PURPOSE: Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
PURPOSE:Urothelial cancers (UCs) have a substantial hereditary component, but, other than their association with Lynch syndrome, the contribution of genetic risk factors to UC pathogenesis has not been systematically defined. We sought to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in patients with UC and identify associated clinical factors. PATIENTS AND METHODS: Overall, 586 patients with UC underwent prospective, matched tumor-normal DNA sequencing. Seventy-seven genes associated with cancer predisposition were analyzed; allele frequencies were compared with publicly available database. RESULTS: P/LP germline variants were identified in 80 (14%) of 586 individuals with UC. The most common P/LP variants in high- or moderate-penetrance genes were BRCA2 (n = 9; 1.5%), MSH2 (n = 8; 1.4%), BRCA1 (n = 8; 1.4%), CHEK2 (n = 6; 1.0%), ERCC3 (n = 4; 0.7%), and NBN and RAD50 (n = 3; 0.5% each). Sixty-six patients (83%) had germline P/LP variants in DNA-damage repair (DDR) genes, of which 28 (42%) had biallelic inactivation. Patients with P/LP variants were more commonly diagnosed at an early age (22% v 6% in those without variants; P = .01). BRCA2 and MSH2 were significantly associated with an increased risk for UC (odds ratio, 3.7 [P = .004] and 4.6 [P = .001], respectively). Current clinical guidelines for referral for genetic testing failed to identify 6 (26%) patients with high-penetrance variants. CONCLUSION: Clinically significant P/LP germline variants in DDR genes frequently are present in patients with advanced UC. The presence of DDR germline variants could guide cancer screening for patients and their families and serve as predictive biomarkers of response to targeted or immunotherapies. Family history-based criteria to identify patients with hereditary UC susceptibility are insensitive. Broader germline testing in UC, particularly in those of young ages, should be considered.
Authors: Min Yuen Teo; Richard M Bambury; Emily C Zabor; Emmet Jordan; Hikmat Al-Ahmadie; Mariel E Boyd; Nancy Bouvier; Stephanie A Mullane; Eugene K Cha; Nitin Roper; Irina Ostrovnaya; David M Hyman; Bernard H Bochner; Maria E Arcila; David B Solit; Michael F Berger; Dean F Bajorin; Joaquim Bellmunt; Gopakumar Iyer; Jonathan E Rosenberg Journal: Clin Cancer Res Date: 2017-01-30 Impact factor: 12.531
Authors: Dung T Le; Jennifer N Uram; Hao Wang; Bjarne R Bartlett; Holly Kemberling; Aleksandra D Eyring; Andrew D Skora; Brandon S Luber; Nilofer S Azad; Dan Laheru; Barbara Biedrzycki; Ross C Donehower; Atif Zaheer; George A Fisher; Todd S Crocenzi; James J Lee; Steven M Duffy; Richard M Goldberg; Albert de la Chapelle; Minori Koshiji; Feriyl Bhaijee; Thomas Huebner; Ralph H Hruban; Laura D Wood; Nathan Cuka; Drew M Pardoll; Nickolas Papadopoulos; Kenneth W Kinzler; Shibin Zhou; Toby C Cornish; Janis M Taube; Robert A Anders; James R Eshleman; Bert Vogelstein; Luis A Diaz Journal: N Engl J Med Date: 2015-05-30 Impact factor: 91.245
Authors: Janice S Kwon; Jenna L Scott; C Blake Gilks; Molly S Daniels; Charlotte C Sun; Karen H Lu Journal: J Clin Oncol Date: 2011-05-02 Impact factor: 44.544
Authors: Mariana C Stern; Jie Lin; Jonine D Figueroa; Karl T Kelsey; Anne E Kiltie; Jian-Min Yuan; Giuseppe Matullo; Tony Fletcher; Simone Benhamou; Jack A Taylor; Donatella Placidi; Zuo-Feng Zhang; Gunnar Steineck; Nathaniel Rothman; Manolis Kogevinas; Debra Silverman; Nuria Malats; Stephen Chanock; Xifeng Wu; Margaret R Karagas; Angeline S Andrew; Heather H Nelson; D Timothy Bishop; Sei Chung Sak; Ananya Choudhury; Jennifer H Barrett; Faye Elliot; Román Corral; Amit D Joshi; Manuela Gago-Dominguez; Victoria K Cortessis; Yong-Bing Xiang; Yu-Tang Gao; Paolo Vineis; Carlotta Sacerdote; Simonetta Guarrera; Silvia Polidoro; Alessandra Allione; Eugen Gurzau; Kvetoslava Koppova; Rajiv Kumar; Peter Rudnai; Stefano Porru; Angela Carta; Marcello Campagna; Cecilia Arici; Sung Shim Lani Park; Montserrat Garcia-Closas Journal: Cancer Res Date: 2009-08-25 Impact factor: 12.701
