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Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer.

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Date
2020-08-27
ICR Author
Saunders, Edward
Eeles, Rosalind
Kote-Jarai, Zsofia
Author
Darst, BF
Dadaev, T
Saunders, E
Sheng, X
Wan, P
Pooler, L
Xia, LY
Chanock, S
Berndt, SI
Gapstur, SM
Stevens, V
Albanes, D
Weinstein, SJ
Gnanapragasam, V
Giles, GG
Nguyen-Dumont, T
Milne, RL
Pomerantz, M
Schmidt, JA
Mucci, L
Catalona, WJ
Hetrick, KN
Doheny, KF
MacInnis, RJ
Southey, MC
Eeles, RA
Wiklund, F
Kote-Jarai, Z
Conti, DV
Haiman, CA
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Type
Journal Article
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Abstract
Background There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive versus non-aggressive disease.Methods Participants were 5,545 European-ancestry men, including 2,775 non-aggressive and 2,770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency<0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are two-sided.Results BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D BRCA2 alleles (OR = 3.19, 95% CI = 1.94 to 5.25, P = 8.58x10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79x10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P=.02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than non-aggressive cases (carrier frequencies=14.2% versus 10.6%, respectively; P = 5.56x10-5). However, this difference was statistically non-significant (P=.18) upon excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI=-1,65 to 0.48, P = 3.71x10-4).Conclusions Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.
URI
https://repository.icr.ac.uk/handle/internal/4190
DOI
https://doi.org/10.1093/jnci/djaa132
Collections
  • Genetics and Epidemiology
  • Radiotherapy and Imaging
Research team
Oncogenetics
Language
eng
Date accepted
2020-08-20
License start date
2020-08-27
Citation
Journal of the National Cancer Institute, 2020

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