BACKGROUND: Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA-repair gene mutations, to facilitate selection of patients for germline testing. METHODS: We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical-grade assay (Color Genomics). This platform utilizes next-generation sequencing from saliva to interrogate 30 cancer-susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA-sequence alterations (pathogenic or variants) were offered genetic counseling. RESULTS: Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation-positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines. CONCLUSIONS: Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancer patients should undergo genetic screening.
BACKGROUND: Germline mutations in genes mediating DNA repair are common in men with recurrent and advanced prostate cancer, and their presence may alter prognosis and management. We aimed to define pathological and clinical characteristics associated with germline DNA-repair gene mutations, to facilitate selection of patients for germline testing. METHODS: We retrospectively evaluated 150 unselected patients with recurrent or metastatic prostate cancer who were offered germline genetic testing by a single oncologist using a clinical-grade assay (Color Genomics). This platform utilizes next-generation sequencing from saliva to interrogate 30 cancer-susceptibility genes. Presence or absence of a deleterious germline mutation was correlated with histological and clinical characteristics, and with family history of cancer. All patients with DNA-sequence alterations (pathogenic or variants) were offered genetic counseling. RESULTS: Between July 2016 and July 2017, 150 consecutive patients underwent germline testing; pathogenic mutations were identified in 21 men (14%). Among those with germline mutations, 9 (43%) were in BRCA2, 3 (14%) were in ATM, 3 (14%) were in CHEK2, and 2 (9%) were in BRCA1. While there were no associations between germline mutations and age, tumor stage, Gleason sum or family history; mutation-positive patients had lower median PSA levels at diagnosis (5.5 vs 8.6 ng/mL, P = 0.01) and unique pathologic features. Namely, men with germline mutations were more likely to harbor intraductal/ductal histology (48% vs 12%, P < 0.01) and lymphovascular invasion (52% vs 14%, P < 0.01). Finally, 44% of patients with a positive germline test would not have been offered genetic screening according to current National Comprehensive Cancer Network (NCCN) guidelines. CONCLUSIONS: Presence of intraductal/ductal histology and lymphovascular invasion appear to be associated with pathogenic germline DNA-repair gene mutations in men with prostate cancer, and identification of these features may help to select patients for germline testing. NCCN guidelines may be inadequate in predicting which prostate cancerpatients should undergo genetic screening.
Authors: A V D'Amico; R Whittington; S B Malkowicz; J Fondurulia; M H Chen; I Kaplan; C J Beard; J E Tomaszewski; A A Renshaw; A Wein; C N Coleman Journal: J Clin Oncol Date: 1999-01 Impact factor: 44.544
Authors: David J Gallagher; Mia M Gaudet; Prodipto Pal; Tomas Kirchhoff; Lisa Balistreri; Kinjal Vora; Jasmine Bhatia; Zsofia Stadler; Samson W Fine; Victor Reuter; Michael Zelefsky; Michael J Morris; Howard I Scher; Robert J Klein; Larry Norton; James A Eastham; Peter T Scardino; Mark E Robson; Kenneth Offit Journal: Clin Cancer Res Date: 2010-03-09 Impact factor: 12.531
Authors: T J Sebo; J C Cheville; D L Riehle; C M Lohse; V S Pankratz; R P Myers; M L Blute; H Zincke Journal: Cancer Date: 2001-06-01 Impact factor: 6.860
Authors: Anthony V D'Amico; Brian J Moran; Michelle H Braccioforte; Daniel Dosoretz; Sharon Salenius; Michael Katin; Rudi Ross; Ming-Hui Chen Journal: J Clin Oncol Date: 2009-07-13 Impact factor: 44.544
Authors: Jonathan Ledermann; Philipp Harter; Charlie Gourley; Michael Friedlander; Ignace Vergote; Gordon Rustin; Clare Scott; Werner Meier; Ronnie Shapira-Frommer; Tamar Safra; Daniela Matei; Euan Macpherson; Claire Watkins; James Carmichael; Ursula Matulonis Journal: N Engl J Med Date: 2012-03-27 Impact factor: 91.245
Authors: Peter C Fong; David S Boss; Timothy A Yap; Andrew Tutt; Peijun Wu; Marja Mergui-Roelvink; Peter Mortimer; Helen Swaisland; Alan Lau; Mark J O'Connor; Alan Ashworth; James Carmichael; Stan B Kaye; Jan H M Schellens; Johann S de Bono Journal: N Engl J Med Date: 2009-06-24 Impact factor: 91.245
Authors: Tamara L Lotan; Harsimar B Kaur; Abdullah M Alharbi; Colin C Pritchard; Jonathan I Epstein Journal: Histopathology Date: 2019-04-01 Impact factor: 5.087
Authors: Brittany M Szymaniak; Lauren A Facchini; Veda N Giri; Emmanuel S Antonarakis; Tomasz M Beer; Maria I Carlo; Daniel C Danila; Mallika Dhawan; Daniel George; Julie N Graff; Shilpa Gupta; Elisabeth Heath; Celestia S Higano; Glenn Liu; Ana M Molina; Channing J Paller; Akash Patnaik; Daniel P Petrylak; Zachery Reichert; Matthew B Rettig; Charles J Ryan; Mary-Ellen Taplin; Jake Vinson; Young E Whang; Alicia K Morgans; Heather H Cheng; Rana R McKay Journal: JCO Oncol Pract Date: 2020-09-28
Authors: Goutam Chakraborty; Joshua Armenia; Ying Z Mazzu; Subhiksha Nandakumar; Konrad H Stopsack; Mohammad O Atiq; Kazumasa Komura; Lina Jehane; Rahim Hirani; Kalyani Chadalavada; Yuki Yoshikawa; Nabeela A Khan; Yu Chen; Wassim Abida; Lorelei A Mucci; Gwo-Shu Mary Lee; Gouri J Nanjangud; Philip W Kantoff Journal: Clin Cancer Res Date: 2019-12-03 Impact factor: 12.531
Authors: Mario A Eisenberger; Tamara L Lotan; Pedro Isaacsson Velho; David Lim; Hao Wang; Jong Chul Park; Harsimar B Kaur; Fawaz Almutairi; Michael A Carducci; Samuel R Denmeade; Mark C Markowski; William B Isaacs; Emmanuel S Antonarakis; Colin C Pritchard Journal: JCO Precis Oncol Date: 2019-07-26