastrectomies.
Research agenda A thorough analysis of the mechanisms responsible for the 2nd hit inactivation of CDH1 in the very early lesions of HDGC is necessary to define strategies for chemoprevention. Identification of the molecular mechanisms underlying disease progression is mandatory to explain why some early intramucosal carcinomas remain indolent for undefined periods of time, while others progress to widely invasive gastric cancer. Significance of CDH1 germline missense mutations needs to be assessed by a multidisciplinary approach to elucidate pathogenicity, penetrance and impact on disease progression. Meta-analysis of available data on type and location of CDH1 mutations and clinical presentations of the disease is necessary to elucidate putative genotype–phenotype correlations. Genetic cause of HDGC not associated with CDH1 germline mutations needs to be identified.
Acknowledgements Fa´tima Carneiro, Carla Oliveira and Raquel Seruca are members of the International Gastric Cancer Linkage Consortium (IGCLC). The work herein reported from the IPATIMUP team was partly funded by the Sixth Framework Programme from EU-FP6 (LSHC-CT-2005-018754) and the Portuguese Science Foundation (POCTI/SAU-OBS/58111/2004 and PTDC/SAU-GMG/72168/2006). Carla Oliveira receives salary support from the Program Cieˆncia 2007, FCT, Portugal.
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