Germline DNA Repair Gene Mutation Incidence Highest In Metastatic Prostate Cancer

Germline alterations to DNA repair genes are significantly more common in men with metastatic prostate cancer than those with localised disease or no prostate cancer

medwireNews: Metastatic prostate cancer is frequently characterised by the presence of germline mutations affecting DNA repair processes, shows research published in The New England Journal of Medicine.

At least one pathogenic germline alteration to a DNA repair gene was identified in 11.8% of 692 UK and US men with metastatic disease, reports Peter Nelson, from the Fred Hutchinson Cancer Research Center in Seattle, Washington, USA, and co-authors.

Mutations were detected in 16 out of the 20 genes assessed, with 44% of alterations occurring in BRCA2, 13% in ATM, 12% in CHEK2 and 7% in BRCA1. In addition, 4% of mutations were each found in RAD51D and PALB2.

There was no significant correlation between the identification of a germline mutation in men with metastatic prostate cancer and age at diagnosis or race, although there was “marginal evidence” to indicate that a germline mutation predicted a Gleason score of 8 to 10 versus 7 or less (odds ratio [OR]=1.8).

By comparison, germline DNA repair gene mutations were identified in just 4.6% of the 499 men with localised prostate cancer entered into the Cancer Genome Atlas prostate cancer study. Thus, men with metastatic prostate cancer were 5.3 and 2.2 times more likely to have such a mutation than those with low-to-intermediate risk and high-risk localised disease, respectively.

And compared with data from 53,105 individuals without cancer entered into the Exome Aggregation Consortium, men with metastatic prostate cancer were 5.0 times more likely to have a germline DNA repair gene mutation, with the relative risk of individual mutations ranging from a significant 3.1 for CHEK2 to 18.6 for BRCA2.

“Because the high frequency of DNA-repair gene mutations is not exclusive to an early-onset phenotype and is associated with clinically and histologically aggressive disease, with compelling evidence for therapeutic relevance, it may be of interest to routinely examine all men with metastatic prostate cancer for the presence of germline mutations in DNA-repair genes”, the authors suggest.

In all, 88% of the metastatic prostate cancer patients with and without DNA repair gene mutations had information on their family history of cancer and over a fifth (22%) of both groups had a first-degree relative with prostate cancer.

But while 71% of the patients with a DNA repair gene mutation had a first-degree relative with other forms of cancer, just 50% of those without such an aberration did so, giving a significant OR of 2.4.

Discussing the clinical impact of their findings, the authors cite researching indicating that prostate cancer with mutated DNA repair genes may be responsive to platinum-based chemotherapy and PARP1 inhibitors.

“[T]he identification of a germline mutation in a DNA-repair gene provides information that is key to relatives, both male and female, and that can prompt ‘cascade’ counseling to identify cancer predisposition and deploy risk-reduction strategies”, they add.

“Prospective studies assessing the prognostic and predictive significance of mutations in DNA-repair genes with regard to clinical outcomes are now needed to inform personalized care.”

Reference

Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med 2016; Advance online publication 6 July. DOI: 10.1056/NEJMoa1603144

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