- Email: [email protected]
Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling
EURURO-6266; No. of Pages 6 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Kidney Cancer Editorial by XXX on pp. x–y of this issue
Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling Sumanta K. Pal a,y, Toni K. Choueiri b,y, Kai Wang c, Depinder Khaira c, Jose A. Karam d, Eliezer Van Allen b, Norma A. Palma c, Mark N. Stein e, Adrienne Johnson c, Rachel Squillace c, Julia A. Elvin c, Juliann Chmielecki c, Roman Yelensky c, Evgeny Yakirevich f, Doron Lipson c, Douglas I. Lin g, Vincent A. Miller c, Philip J. Stephens c, Siraj M. Ali c,*, Jeffrey S. Ross c,h a
Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; b Division of Medical Oncology,
Dana Farber Cancer Institute, Boston, MA, USA; c Foundation Medicine, Cambridge, MA, USA; Cancer Center, Houston, TX, USA;
e
d
Department of Urology, University of Texas MD Anderson
Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; f Department of
Pathology and Laboratory Medicine, Warren Alpert School of Medicine at Brown University, Providence, RI, USA; g Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; h Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, USA
Article info
Abstract
Article history: Accepted June 14, 2015
Background: Collecting duct carcinoma (CDC) is a rare type of renal cell carcinoma (RCC) originating from the renal medulla. Clinical outcomes are poor, and there are no consensus guidelines to guide therapy. Objective: To determine genomic alterations (GAs) in a series of patients with locally advanced or metastatic CDC for whom genomic profiling was performed during the course of clinical care. Design, setting, and participants: Formalin-fixed, paraffin-embedded blocks or slides were obtained for 17 patients with CDC. DNA was extracted and comprehensive genomic profiling was performed in a laboratory certified under the Clinical Laboratory Improvement Amendments. Outcome measurements and statistical analysis: Bayesian algorithms and local alignment algorithms were used to detect substitutions and insertions/deletions, respectively. A comparison to normal control samples was used to detect copy number alterations. Clinically relevant GAs (CRGAs) were defined as those linked to approved or investigational targeted therapies. Results and limitations: The median age in the cohort was 53 yr (range 26–73), and 14 primary tumors and three metastatic sites assessed. A total of 36 GAs were detected in this series of patients, with an average of 2.1 GAs per case. The most common GAs were in NF2 (5/17, 29%), SETD2 (4/17, 24%), SMARCB1 (3/17, 18%), and CDKN2A (2/17, 12%). Of nine cases assessed for FH GAs, two patients had FH homozygous loss. A limitation is that targeted interrogation of genes known to be implicated in other cancers was performed, so mutations outside of these cannot be excluded. Conclusions: Recurrent CRGAs were detected in this series of CDC cases and suggest a possible benefit from targeted therapy. In particular, mTOR inhibitors may be of interest in patients with NF2 alterations. Alterations in FH and SMARCB1 also occurred in a mutually exclusive manner to NF2 alterations. Patient summary: This report provides important genomic insights into collecting duct carcinoma, a rare type of renal cell carcinoma with a very aggressive course. These insights could further rationalize the use of targeted therapies for rare tumors according to the individual genomic alterations harbored. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Keywords: Collecting duct carcinoma Genomic profiling Medullary carcinoma NF2
y These authors contributed equally to this work. * Corresponding author. Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA. Tel. +1 617 4182200; Fax: +1 617 418 2201. E-mail address: [email protected] (S.M. Ali).
http://dx.doi.org/10.1016/j.eururo.2015.06.019 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
1.
Introduction
of established cancer-related genes was performed on hybridizationcaptured, adaptor ligation-based libraries in a laboratory certified under
The advent of targeted therapies for metastatic renal cell carcinoma (RCC) has had a dramatic impact on overall survival (OS) for this disease. Whereas median OS was estimated at 12–13 mo with cytokine therapies, recent studies of targeted agents suggest a median OS approaching 30 mo [1,2] Targeted therapies, such as agents directed at vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), have principally been assessed in the roughly 80% of patients with clear cell histology. Treatment of non–clear cell histologies remains a therapeutic conundrum, especially for exquisitely rare subtypes such as collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) which have a notoriously poor prognosis, with median survival not exceeding 1 yr [3]. A Surveillance, Epidemiology, and End Results (SEER) database review encompassing diagnoses from 1974 to 2003 only identified 98 patients with CDC, and a second study using SEER cases from 2001 to 2005 identified 160 patients [4,5]. According to the small series available, the median age at diagnosis of CDC is similar to that for clear cell RCC (63 and 65 yr, respectively), but CDC has a higher male predominance (70% vs 62%) and occurs more frequently in African Americans (23% vs 9%) [4]. RMC is even less studied and appears to be less frequent. In a detailed comparison of 13 patients with RMC and 39 patients with CDC, patients with RMC were younger and had a high frequency of sickle cell trait or disease [6]. It is challenging to reliably distinguish CDC and RMC using histology alone because it is thought that both diseases have histogenetic origins in the renal medulla. Discussion regarding definitive diagnostic criteria is ongoing [7]. Genomic profiling of these rare non–clear cell RCCs may offer improved clinicopathologic delineation of these entities. To this end, the diagnosis of RMC has been associated with loss of SMARCB1 (a component of the SWI/SNF chromatin regulatory complex) in multiple studies [8–10]. However, this criterion is the subject of much debate, and has not yet been incorporated in International Society of Urological Pathology (ISUP) Vancouver Classification criteria for CDC or RMC [11]. Comprehensive genomic profiling (CGP) was performed in the course of clinical care for 17 patients with a diagnosis of CDC to identify clinically relevant GAs that could point towards pathways of benefit from targeted therapy. To the best of our knowledge, this represents the largest effort to date to provide CGP data for CDC.
2.
Material and methods
Methods used in the current study parallel our previous characterization of rare subsets of other malignancies [12]. In brief, formalin-fixed, paraffin-embedded slides or blocks were obtained for 17 patients with CDC. For inclusion in the current study, histologic verification of specimens was performed by a trained pathologist (S.A.M.) using established criteria for the diagnosis of CDC [7]. DNA was extracted (with at least 20% of DNA derived from tumor cells) and comprehensive genomic profiling based on targeted next-generation sequencing (NGS)
the Clinical Laboratory Improvement Amendments (Foundation Medicine, Cambridge, MA, USA). Nine cases were sequenced with deep coverage across all coding exons on 236 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer; for another eight cases, 405 cancer genes and 31 genes often related to rearrangement were targeted. Cases were sequenced to a median depth of 650 [13,14]. Using previously published methods, base substitutions, short insertions, deletions, copy number changes, gene fusions, and rearrangements were assessed. Variants present in COSMIC that have been confirmed as somatic are reported as known somatic alterations. Nonsynonymous variants of known oncogenes not found in dbSNP or COSMIC are reported as likely somatic variants. Statistical interpretation of the resulting data included use of Bayesian algorithms to detect substitutions and local assembly algorithms to detect insertions/deletions. Copy number alterations were detected by comparison to normal control samples. Actionable genomic alterations were defined as those linked to approved or investigational targeted therapies. Deidentified patient data were used for the analysis. Local site permissions and approval from the institutional review board of Albany Medical Center were obtained for the study.
3.
Results
Of the 17 CDC cases identified (Supplementary Table 1), 13 patients (76%) were male. The median age in the cohort was 53 yr (range 26–73). At the time of specimen analysis, five cases had stage III (29%) and 12 cases stage IV (71%) disease. Site of specimens profiled included 14 derived from the primary kidney tumor and 3 from metastatic sites: 2 from lymph nodes and 1 from the adrenal gland. A total of 36 genomic alterations were detected in this series of patients, with an average of 2.1 genomic alterations per case (Fig. 1). Of these, 12 were clinically relevant genomic alterations (CRGA), with an average of 0.7 CRGAs per case. Nine patients (53%) had at least one CRGA. The most common genomic alterations were in NF2 (5/17, 29%), SETD2 (4/17, 24%), SMARCB1 (3/17, 18%), and CDKN2A (2/17, 12%). Sites of NF2 alteration are identified in Fig. 2. In addition to five patients with NF2 truncations, CRGAs of PIK3CA, PIK3R2, FBXW7, BAP1, DNMT3A, VHL, and HRAS were also identified at a frequency of 6% each (1/17 patients carried mutations in each of these genes). Notably, these mutations were defined as clinically relevant given their ability to aid in selection of approved or investigational targeted therapies. These CRGAs were deemed relevant on the basis of the following putative therapeutic strategies: (1) mTOR pathway inhibition (VHL, NF2, PIK3CA, and PIK3R2) [15–20]; (2) histone deacetylase inhibition (FBXW7) [21]; (3) EZH2 inhibition (BAP1 and SMARCB1) [22]; (4) VEGF inhibition (VHL); (5) DNA methyltransferase inhibition (DNMT3A) [23]; (6) EGFR inhibitor resistance (HRAS) [24]; and (7) CDK4/6 inhibition (CDKN2A) [25]. FH homozygous loss was identified in two out of nine patients (22%) in whom the newer version of the assay assessed FH alterations. We also observed that alterations in FH and SMARCB1 occurred in a mutually exclusive manner to NF2 alterations. Notably, Figure 3 highlights the case of a 30-yr-old man of Middle Eastern descent with an SMARCB1
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 EUROPEAN UROLOGY XXX (2015) XXX–XXX
3
Fig. 1 – Tile plot of genomic alterations observed in 17 cases of collecting duct carcinoma and renal medullary carcinoma.
Fig. 2 – Graphical depiction of NF2 alterations observed in the current series.
splice site mutation predicted as gene loss in the absence of abnormal hemoglobin on electrophoresis. 4.
Discussion
Clinical outcomes for CDC are extremely poor. One study of 23 treatment-naı¨ve patients with metastatic CDC demonstrated that treatment with platinum/gemcitabine yielded median progression-free survival of 7.1 mo and OS of 10.5 mo [26]. It is unclear whether targeted therapies approved for RCC will benefit CDC, and the extremely low incidence of this disease makes it very difficult to perform prospective randomized clinical trials. This study describes the only series of RCC patients diagnosed with CDC to have undergone CGP in the course of clinical care to identify pathways of potential benefit from targeted therapy. As a by-product, the study provides some insight into the ongoing difficulty of diagnosing CDC in practice settings, as new diagnostic criteria are being proposed. Our series included five patients harboring truncating alterations of NF2 (29%). Of the NF2 mutations noted (Fig. 2),
only R196*, occurring in the FERM domain of merlin, has been described [27]. By contrast, NF2 alterations were found at a frequency of only 1% in clear cell RCC [28]. Merlin is encoded by NF2 and coordinates a variety of receptor tyrosine kinases (eg, EGFR, VEGFR) with cell contact. Thus, inactivation of merlin leads to unrestrained receptor tyrosine kinase signaling despite cell contact [29]. It is thought that the NF2 alterations seen here lead to truncation of the merlin protein within the FERM domain; the resulting protein lacks most of the FERM domain and the C-terminal ERM (ezrin/radixin/moesin) domain. The C-terminal ERM domain, along with the N-terminal FERM domain, mediates the headto-tail binding of merlin to itself and other ERM proteins required for the tumor suppressor activity of merlin [30]. Therefore, this alteration is predicted to be inactivating. In preclinical models with loss of merlin, activity was observed for mTOR inhibitors [31]. A near complete response to everolimus, a first-generation inhibitor, with a chemotherapy backbone was observed in a patient with metastatic urothelial carcinoma harboring a truncating NF2 alteration, and other responses have been observed in NF2-driven
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 4
EUROPEAN UROLOGY XXX (2015) XXX–XXX
Fig. 3 – SMARCB1 loss in a collecting duct carcinoma of the kidney not associated with abnormal hemoglobin electrophoresis.
