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

Authors :
Tú Nguyen-Dumont
James G. Dowty
Robert J. MacInnis
Jason A. Steen
Moeen Riaz
Pierre-Antoine Dugué
Anne-Laure Renault
Fleur Hammet
Maryam Mahmoodi
Derrick Theys
Helen Tsimiklis
Gianluca Severi
Damien Bolton
Paul Lacaze
Robert Sebra
Eric Schadt
John McNeil
Graham G. Giles
Roger L. Milne
Melissa C. Southey
Source :
Cancers, Vol 13, Iss 7, p 1495 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
20726694
Volume :
13
Issue :
7
Database :
Directory of Open Access Journals
Journal :
Cancers
Publication Type :
Academic Journal
Accession number :
edsdoj.565cd4bbbb5436591c6e6cea51f2897
Document Type :
article
Full Text :
https://doi.org/10.3390/cancers13071495