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Rare germline genetic variants and risk of aggressive prostate cancer |
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| Authors: | Tú Nguyen-Dumont Robert J. MacInnis Jason A. Steen Derrick Theys Helen Tsimiklis Fleur Hammet Maryam Mahmoodi Bernard J. Pope Daniel J. Park Khalid Mahmood Gianluca Severi Damien Bolton Roger L. Milne Graham G. Giles Melissa C. Southey |
| Affiliation: | 1. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia;2. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Victoria, Australia;3. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia;4. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia The University of Melbourne Centre for Cancer Research, Victoria Comprehensive Cancer Centre, Melbourne, Victoria, Australia Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia;5. Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia;6. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia Melbourne Bioinformatics, The University of Melbourne, Melbourne, Victoria, Australia;7. CESP Inserm U1018, Faculté de Médecine - Université Paris-Sud, Faculté de Médecine - UVSQ, Université Paris-Saclay, Villejuif, France Gustave Roussy, Villejuif, France;8. Department of Surgery, The University of Melbourne, Austin Health, Melbourne, Victoria, Australia;9. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne, Victoria, Australia |
| Abstract: | Few genetic risk factors have been demonstrated to be specifically associated with aggressive prostate cancer (PrCa). Here, we report a case-case study of PrCa comparing the prevalence of germline pathogenic/likely pathogenic (P/LP) genetic variants in 787 men with aggressive disease and 769 with nonaggressive disease. Overall, we observed P/LP variants in 11.4% of men with aggressive PrCa and 9.8% of men with nonaggressive PrCa (two-tailed Fisher's exact tests, P = .28). The proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive PrCa exceeded that observed in men with nonaggressive PrCa; 18/787 carriers (2.3%) and 4/769 carriers (0.5%), P = .004, and 14/787 carriers (0.02%) and 5/769 carriers (0.01%), P = .06, respectively. Our findings contribute to the extensive international effort to interpret the genetic variation identified in genes included on gene-panel tests, for which there is currently an insufficient evidence-base for clinical translation in the context of PrCa risk. |
| Keywords: | aggressive prostate cancer gene panel testing germline genetic variants |