malignancies [19,32]. Further exploration of mTOR inhibitors in NF2-mutated CDC is warranted to assess the clinical benefit to this population. In this series, three patients with CDC (3/17, 18%) harbored SMARCB1 truncations caused by splice-site base substitution and indels on the SNF5 domain. Although controversial, an expert panel has recently suggested histology and hemoglobin electrophoresis as a means of characterizing RMC, with some studies strongly associating
SMARCB1 loss with RMC [7]. Case 6 in our series (Fig. 3), a 30-yr-old male of Middle Eastern descent, had a diagnosis of CDC, but CGP demonstrated loss of SMARCB1. In considering an alternative diagnosis of RMC for this patient, it was noted that hemoglobin electrophoresis was normal. Regarding therapeutic options for such cases, recent work has suggested that advanced tumors with SMARCB1 loss may be sensitive to EZH2 and AURKA inhibitors, both of which are currently in clinical development [22,33].
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 EUROPEAN UROLOGY XXX (2015) XXX–XXX
FH (fumarate hydratase, a citric acid cycle enzyme) is only covered in the most recent assay version (436 genes vs 236 previously), so only the nine most recent cases were surveyed for FH genomic alterations. Of these nine cases, two (22%) had FH homozygous deletions. Hereditary leiomyomatosis and (papillary) renal cell cancer syndrome, which is associated with FH deficiency, can respond to targeted therapy, such as the combination of bevacizumab and erlotinib as illustrated in one study [34]. This clinical evidence suggests that further investigation of VEGFdirected therapies in specific subsets of CDC patients may be warranted, possibly in the context of a histology agnostic trial including FH-deficient tumors. In this series of cases with a CDC diagnosis, alterations in NF2, SMARCB1, and FH were all mutually exclusive. Moreover, if we posit that the three cases with SMARCB1 alterations represent renal medullary carcinoma, then the frequency of NF2 alterations in patients with CDC is effectively increased to 36% (5/14), and the frequency of FH alterations similarly increases to 28% (with a denominator constricted by nine cases for whom FH was assayed and excluded two cases with SMARCB1 alteration). Of note, recent work has proposed diagnostic criteria that would exclude cases with FH mutations from the diagnostic category for CDC, but this suggestion has yet to be acted on by the ISUP [35]. The findings in this study reinforce the suggestion of possible avenues to benefit from targeted therapy, as well as potential genome-based groupings for this extremely rare tumor type.
5.
Conclusions
The current study represents the largest effort to characterize CDC using CGP to date, and was performed with clinical specimens from patients diagnosed with CDC in the course of clinical care. The results suggest that some CDC patients could benefit from treatment with targeted therapy when rationally administered according to CGP results. Ultimately, we envision prospective clinical trials for better validation of a genomically driven approach to CDC therapy; the results of the current study could inform the design of such trials. The relatively high frequency of NF2 alterations in particular could prompt interest in examining mTOR inhibitors, already approved in RCC, in selected CDC harboring an NF2 alteration. Thus, CGP offers the potential to reveal novel therapeutic targets for this rare form of renal cell carcinoma. Author contributions: Siraj M. Ali had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
5
Drafting of the manuscript: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Critical revision of the manuscript for important intellectual content: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Statistical analysis: Wang, Ross. Obtaining funding: None. Administrative, technical, or material support: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Supervision: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Other: None. Financial disclosures: Siraj M. Ali certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Kai Wang, Norma A. Palma, Depinder Khaira, Adrienne Johnson, Julia A. Elvin, Rachel Squillace, Juliann Chmielecki, Roman Yelensky, Doron Lipson, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, and Siraj M. Ali are employees of and have equity interest in Foundation Medicine. Sumanta K. Pal and Toni K. Choueiri have research collaborations with Foundation Medicine. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2015.06.019.
References [1] Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454–63. [2] Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 2014;370:1769–70. [3] Dason S, Allard C, Sheridan-Jonah A, et al. Management of renal collecting duct carcinoma: a systematic review and the McMaster experience. Curr Oncol 2013;20:e223–32. [4] Wright JL, Risk MC, Hotaling J, Lin DW. Effect of collecting duct histology on renal cell cancer outcome. J Urol 2009;182:2595–9. [5] Pepek JM, Johnstone PA, Jani AB. Influence of demographic factors on outcome of collecting duct carcinoma: a Surveillance, Epidemiology, and End Results (SEER) database analysis. Clin Genitourin Cancer 2009;7:E24–7. [6] Gupta R, Billis A, Shah RB, et al. Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of
Study concept and design: Pal, Choueiri, Wang, Khaira, Karam, Van Allen,
52 cases of rare aggressive subtypes of renal cell carcinoma with a
Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich,
focus on their interrelationship. Am J Surg Pathol 2012;36:1265–78.
Lipson, Lin, Miller, Stephens, Ali, Ross. Acquisition of data: Ross, Ali. Analysis and interpretation of data: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross.
[7] Amin MB, Smith SC, Agaimy A, et al. Collecting duct carcinoma versus renal medullary carcinoma: an appeal for nosologic and biological clarity. Am J Surg Pathol 2014;38:871–4. [8] Calderaro J, Moroch J, Pierron G, et al. SMARCB1/INI1 inactivation in renal medullary carcinoma. Histopathology 2012;61:428–35.