Authors: A Gordon Robertson; Jaegil Kim; Hikmat Al-Ahmadie; Joaquim Bellmunt; Guangwu Guo; Andrew D Cherniack; Toshinori Hinoue; Peter W Laird; Katherine A Hoadley; Rehan Akbani; Mauro A A Castro; Ewan A Gibb; Rupa S Kanchi; Dmitry A Gordenin; Sachet A Shukla; Francisco Sanchez-Vega; Donna E Hansel; Bogdan A Czerniak; Victor E Reuter; Xiaoping Su; Benilton de Sa Carvalho; Vinicius S Chagas; Karen L Mungall; Sara Sadeghi; Chandra Sekhar Pedamallu; Yiling Lu; Leszek J Klimczak; Jiexin Zhang; Caleb Choo; Akinyemi I Ojesina; Susan Bullman; Kristen M Leraas; Tara M Lichtenberg; Catherine J Wu; Nicholaus Schultz; Gad Getz; Matthew Meyerson; Gordon B Mills; David J McConkey; John N Weinstein; David J Kwiatkowski; Seth P Lerner Journal: Cell Date: 2017-10-05 Impact factor: 41.582
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: Alicia Latham; Preethi Srinivasan; Yelena Kemel; Jinru Shia; Chaitanya Bandlamudi; Diana Mandelker; Sumit Middha; Jaclyn Hechtman; Ahmet Zehir; Marianne Dubard-Gault; Christina Tran; Carolyn Stewart; Margaret Sheehan; Alexander Penson; Deborah DeLair; Rona Yaeger; Joseph Vijai; Semanti Mukherjee; Jesse Galle; Mark A Dickson; Yelena Janjigian; Eileen M O'Reilly; Neil Segal; Leonard B Saltz; Diane Reidy-Lagunes; Anna M Varghese; Dean Bajorin; Maria I Carlo; Karen Cadoo; Michael F Walsh; Martin Weiser; Julio Garcia Aguilar; David S Klimstra; Luis A Diaz; Jose Baselga; Liying Zhang; Marc Ladanyi; David M Hyman; David B Solit; Mark E Robson; Barry S Taylor; Kenneth Offit; Michael F Berger; Zsofia K Stadler Journal: J Clin Oncol Date: 2018-10-30 Impact factor: 50.717
Authors: Semanti Mukherjee; Chaitanya Bandlamudi; Matthew D Hellmann; Yelena Kemel; Esther Drill; Hira Rizvi; Kaitlyn Tkachuk; Aliya Khurram; Michael F Walsh; Marjorie G Zauderer; Diana Mandelker; Sabine Topka; Ahmet Zehir; Preethi Srinivasan; Myvizhi Esai Selvan; Maria I Carlo; Karen A Cadoo; Alicia Latham; Jada G Hamilton; Ying L Liu; Steven M Lipkin; Sami Belhadj; Gareth L Bond; Zeynep H Gümüş; Robert J Klein; Marc Ladanyi; David B Solit; Mark E Robson; David R Jones; Mark G Kris; Joseph Vijai; Zsofia K Stadler; Christopher I Amos; Barry S Taylor; Michael F Berger; Charles M Rudin; Kenneth Offit Journal: Cancer Epidemiol Biomarkers Prev Date: 2022-07-01 Impact factor: 4.090
Authors: Chenjie Zeng; Lisa A Bastarache; Ran Tao; Eric Venner; Scott Hebbring; Justin D Andujar; Sarah T Bland; David R Crosslin; Siddharth Pratap; Ayorinde Cooley; Jennifer A Pacheco; Kurt D Christensen; Emma Perez; Carrie L Blout Zawatsky; Leora Witkowski; Hana Zouk; Chunhua Weng; Kathleen A Leppig; Patrick M A Sleiman; Hakon Hakonarson; Marc S Williams; Yuan Luo; Gail P Jarvik; Robert C Green; Wendy K Chung; Ali G Gharavi; Niall J Lennon; Heidi L Rehm; Richard A Gibbs; Josh F Peterson; Dan M Roden; Georgia L Wiesner; Joshua C Denny Journal: JAMA Oncol Date: 2022-06-01 Impact factor: 33.006
Authors: Juan Carlos Pardo; Vicenç Ruiz de Porras; Andrea Plaja; Cristina Carrato; Olatz Etxaniz; Oscar Buisan; Albert Font Journal: Int J Mol Sci Date: 2020-08-29 Impact factor: 5.923
Authors: Monika Joshi; Petros Grivas; Amir Mortazavi; Paul Monk; Steven K Clinton; Michele Sue-Ann Woo; Sheldon L Holder; Joseph J Drabick; Ming Yin Journal: Cancer Med Date: 2020-10-23 Impact factor: 4.452