Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer

Cancers

Gianluca Severi¹  RobertJ. MacInnis²  JamesG. Dowty²  John McNeil³  Moeen Riaz³  Paul Lacaze³  Robert Sebra⁴  Eric Schadt⁴  Damien Bolton⁵  Maryam Mahmoodi⁶  Tú Nguyen-Dumont⁶  Helen Tsimiklis⁶  Derrick Theys⁶  Fleur Hammet⁶  RogerL. Milne⁶  Anne-Laure Renault⁶  JasonA. Steen⁶  Pierre-Antoine Dugué⁶  MelissaC. Southey⁶  GrahamG. Giles⁶ 

[1] CESP Inserm U1018, Faculté de Médecine—Univ. Paris-Sud, Faculté de Médecine—UVSQ, Université Paris-Saclay, 94805 Villejuif, France;Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia;Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia;Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;Department of Surgery, Austin Health, The University of Melbourne, Heidelberg, VIC 3084, Australia;Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, VIC 3168, Australia;

关键词: aggressive prostate cancer;    gene panel testing;    predisposition;    genetic risk factors;   

DOI  :  10.3390/cancers13071495

来源: DOAJ

【 摘 要 】

While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (p < 0.0001). Aggressive PrCa odds ratios (ORs) were estimated using unconditional logistic regression. Increased risk of aggressive PrCa (OR (95% confidence interval)) was identified for pathogenic variants in BRCA2 (5.8 (2.7–12.4)), BRCA1 (5.5 (1.8–16.6)), and ATM (3.8 (1.6–9.1)). Our study provides further evidence that rare germline pathogenic variants in these genes are associated with increased risk of this aggressive, clinically relevant subset of PrCa. These rare genetic variants could be incorporated into risk prediction models to improve their precision to identify men at highest risk of aggressive prostate cancer and be used to identify men with newly diagnosed prostate cancer who require urgent treatment.

【 授权许可】

Unknown