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 6
EUROPEAN UROLOGY XXX (2015) XXX–XXX
[9] Elwood H, Chaux A, Schultz L, et al. Immunohistochemical analysis
[23] Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations
of SMARCB1/INI-1 expression in collecting duct carcinoma. Urology
in acute myeloid leukemia and other myeloid malignancies:
2011;78:474. [10] Rao Q, Xia QY, Wang ZY, et al. Frequent co-inactivation of the SWI/
associations with prognosis and potential treatment strategies. Leukemia 2014;28:1774–83.
SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhab-
[24] Hah JH, Zhao M, Pickering CR, et al. HRAS mutations and resistance
doid tumours. Histopathology. In press. http://dx.doi.org/10.1111/
to the epidermal growth factor receptor tyrosine kinase inhibitor
his.12632 [11] Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol 2013;37:1469–89. [12] Ross JS, Wang K, Gay LM, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res 2014;20:68–75.
erlotinib in head and neck squamous cell carcinoma cells. Head Neck 2014;36:1547–54. [25] Young RJ, Waldeck K, Martin C, et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res 2014;27:590–600. [26] Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase
[13] Frampton GM, Fichtenholtz A, Otto GA, et al. Development and
II tudy of gemcitabine plus platinum salt for metastatic collecting
validation of a clinical cancer genomic profiling test based on mas-
duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs
sively parallel DNA sequencing. Nat Biotechnol 2013;31:1023–31. [14] Foundation Medicine. FoundationOne technical specifications. http://foundationone.com/learn.php#2 [15] Pal SK, Kortylewski M, Yu H, Figlin RA. Breaking through a plateau in renal cell carcinoma therapeutics: development and incorporation of biomarkers. Mol Cancer Ther 2010;9:3115–25. [16] Elkabets M, Vora S, Juric D, et al. mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med 2013;5:196ra99. [17] Park JH, Ryu MH, Park YS, et al. Successful control of heavily
Uro-Genitales) study. J Urol 2007;177:1698–702. [27] Wellcome Trust Sanger Institute. R196* mutation in NF2. In: COSMIC database. http://cancer.sanger.ac.uk/cosmic/mutation/overview? id=22254 [28] The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499:43–9. [29] Curto M, McClatchey AI. NF2/merlin: a coordinator of receptor signalling and intercellular contact. Br J Cancer 2008;98:256–62. [30] Yogesha SD, Sharff AJ, Giovannini M, Bricogne G, Izard T. Unfurling
pretreated metastatic gastric cancer with the mTOR inhibitor ever-
of the band 4.1, ezrin, radixin, moesin (FERM) domain of the merlin
olimus (RAD001) in a patient with PIK3CA mutation and pS6
tumor suppressor. Protein Sci 2011;20:2113–20.
overexpression. BMC Cancer 2015;15:119.
[31] Lopez-Lago MA, Okada T, Murillo MM, Socci N, Giancotti FG. Loss
[18] Cheung LW, Hennessy BT, Li J, et al. High frequency of PIK3R1 and
of the tumor suppressor gene NF2, encoding merlin, constitutively
PIK3R2 mutations in endometrial cancer elucidates a novel mecha-
activates integrin-dependent mTORC1 signaling. Mol Cell Biol 2009;
nism for regulation of PTEN protein stability. Cancer Discov 2011; 1:170–85.
29:4235–49. [32] Ross JS, Ali SM, Elvin JA, et al. Comprehensive genomic profiling
[19] Ali SM, Miller VA, Ross JS, Pal SK. Exceptional response on addition
urinary bladder urothelial carcinoma (UC) to reveal frequency
of everolimus to taxane in urothelial carcinoma bearing an NF2
of clinically relevant genomic alterations. J Clin Oncol 2015;33
mutation. Eur Urol 2015;67:1195–6.
(Suppl 7):289.
[20] James MF, Han S, Polizzano C, et al. NF2/merlin is a novel negative
[33] Wetmore C, Boyett J, Li S, Lin T, Bendel A, Gajjar A, et al. Alisertib
regulator of mTOR complex 1, and activation of mTORC1 is associ-
is active as single agent in recurrent atypical teratoid rhabdoid
ated with meningioma and schwannoma growth. Mol Cell Biol
tumors in 4 children. Neuro Ooncol. In press. http://dx.doi.org/10.
2009;29:4250–61.
1093/neuonc/nov017
[21] He L, Torres-Lockhart K, Forster N, et al. Mcl-1 and FBW7 control a
[34] Linehan WM, Rouault TA. Molecular pathways: Fumarate hydratase-
dominant survival pathway underlying HDAC and Bcl-2 inhibitor
deficient kidney cancer–targeting the Warburg effect in cancer. Clin
synergy in squamous cell carcinoma. Cancer Discov 2013;3:324–37.
Cancer Res 2013;19:3345–52.
[22] Knutson SK, Warholic NM, Wigle TJ, et al. Durable tumor regression in
[35] Divatia M, Smith S, Hes O, et al. Refining the diagnostic criteria and
genetically altered malignant rhabdoid tumors by inhibition of
immunophenotype of collecting duct carcinoma (CDC) in light of
methyltransferase EZH2. Proc Natl Acad Sci U S A 2013;110:7922–7.
emerging entities. Lab Invest 2015;95(Suppl):216–7A.
