sábado, 2 de marzo de 2019

Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel. - PubMed - NCBI

2019 Feb 15. pii: S0302-2838(19)30096-X. doi: 10.1016/j.eururo.2019.01.050. [Epub ahead of print]

Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel.

Leongamornlert DA1, Saunders EJ1, Wakerell S1, Whitmore I1, Dadaev T1, Cieza-Borrella C1, Benafif S1, Brook MN1, Donovan JL2, Hamdy FC3, Neal DE4, Muir K5, Govindasami K1, Conti DV6, Kote-Jarai Z7, Eeles RA8.

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Abstract

BACKGROUND:

Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis.

OBJECTIVE:

To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease.

DESIGN, SETTING, AND PARTICIPANTS:

We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60yr) and 1160 selected controls.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n=201) versus nonaggressive (Gleason score ≤7, n=1048) cases.

RESULTS AND LIMITATIONS:

We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR]=1.29, 95% confidence interval [CI] 1.01-1.64, p=0.036). Gene-level analyses selected NBN (pSKAT-O=2.4×10-4) for overall risk and XPC (pSKAT-O=1.6×10-4) for aggressive disease, both at candidate-level significance (p<3.1×10-4 and p<3.4×10-4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR=3.2, 95% CI 2.1-4.8, pADA=4.1×10-3) and four genes that increased risk of aggressive disease (OR=11.2, 95% CI 4.6-27.7, pADA=5.6×10-3), three of which overlap the predisposition gene set.

CONCLUSIONS:

The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential.

PATIENT SUMMARY:

This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice.