Importance: Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown. Objectives: To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. Design, Setting, and Participants: In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing. Main Outcomes and Measures: Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status. Results: Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB). The most frequent mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not previously associated with RCC risk, CHEK2 was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8; P = .003). Patients with non-clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177; P = .001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing. Conclusions and Relevance: Of patients with non-clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.
Importance: Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown. Objectives: To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. Design, Setting, and Participants: In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing. Main Outcomes and Measures: Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status. Results: Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB). The most frequent mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not previously associated with RCC risk, CHEK2 was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8; P = .003). Patients with non-clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177; P = .001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing. Conclusions and Relevance: Of patients with non-clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.
Authors: Berton Zbar; Gladys Glenn; Maria Merino; Lindsay Middelton; James Peterson; Jorge Toro; Jonathan Coleman; Peter Pinto; Laura S Schmidt; Peter Choyke; W Marston Linehan Journal: J Urol Date: 2007-02 Impact factor: 7.450
Authors: Kevin A Nguyen; Jamil S Syed; Carin R Espenschied; Holly LaDuca; Ansh M Bhagat; Alfredo Suarez-Sarmiento; Timothy K O'Rourke; Karina L Brierley; Erin W Hofstatter; Brian Shuch Journal: Cancer Date: 2017-08-08 Impact factor: 6.860
Authors: A Ari Hakimi; Irina Ostrovnaya; Boris Reva; Nikolaus Schultz; Ying-Bei Chen; Mithat Gonen; Han Liu; Shugaku Takeda; Martin H Voss; Satish K Tickoo; Victor E Reuter; Paul Russo; Emily H Cheng; Chris Sander; Robert J Motzer; James J Hsieh Journal: Clin Cancer Res Date: 2013-04-25 Impact factor: 12.531
Authors: N A Alam; A J Rowan; N C Wortham; P J Pollard; M Mitchell; J P Tyrer; E Barclay; E Calonje; S Manek; S J Adams; P W Bowers; N P Burrows; R Charles-Holmes; L J Cook; B M Daly; G P Ford; L C Fuller; S E Hadfield-Jones; N Hardwick; A S Highet; M Keefe; S P MacDonald-Hull; E D A Potts; M Crone; S Wilkinson; F Camacho-Martinez; S Jablonska; R Ratnavel; A MacDonald; R J Mann; K Grice; G Guillet; M S Lewis-Jones; H McGrath; D C Seukeran; P J Morrison; S Fleming; S Rahman; D Kelsell; I Leigh; S Olpin; I P M Tomlinson Journal: Hum Mol Genet Date: 2003-06-01 Impact factor: 6.150
Authors: Sue Richards; Nazneen Aziz; Sherri Bale; David Bick; Soma Das; Julie Gastier-Foster; Wayne W Grody; Madhuri Hegde; Elaine Lyon; Elaine Spector; Karl Voelkerding; Heidi L Rehm Journal: Genet Med Date: 2015-03-05 Impact factor: 8.822