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Kidney Cancer Editorial by XXX on pp. x–y of this issue
Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling Sumanta K. Pal a,y, Toni K. Choueiri b,y, Kai Wang c, Depinder Khaira c, Jose A. Karam d, Eliezer Van Allen b, Norma A. Palma c, Mark N. Stein e, Adrienne Johnson c, Rachel Squillace c, Julia A. Elvin c, Juliann Chmielecki c, Roman Yelensky c, Evgeny Yakirevich f, Doron Lipson c, Douglas I. Lin g, Vincent A. Miller c, Philip J. Stephens c, Siraj M. Ali c,*, Jeffrey S. Ross c,h a
Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; b Division of Medical Oncology,
Dana Farber Cancer Institute, Boston, MA, USA; c Foundation Medicine, Cambridge, MA, USA; Cancer Center, Houston, TX, USA;
e
d
Department of Urology, University of Texas MD Anderson
Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; f Department of
Pathology and Laboratory Medicine, Warren Alpert School of Medicine at Brown University, Providence, RI, USA; g Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; h Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY, USA
Article info
Abstract
Article history: Accepted June 14, 2015
Background: Collecting duct carcinoma (CDC) is a rare type of renal cell carcinoma (RCC) originating from the renal medulla. Clinical outcomes are poor, and there are no consensus guidelines to guide therapy. Objective: To determine genomic alterations (GAs) in a series of patients with locally advanced or metastatic CDC for whom genomic profiling was performed during the course of clinical care. Design, setting, and participants: Formalin-fixed, paraffin-embedded blocks or slides were obtained for 17 patients with CDC. DNA was extracted and comprehensive genomic profiling was performed in a laboratory certified under the Clinical Laboratory Improvement Amendments. Outcome measurements and statistical analysis: Bayesian algorithms and local alignment algorithms were used to detect substitutions and insertions/deletions, respectively. A comparison to normal control samples was used to detect copy number alterations. Clinically relevant GAs (CRGAs) were defined as those linked to approved or investigational targeted therapies. Results and limitations: The median age in the cohort was 53 yr (range 26–73), and 14 primary tumors and three metastatic sites assessed. A total of 36 GAs were detected in this series of patients, with an average of 2.1 GAs per case. The most common GAs were in NF2 (5/17, 29%), SETD2 (4/17, 24%), SMARCB1 (3/17, 18%), and CDKN2A (2/17, 12%). Of nine cases assessed for FH GAs, two patients had FH homozygous loss. A limitation is that targeted interrogation of genes known to be implicated in other cancers was performed, so mutations outside of these cannot be excluded. Conclusions: Recurrent CRGAs were detected in this series of CDC cases and suggest a possible benefit from targeted therapy. In particular, mTOR inhibitors may be of interest in patients with NF2 alterations. Alterations in FH and SMARCB1 also occurred in a mutually exclusive manner to NF2 alterations. Patient summary: This report provides important genomic insights into collecting duct carcinoma, a rare type of renal cell carcinoma with a very aggressive course. These insights could further rationalize the use of targeted therapies for rare tumors according to the individual genomic alterations harbored. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Keywords: Collecting duct carcinoma Genomic profiling Medullary carcinoma NF2
y These authors contributed equally to this work. * Corresponding author. Foundation Medicine, Inc., 150 Second Street, Cambridge, MA 02141, USA. Tel. +1 617 4182200; Fax: +1 617 418 2201. E-mail address: [email protected] (S.M. Ali).
http://dx.doi.org/10.1016/j.eururo.2015.06.019 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 2
EUROPEAN UROLOGY XXX (2015) XXX–XXX
1.
Introduction
of established cancer-related genes was performed on hybridizationcaptured, adaptor ligation-based libraries in a laboratory certified under
The advent of targeted therapies for metastatic renal cell carcinoma (RCC) has had a dramatic impact on overall survival (OS) for this disease. Whereas median OS was estimated at 12–13 mo with cytokine therapies, recent studies of targeted agents suggest a median OS approaching 30 mo [1,2] Targeted therapies, such as agents directed at vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), have principally been assessed in the roughly 80% of patients with clear cell histology. Treatment of non–clear cell histologies remains a therapeutic conundrum, especially for exquisitely rare subtypes such as collecting duct carcinoma (CDC) and renal medullary carcinoma (RMC) which have a notoriously poor prognosis, with median survival not exceeding 1 yr [3]. A Surveillance, Epidemiology, and End Results (SEER) database review encompassing diagnoses from 1974 to 2003 only identified 98 patients with CDC, and a second study using SEER cases from 2001 to 2005 identified 160 patients [4,5]. According to the small series available, the median age at diagnosis of CDC is similar to that for clear cell RCC (63 and 65 yr, respectively), but CDC has a higher male predominance (70% vs 62%) and occurs more frequently in African Americans (23% vs 9%) [4]. RMC is even less studied and appears to be less frequent. In a detailed comparison of 13 patients with RMC and 39 patients with CDC, patients with RMC were younger and had a high frequency of sickle cell trait or disease [6]. It is challenging to reliably distinguish CDC and RMC using histology alone because it is thought that both diseases have histogenetic origins in the renal medulla. Discussion regarding definitive diagnostic criteria is ongoing [7]. Genomic profiling of these rare non–clear cell RCCs may offer improved clinicopathologic delineation of these entities. To this end, the diagnosis of RMC has been associated with loss of SMARCB1 (a component of the SWI/SNF chromatin regulatory complex) in multiple studies [8–10]. However, this criterion is the subject of much debate, and has not yet been incorporated in International Society of Urological Pathology (ISUP) Vancouver Classification criteria for CDC or RMC [11]. Comprehensive genomic profiling (CGP) was performed in the course of clinical care for 17 patients with a diagnosis of CDC to identify clinically relevant GAs that could point towards pathways of benefit from targeted therapy. To the best of our knowledge, this represents the largest effort to date to provide CGP data for CDC.
2.
