Hong Truong1, Rania Sheikh2, Ritesh Kotecha3, Yelena Kemel4, Peter A Reisz1, Andrew T Lenis1, Nikita N Mehta5, Aliya Khurram3, Vijai Joseph4, Diana Mandelker5, Alicia Latham2, Ozge Ceyhan-Birsoy6, Marc Ladanyi5, Neil J Shah3, Michael F Walsh7, Martin H Voss3, Chung-Han Lee3, Paul Russo1, Jonathan A Coleman1, A Ari Hakimi1, Darren R Feldman3, Zsofia K Stadler8, Mark E Robson9, Robert J Motzer3, Kenneth Offit9, Sujata Patil10, Maria I Carlo11. 1. Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 2. Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 3. Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 4. Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 5. Department of Pathology, Diagnostic Molecular Pathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 6. Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology, Diagnostic Molecular Pathology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 7. Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 8. Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Gastrointestinal Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 9. Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Niehaus Center for Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 10. Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. 11. Department of Medicine, Clinical Genetics Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: carlom@mskcc.org.
Abstract
BACKGROUND: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. OBJECTIVE: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ2 test). RESULTS AND LIMITATIONS: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively. CONCLUSIONS: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. PATIENT SUMMARY: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.
BACKGROUND: Despite guidelines recommending genetic counseling for patients with early-onset renal cell carcinoma (RCC), studies interrogating the spectrum of germline mutations and clinical associations in patients with early-onset RCC are lacking. OBJECTIVE: To define the germline genetic spectrum and clinical associations for patients with early-onset RCC diagnosed at age ≤46 yr who underwent genetic testing. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with early-onset RCC who underwent germline testing at our institution from February 2003 to June 2020. OUTCOME MEASUREMENT AND STATISTICAL ANALYSIS: The frequency and spectrum of pathogenic/likely pathogenic (P/LP) variants were determined. Clinical characteristics associated with mutation status were analyzed using two-sample comparison (Fisher's exact or χ2 test). RESULTS AND LIMITATIONS: Of 232 patients with early-onset RCC, 50% had non-clear-cell histology, including unclassified RCC (12.1%), chromophobe RCC (9.7%), FH-deficient RCC (7.0%), papillary RCC (6.6%), and translocation-associated RCC (4.3%). Overall, 43.5% had metastatic disease. Germline P/LP variants were identified in 41 patients (17.7%), of which 21 (9.1%) were in an RCC-associated gene and 20 (8.6%) in a non-RCC-associated gene, including 17 (7.3%) in DNA damage repair genes such as BRCA1/2, ATM, and CHEK2. Factors associated with RCC P/LP variants include bilateral/multifocal renal tumors, non-clear-cell histology, and additional extrarenal primary malignancies. In patients with only a solitary clear-cell RCC, the prevalence of P/LP variants in RCC-associated and non-RCC-associated genes was 0% and 9.9%, respectively. CONCLUSIONS: Patients with early-onset RCC had high frequencies of germline P/LP variants in genes associated with both hereditary RCC and other cancer predispositions. Germline RCC panel testing has the highest yield when patients have clinical phenotypes suggestive of underlying RCC gene mutations. Patients with early-onset RCC should undergo comprehensive assessment of personal and family history to guide appropriate genetic testing. PATIENT SUMMARY: In this study of 232 patients with early-onset kidney cancer who underwent genetic testing, we found a high prevalence of mutations in genes that increase the risk of cancer in both kidneys and other organs for patients and their at-risk family members. Our study suggests that patients with early-onset kidney cancer should undergo comprehensive genetic risk assessment.
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: Diana Mandelker; Liying Zhang; Yelena Kemel; Zsofia K Stadler; Vijai Joseph; Ahmet Zehir; Nisha Pradhan; Angela Arnold; Michael F Walsh; Yirong Li; Anoop R Balakrishnan; Aijazuddin Syed; Meera Prasad; Khedoudja Nafa; Maria I Carlo; Karen A Cadoo; Meg Sheehan; Megan H Fleischut; Erin Salo-Mullen; Magan Trottier; Steven M Lipkin; Anne Lincoln; Semanti Mukherjee; Vignesh Ravichandran; Roy Cambria; Jesse Galle; Wassim Abida; Marcia E Arcila; Ryma Benayed; Ronak Shah; Kenneth Yu; Dean F Bajorin; Jonathan A Coleman; Steven D Leach; Maeve A Lowery; Julio Garcia-Aguilar; Philip W Kantoff; Charles L Sawyers; Maura N Dickler; Leonard Saltz; Robert J Motzer; Eileen M O'Reilly; Howard I Scher; Jose Baselga; David S Klimstra; David B Solit; David M Hyman; Michael F Berger; Marc Ladanyi; Mark E Robson; Kenneth Offit Journal: JAMA Date: 2017-09-05 Impact factor: 56.272
Authors: Maria I Carlo; Semanti Mukherjee; Diana Mandelker; Joseph Vijai; Yelena Kemel; Liying Zhang; Andrea Knezevic; Sujata Patil; Ozge Ceyhan-Birsoy; Kuo-Cheng Huang; Almedina Redzematovic; Devyn T Coskey; Carolyn Stewart; Nisha Pradhan; Angela G Arnold; A Ari Hakimi; Ying-Bei Chen; Jonathan A Coleman; David M Hyman; Marc Ladanyi; Karen A Cadoo; Michael F Walsh; Zsofia K Stadler; Chung-Han Lee; Darren R Feldman; Martin H Voss; Mark Robson; Robert J Motzer; Kenneth Offit Journal: JAMA Oncol Date: 2018-09-01 Impact factor: 31.777
Authors: Jinghui Zhang; Michael F Walsh; Gang Wu; Kim E Nichols; Michael N Edmonson; Tanja A Gruber; John Easton; Dale Hedges; Xiaotu Ma; Xin Zhou; Donald A Yergeau; Mark R Wilkinson; Bhavin Vadodaria; Xiang Chen; Rose B McGee; Stacy Hines-Dowell; Regina Nuccio; Emily Quinn; Sheila A Shurtleff; Michael Rusch; Aman Patel; Jared B Becksfort; Shuoguo Wang; Meaghann S Weaver; Li Ding; Elaine R Mardis; Richard K Wilson; Amar Gajjar; David W Ellison; Alberto S Pappo; Ching-Hon Pui; James R Downing Journal: N Engl J Med Date: 2015-11-18 Impact factor: 91.245
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: Donavan T Cheng; Meera Prasad; Yvonne Chekaluk; Ryma Benayed; Justyna Sadowska; Ahmet Zehir; Aijazuddin Syed; Yan Elsa Wang; Joshua Somar; Yirong Li; Zarina Yelskaya; Donna Wong; Mark E Robson; Kenneth Offit; Michael F Berger; Khedoudja Nafa; Marc Ladanyi; Liying Zhang Journal: BMC Med Genomics Date: 2017-05-19 Impact factor: 3.063