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

2021-03-24

Nguyen-Dumont, Tú

Dowty, James G

MacInnis, Robert J

Steen, Jason A

Riaz, Moeen

Dugué, Pierre-Antoine

Renault, Anne-Laure

Hammet, Fleur

Mahmoodi, Maryam

Theys, Derrick

Tsimiklis, Helen

Severi, Gianluca

Bolton, Damien M

Lacaze, Paul

Sebra, Robert

Schadt, Eric

McNeil, John

Giles, Graham G

Milne, Roger L

Southey, Melissa C

aggressive Prostate cancer

gene panel testing

genetic risk factors

predisposition

Journal Article

0000-0002-6217-0182

0000-0002-1049-5129

10.3390/cancers13071495

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.

link

Cancers 2021; 13(7): 1495

Cancers

2072-6694