Material and methods
Methods used in the current study parallel our previous characterization of rare subsets of other malignancies [12]. In brief, formalin-fixed, paraffin-embedded slides or blocks were obtained for 17 patients with CDC. For inclusion in the current study, histologic verification of specimens was performed by a trained pathologist (S.A.M.) using established criteria for the diagnosis of CDC [7]. DNA was extracted (with at least 20% of DNA derived from tumor cells) and comprehensive genomic profiling based on targeted next-generation sequencing (NGS)
the Clinical Laboratory Improvement Amendments (Foundation Medicine, Cambridge, MA, USA). Nine cases were sequenced with deep coverage across all coding exons on 236 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer; for another eight cases, 405 cancer genes and 31 genes often related to rearrangement were targeted. Cases were sequenced to a median depth of 650 [13,14]. Using previously published methods, base substitutions, short insertions, deletions, copy number changes, gene fusions, and rearrangements were assessed. Variants present in COSMIC that have been confirmed as somatic are reported as known somatic alterations. Nonsynonymous variants of known oncogenes not found in dbSNP or COSMIC are reported as likely somatic variants. Statistical interpretation of the resulting data included use of Bayesian algorithms to detect substitutions and local assembly algorithms to detect insertions/deletions. Copy number alterations were detected by comparison to normal control samples. Actionable genomic alterations were defined as those linked to approved or investigational targeted therapies. Deidentified patient data were used for the analysis. Local site permissions and approval from the institutional review board of Albany Medical Center were obtained for the study.
3.
Results
Of the 17 CDC cases identified (Supplementary Table 1), 13 patients (76%) were male. The median age in the cohort was 53 yr (range 26–73). At the time of specimen analysis, five cases had stage III (29%) and 12 cases stage IV (71%) disease. Site of specimens profiled included 14 derived from the primary kidney tumor and 3 from metastatic sites: 2 from lymph nodes and 1 from the adrenal gland. A total of 36 genomic alterations were detected in this series of patients, with an average of 2.1 genomic alterations per case (Fig. 1). Of these, 12 were clinically relevant genomic alterations (CRGA), with an average of 0.7 CRGAs per case. Nine patients (53%) had at least one CRGA. The most common genomic alterations were in NF2 (5/17, 29%), SETD2 (4/17, 24%), SMARCB1 (3/17, 18%), and CDKN2A (2/17, 12%). Sites of NF2 alteration are identified in Fig. 2. In addition to five patients with NF2 truncations, CRGAs of PIK3CA, PIK3R2, FBXW7, BAP1, DNMT3A, VHL, and HRAS were also identified at a frequency of 6% each (1/17 patients carried mutations in each of these genes). Notably, these mutations were defined as clinically relevant given their ability to aid in selection of approved or investigational targeted therapies. These CRGAs were deemed relevant on the basis of the following putative therapeutic strategies: (1) mTOR pathway inhibition (VHL, NF2, PIK3CA, and PIK3R2) [15–20]; (2) histone deacetylase inhibition (FBXW7) [21]; (3) EZH2 inhibition (BAP1 and SMARCB1) [22]; (4) VEGF inhibition (VHL); (5) DNA methyltransferase inhibition (DNMT3A) [23]; (6) EGFR inhibitor resistance (HRAS) [24]; and (7) CDK4/6 inhibition (CDKN2A) [25]. FH homozygous loss was identified in two out of nine patients (22%) in whom the newer version of the assay assessed FH alterations. We also observed that alterations in FH and SMARCB1 occurred in a mutually exclusive manner to NF2 alterations. Notably, Figure 3 highlights the case of a 30-yr-old man of Middle Eastern descent with an SMARCB1
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 EUROPEAN UROLOGY XXX (2015) XXX–XXX
3
Fig. 1 – Tile plot of genomic alterations observed in 17 cases of collecting duct carcinoma and renal medullary carcinoma.
Fig. 2 – Graphical depiction of NF2 alterations observed in the current series.
splice site mutation predicted as gene loss in the absence of abnormal hemoglobin on electrophoresis. 4.
Discussion
Clinical outcomes for CDC are extremely poor. One study of 23 treatment-naı¨ve patients with metastatic CDC demonstrated that treatment with platinum/gemcitabine yielded median progression-free survival of 7.1 mo and OS of 10.5 mo [26]. It is unclear whether targeted therapies approved for RCC will benefit CDC, and the extremely low incidence of this disease makes it very difficult to perform prospective randomized clinical trials. This study describes the only series of RCC patients diagnosed with CDC to have undergone CGP in the course of clinical care to identify pathways of potential benefit from targeted therapy. As a by-product, the study provides some insight into the ongoing difficulty of diagnosing CDC in practice settings, as new diagnostic criteria are being proposed. Our series included five patients harboring truncating alterations of NF2 (29%). Of the NF2 mutations noted (Fig. 2),
only R196*, occurring in the FERM domain of merlin, has been described [27]. By contrast, NF2 alterations were found at a frequency of only 1% in clear cell RCC [28]. Merlin is encoded by NF2 and coordinates a variety of receptor tyrosine kinases (eg, EGFR, VEGFR) with cell contact. Thus, inactivation of merlin leads to unrestrained receptor tyrosine kinase signaling despite cell contact [29]. It is thought that the NF2 alterations seen here lead to truncation of the merlin protein within the FERM domain; the resulting protein lacks most of the FERM domain and the C-terminal ERM (ezrin/radixin/moesin) domain. The C-terminal ERM domain, along with the N-terminal FERM domain, mediates the headto-tail binding of merlin to itself and other ERM proteins required for the tumor suppressor activity of merlin [30]. Therefore, this alteration is predicted to be inactivating. In preclinical models with loss of merlin, activity was observed for mTOR inhibitors [31]. A near complete response to everolimus, a first-generation inhibitor, with a chemotherapy backbone was observed in a patient with metastatic urothelial carcinoma harboring a truncating NF2 alteration, and other responses have been observed in NF2-driven
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 4
EUROPEAN UROLOGY XXX (2015) XXX–XXX
Fig. 3 – SMARCB1 loss in a collecting duct carcinoma of the kidney not associated with abnormal hemoglobin electrophoresis.