Authors: Ahmet Zehir; Ryma Benayed; Ronak H Shah; Aijazuddin Syed; Sumit Middha; Hyunjae R Kim; Preethi Srinivasan; Jianjiong Gao; Debyani Chakravarty; Sean M Devlin; Matthew D Hellmann; David A Barron; Alison M Schram; Meera Hameed; Snjezana Dogan; Dara S Ross; Jaclyn F Hechtman; Deborah F DeLair; JinJuan Yao; Diana L Mandelker; Donavan T Cheng; Raghu Chandramohan; Abhinita S Mohanty; Ryan N Ptashkin; Gowtham Jayakumaran; Meera Prasad; Mustafa H Syed; Anoop Balakrishnan Rema; Zhen Y Liu; Khedoudja Nafa; Laetitia Borsu; Justyna Sadowska; Jacklyn Casanova; Ruben Bacares; Iwona J Kiecka; Anna Razumova; Julie B Son; Lisa Stewart; Tessara Baldi; Kerry A Mullaney; Hikmat Al-Ahmadie; Efsevia Vakiani; Adam A Abeshouse; Alexander V Penson; Philip Jonsson; Niedzica Camacho; Matthew T Chang; Helen H Won; Benjamin E Gross; Ritika Kundra; Zachary J Heins; Hsiao-Wei Chen; Sarah Phillips; Hongxin Zhang; Jiaojiao Wang; Angelica Ochoa; Jonathan Wills; Michael Eubank; Stacy B Thomas; Stuart M Gardos; Dalicia N Reales; Jesse Galle; Robert Durany; Roy Cambria; Wassim Abida; Andrea Cercek; Darren R Feldman; Mrinal M Gounder; A Ari Hakimi; James J Harding; Gopa Iyer; Yelena Y Janjigian; Emmet J Jordan; Ciara M Kelly; Maeve A Lowery; Luc G T Morris; Antonio M Omuro; Nitya Raj; Pedram Razavi; Alexander N Shoushtari; Neerav Shukla; Tara E Soumerai; Anna M Varghese; Rona Yaeger; Jonathan Coleman; Bernard Bochner; Gregory J Riely; Leonard B Saltz; Howard I Scher; Paul J Sabbatini; Mark E Robson; David S Klimstra; Barry S Taylor; Jose Baselga; Nikolaus Schultz; David M Hyman; Maria E Arcila; David B Solit; Marc Ladanyi; Michael F Berger Journal: Nat Med Date: 2017-05-08 Impact factor: 53.440
Authors: Dan R Robinson; Yi-Mi Wu; Robert J Lonigro; Pankaj Vats; Erin Cobain; Jessica Everett; Xuhong Cao; Erica Rabban; Chandan Kumar-Sinha; Victoria Raymond; Scott Schuetze; Ajjai Alva; Javed Siddiqui; Rashmi Chugh; Francis Worden; Mark M Zalupski; Jeffrey Innis; Rajen J Mody; Scott A Tomlins; David Lucas; Laurence H Baker; Nithya Ramnath; Ann F Schott; Daniel F Hayes; Joseph Vijai; Kenneth Offit; Elena M Stoffel; J Scott Roberts; David C Smith; Lakshmi P Kunju; Moshe Talpaz; Marcin Cieślik; Arul M Chinnaiyan Journal: Nature Date: 2017-08-02 Impact factor: 49.962
Authors: Maria I Carlo; A Ari Hakimi; Grant D Stewart; Gennady Bratslavsky; James Brugarolas; Ying-Bei Chen; W Marston Linehan; Eamonn R Maher; Maria J Merino; Kenneth Offit; Victor E Reuter; Brian Shuch; Jonathan A Coleman Journal: Eur Urol Date: 2019-07-18 Impact factor: 20.096
Authors: Hong Truong; Rania Sheikh; Ritesh Kotecha; Yelena Kemel; Peter A Reisz; Andrew T Lenis; Nikita N Mehta; Aliya Khurram; Vijai Joseph; Diana Mandelker; Alicia Latham; Ozge Ceyhan-Birsoy; Marc Ladanyi; Neil J Shah; Michael F Walsh; Martin H Voss; Chung-Han Lee; Paul Russo; Jonathan A Coleman; A Ari Hakimi; Darren R Feldman; Zsofia K Stadler; Mark E Robson; Robert J Motzer; Kenneth Offit; Sujata Patil; Maria I Carlo Journal: Eur Urol Oncol Date: 2021-10-12
Authors: Mark W Ball; Julie Y An; Patrick T Gomella; Rabindra Gautam; Christopher J Ricketts; Cathy D Vocke; Laura S Schmidt; Maria J Merino; Ramaprasad Srinivasan; Ashkan A Malayeri; Adam R Metwalli; W Marston Linehan Journal: J Clin Oncol Date: 2020-02-21 Impact factor: 44.544
Authors: Yin P Hung; Fei Dong; Adrian M Dubuc; Paola Dal Cin; Raphael Bueno; Lucian R Chirieac Journal: Mod Pathol Date: 2019-08-01 Impact factor: 7.842
Authors: Gennady Bratslavsky; Neil Mendhiratta; Michael Daneshvar; James Brugarolas; Mark W Ball; Adam Metwalli; Katherine L Nathanson; Phillip M Pierorazio; Ronald S Boris; Eric A Singer; Maria I Carlo; Mary B Daly; Elizabeth P Henske; Colette Hyatt; Lindsay Middleton; Gloria Morris; Anhyo Jeong; Vivek Narayan; W Kimryn Rathmell; Ulka Vaishampayan; Bruce H Lee; Dena Battle; Michael J Hall; Khaled Hafez; Michael A S Jewett; Christina Karamboulas; Sumanta K Pal; A Ari Hakimi; Alexander Kutikov; Othon Iliopoulos; W Marston Linehan; Eric Jonasch; Ramaprasad Srinivasan; Brian Shuch Journal: Cancer Date: 2021-08-03 Impact factor: 6.860