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DNA-Repair Gene Mutations Found Among Men With Metastatic Prostate Cancer

NEW YORK (GenomeWeb) – More than 10 percent of men with metastatic prostate cancer have germline mutations in DNA-repair genes like BRCA2, a new study has found.

Researchers from the US and UK pulled together a cohort of nearly 700 men with metastatic prostate cancer and used next-generation sequencing-based approaches to gauge whether or not they harbored germline mutations in DNA-repair genes. Eighty-two of the men did, at a frequency that exceeded that of men with localized prostate cancer, as the researchers reported in the New England Journal of Medicine yesterday. The most common mutated DNA-repair gene among men with metastatic prostate cancer was BRCA2.

"Our study has shown that a significant proportion of men with advanced prostate cancer are born with DNA repair mutations — and this could have important implications for patients," study author Johann de Bono from the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust said in a statement.

For instance, patients with certain DNA repair mutations have been shown to respond to drugs like PARP inhibitors as well as to platinum-based chemotherapy, and knowing whether a patient harbors such a mutation — and in which gene — may be able to guide treatment decisions.

In this study, de Bono and his colleagues combined seven case series, both from the US and the UK, to create a cohort of 692 patients with metastatic prostate cancer. While each of the seven series followed slightly different approaches for determining patients' mutational status — one site used whole-exome sequencing, for instance, while another relied on targeted deep sequencing using the BROCA panel — the mean sequencing depth was more than 100X for all case series.

The researchers focused on 20 DNA-repair genes associated with autosomal dominant cancer-predisposing syndromes. They then called variants as pathogenic or not based on American College of Medical Genetics and Genomics and International Agency for Research on Cancer guidelines.

Of these men, 11.8 percent had at least one pathogenic germline mutation in a DNA-repair gene. Overall, the researchers uncovered 84 pathogenic germline mutations, including 79 truncating and five missense mutations, in 16 genes.

The most common mutated gene in their cohort was BRCA2, as 37 men had mutations in that gene. Other affected genes included ATM, CHEK2, BRCA1, RAD51D, and PALB2.

Gleason scores describing prostate cancer stages were available for a subset of tumors, and the researchers noted that there was marginal evidence that a DNA-repair gene mutation was associated with a higher Gleason score.

Some 22 percent of men with and without DNA-repair gene mutations also had a first-degree relative with prostate cancer, and, as the researchers reported, 71 percent of men with DNA-repair gene mutations had a first-degree relative with a cancer other than prostate cancer.

The number of DNA-repair gene mutations observed in men with metastatic prostate cancer exceeded what would have been expected based on their frequency among men with localized prostate cancer. For instance, of the 499 men with prostate cancer included in the Cancer Genome Atlas, 4.6 percent had germline DNA-repair gene mutations.

In addition, such mutations had a prevalence of 2.7 percent in the Exome Aggregation Consortium dataset.

Based on that, the researchers calculated that the relative risk of mutations in DNA-repair genes among men with metastatic prostate cancer, as compared to ExAC, ranged from 18.6 for BRCA2 to 3.1 for CHEK2.

As DNA-repair gene mutations occur at high frequency in men with metastatic prostate cancer and as such mutations are linked to aggressive disease and may indicate possible treatment approaches, the researchers write that it might be prudent to examine men with metastatic prostate cancer for such mutations.

"Genetic testing for these mutations could identify men with advanced prostate cancer who may benefit from precision treatment," de Bono added. "We could offer these men drugs such as PARP inhibitors, which are effective in patients with certain DNA repair mutations and are showing important anti-tumor activity in ongoing clinical trials."