malignancies [19,32]. Further exploration of mTOR inhibitors in NF2-mutated CDC is warranted to assess the clinical benefit to this population. In this series, three patients with CDC (3/17, 18%) harbored SMARCB1 truncations caused by splice-site base substitution and indels on the SNF5 domain. Although controversial, an expert panel has recently suggested histology and hemoglobin electrophoresis as a means of characterizing RMC, with some studies strongly associating
SMARCB1 loss with RMC [7]. Case 6 in our series (Fig. 3), a 30-yr-old male of Middle Eastern descent, had a diagnosis of CDC, but CGP demonstrated loss of SMARCB1. In considering an alternative diagnosis of RMC for this patient, it was noted that hemoglobin electrophoresis was normal. Regarding therapeutic options for such cases, recent work has suggested that advanced tumors with SMARCB1 loss may be sensitive to EZH2 and AURKA inhibitors, both of which are currently in clinical development [22,33].
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 EUROPEAN UROLOGY XXX (2015) XXX–XXX
FH (fumarate hydratase, a citric acid cycle enzyme) is only covered in the most recent assay version (436 genes vs 236 previously), so only the nine most recent cases were surveyed for FH genomic alterations. Of these nine cases, two (22%) had FH homozygous deletions. Hereditary leiomyomatosis and (papillary) renal cell cancer syndrome, which is associated with FH deficiency, can respond to targeted therapy, such as the combination of bevacizumab and erlotinib as illustrated in one study [34]. This clinical evidence suggests that further investigation of VEGFdirected therapies in specific subsets of CDC patients may be warranted, possibly in the context of a histology agnostic trial including FH-deficient tumors. In this series of cases with a CDC diagnosis, alterations in NF2, SMARCB1, and FH were all mutually exclusive. Moreover, if we posit that the three cases with SMARCB1 alterations represent renal medullary carcinoma, then the frequency of NF2 alterations in patients with CDC is effectively increased to 36% (5/14), and the frequency of FH alterations similarly increases to 28% (with a denominator constricted by nine cases for whom FH was assayed and excluded two cases with SMARCB1 alteration). Of note, recent work has proposed diagnostic criteria that would exclude cases with FH mutations from the diagnostic category for CDC, but this suggestion has yet to be acted on by the ISUP [35]. The findings in this study reinforce the suggestion of possible avenues to benefit from targeted therapy, as well as potential genome-based groupings for this extremely rare tumor type.
5.
Conclusions
The current study represents the largest effort to characterize CDC using CGP to date, and was performed with clinical specimens from patients diagnosed with CDC in the course of clinical care. The results suggest that some CDC patients could benefit from treatment with targeted therapy when rationally administered according to CGP results. Ultimately, we envision prospective clinical trials for better validation of a genomically driven approach to CDC therapy; the results of the current study could inform the design of such trials. The relatively high frequency of NF2 alterations in particular could prompt interest in examining mTOR inhibitors, already approved in RCC, in selected CDC harboring an NF2 alteration. Thus, CGP offers the potential to reveal novel therapeutic targets for this rare form of renal cell carcinoma. Author contributions: Siraj M. Ali had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
5
Drafting of the manuscript: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Critical revision of the manuscript for important intellectual content: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Statistical analysis: Wang, Ross. Obtaining funding: None. Administrative, technical, or material support: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Supervision: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross. Other: None. Financial disclosures: Siraj M. Ali certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Kai Wang, Norma A. Palma, Depinder Khaira, Adrienne Johnson, Julia A. Elvin, Rachel Squillace, Juliann Chmielecki, Roman Yelensky, Doron Lipson, Philip J. Stephens, Vincent A. Miller, Jeffrey S. Ross, and Siraj M. Ali are employees of and have equity interest in Foundation Medicine. Sumanta K. Pal and Toni K. Choueiri have research collaborations with Foundation Medicine. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2015.06.019.
References [1] Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454–63. [2] Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 2014;370:1769–70. [3] Dason S, Allard C, Sheridan-Jonah A, et al. Management of renal collecting duct carcinoma: a systematic review and the McMaster experience. Curr Oncol 2013;20:e223–32. [4] Wright JL, Risk MC, Hotaling J, Lin DW. Effect of collecting duct histology on renal cell cancer outcome. J Urol 2009;182:2595–9. [5] Pepek JM, Johnstone PA, Jani AB. Influence of demographic factors on outcome of collecting duct carcinoma: a Surveillance, Epidemiology, and End Results (SEER) database analysis. Clin Genitourin Cancer 2009;7:E24–7. [6] Gupta R, Billis A, Shah RB, et al. Carcinoma of the collecting ducts of Bellini and renal medullary carcinoma: clinicopathologic analysis of
Study concept and design: Pal, Choueiri, Wang, Khaira, Karam, Van Allen,
52 cases of rare aggressive subtypes of renal cell carcinoma with a
Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich,
focus on their interrelationship. Am J Surg Pathol 2012;36:1265–78.
Lipson, Lin, Miller, Stephens, Ali, Ross. Acquisition of data: Ross, Ali. Analysis and interpretation of data: Pal, Choueiri, Wang, Khaira, Karam, Van Allen, Palma, Stein, Johnson, Squillace, Elvin, Chmielecki, Yelensky, Yakirevich, Lipson, Lin, Miller, Stephens, Ross.
[7] Amin MB, Smith SC, Agaimy A, et al. Collecting duct carcinoma versus renal medullary carcinoma: an appeal for nosologic and biological clarity. Am J Surg Pathol 2014;38:871–4. [8] Calderaro J, Moroch J, Pierron G, et al. SMARCB1/INI1 inactivation in renal medullary carcinoma. Histopathology 2012;61:428–35.
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019
EURURO-6266; No. of Pages 6 6
EUROPEAN UROLOGY XXX (2015) XXX–XXX
[9] Elwood H, Chaux A, Schultz L, et al. Immunohistochemical analysis
[23] Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations
of SMARCB1/INI-1 expression in collecting duct carcinoma. Urology
in acute myeloid leukemia and other myeloid malignancies:
2011;78:474. [10] Rao Q, Xia QY, Wang ZY, et al. Frequent co-inactivation of the SWI/
associations with prognosis and potential treatment strategies. Leukemia 2014;28:1774–83.
SNF subunits SMARCB1, SMARCA2 and PBRM1 in malignant rhab-
[24] Hah JH, Zhao M, Pickering CR, et al. HRAS mutations and resistance
doid tumours. Histopathology. In press. http://dx.doi.org/10.1111/
to the epidermal growth factor receptor tyrosine kinase inhibitor
his.12632 [11] Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasia. Am J Surg Pathol 2013;37:1469–89. [12] Ross JS, Wang K, Gay LM, et al. A high frequency of activating extracellular domain ERBB2 (HER2) mutation in micropapillary urothelial carcinoma. Clin Cancer Res 2014;20:68–75.
erlotinib in head and neck squamous cell carcinoma cells. Head Neck 2014;36:1547–54. [25] Young RJ, Waldeck K, Martin C, et al. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res 2014;27:590–600. [26] Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase
[13] Frampton GM, Fichtenholtz A, Otto GA, et al. Development and
II tudy of gemcitabine plus platinum salt for metastatic collecting
validation of a clinical cancer genomic profiling test based on mas-
duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs
sively parallel DNA sequencing. Nat Biotechnol 2013;31:1023–31. [14] Foundation Medicine. FoundationOne technical specifications. http://foundationone.com/learn.php#2 [15] Pal SK, Kortylewski M, Yu H, Figlin RA. Breaking through a plateau in renal cell carcinoma therapeutics: development and incorporation of biomarkers. Mol Cancer Ther 2010;9:3115–25. [16] Elkabets M, Vora S, Juric D, et al. mTORC1 inhibition is required for sensitivity to PI3K p110alpha inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med 2013;5:196ra99. [17] Park JH, Ryu MH, Park YS, et al. Successful control of heavily
Uro-Genitales) study. J Urol 2007;177:1698–702. [27] Wellcome Trust Sanger Institute. R196* mutation in NF2. In: COSMIC database. http://cancer.sanger.ac.uk/cosmic/mutation/overview? id=22254 [28] The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499:43–9. [29] Curto M, McClatchey AI. NF2/merlin: a coordinator of receptor signalling and intercellular contact. Br J Cancer 2008;98:256–62. [30] Yogesha SD, Sharff AJ, Giovannini M, Bricogne G, Izard T. Unfurling
pretreated metastatic gastric cancer with the mTOR inhibitor ever-
of the band 4.1, ezrin, radixin, moesin (FERM) domain of the merlin
olimus (RAD001) in a patient with PIK3CA mutation and pS6
tumor suppressor. Protein Sci 2011;20:2113–20.
overexpression. BMC Cancer 2015;15:119.
[31] Lopez-Lago MA, Okada T, Murillo MM, Socci N, Giancotti FG. Loss
[18] Cheung LW, Hennessy BT, Li J, et al. High frequency of PIK3R1 and
of the tumor suppressor gene NF2, encoding merlin, constitutively
PIK3R2 mutations in endometrial cancer elucidates a novel mecha-
activates integrin-dependent mTORC1 signaling. Mol Cell Biol 2009;
nism for regulation of PTEN protein stability. Cancer Discov 2011; 1:170–85.
29:4235–49. [32] Ross JS, Ali SM, Elvin JA, et al. Comprehensive genomic profiling
[19] Ali SM, Miller VA, Ross JS, Pal SK. Exceptional response on addition
urinary bladder urothelial carcinoma (UC) to reveal frequency
of everolimus to taxane in urothelial carcinoma bearing an NF2
of clinically relevant genomic alterations. J Clin Oncol 2015;33
mutation. Eur Urol 2015;67:1195–6.
(Suppl 7):289.
[20] James MF, Han S, Polizzano C, et al. NF2/merlin is a novel negative
[33] Wetmore C, Boyett J, Li S, Lin T, Bendel A, Gajjar A, et al. Alisertib
regulator of mTOR complex 1, and activation of mTORC1 is associ-
is active as single agent in recurrent atypical teratoid rhabdoid
ated with meningioma and schwannoma growth. Mol Cell Biol
tumors in 4 children. Neuro Ooncol. In press. http://dx.doi.org/10.
2009;29:4250–61.
1093/neuonc/nov017
[21] He L, Torres-Lockhart K, Forster N, et al. Mcl-1 and FBW7 control a
[34] Linehan WM, Rouault TA. Molecular pathways: Fumarate hydratase-
dominant survival pathway underlying HDAC and Bcl-2 inhibitor
deficient kidney cancer–targeting the Warburg effect in cancer. Clin
synergy in squamous cell carcinoma. Cancer Discov 2013;3:324–37.
Cancer Res 2013;19:3345–52.
[22] Knutson SK, Warholic NM, Wigle TJ, et al. Durable tumor regression in
[35] Divatia M, Smith S, Hes O, et al. Refining the diagnostic criteria and
genetically altered malignant rhabdoid tumors by inhibition of
immunophenotype of collecting duct carcinoma (CDC) in light of
methyltransferase EZH2. Proc Natl Acad Sci U S A 2013;110:7922–7.
emerging entities. Lab Invest 2015;95(Suppl):216–7A.
Please cite this article in press as: Pal SK, et al. Characterization of Clinical Cases of Collecting Duct Carcinoma of the Kidney Assessed by Comprehensive Genomic Profiling. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.06.019