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Subset of Aggressive Prostate Tumors Contain BRCA2 Mutations

NEW YORK (GenomeWeb) – A new study in the American Journal of Human Genetics suggests a subset of aggressive prostate tumors are marked by alterations affecting both copies of BRCA2, a gene best known for its role in breast and ovarian cancer risk.

A National Human Genome Research Institute-led team did deep genome sequencing on prostate cancer and matched normal samples from 10 individuals, focusing on both germline and somatic mutation with potential clinical relevance. The search led to three tumors with germline and/or somatic mutations that interfere with both copies of BRCA2. Another 18 BRCA2-mutated tumors turned up when the team scoured available data for 150 metastatic prostate cancer tumors.

About half of the BRCA2-mutated tumors came from individuals with germline mutations in the gene. The researchers noted that the biallelic loss of BRCA2 coincided with several notable tumor features — including a rise in overall somatic mutation rate and shift in the prevalence of certain nucleotide substitutions.

"Our observations clearly demonstrate that BRCA2-disrupted tumors represent a unique and clinically relevant molecular subtype of aggressive [prostate cancer], highlighting both the promise and utility of this mutation signature as a prognostic and treatment-selection biomarker," senior author Elaine Ostrander, cancer genetics and comparative genomics branch chief with NHGRI, and her co-authors wrote.

While almost all individuals with local prostate cancer are alive five years after diagnosis, the team noted, the five-year survival rate declines dramatically to around 28 percent for individuals with metastatic prostate cancer.

In the hopes of finding molecular markers for aggressive prostate cancers that are more likely to spread to other parts of the body, Ostrander and colleagues used the Illumina HiSeq 2000 instrument to do deep whole-genome sequencing on 10 prostate cancers classified as aggressive based on their Gleason score, a pathology-based measure of prostate cancer aggressiveness ascertained from microscopic tumor features.

The team generated about 95-fold coverage of the tumor genomes, on average, using DNA from nine fresh frozen prostate cancer samples and one prostate cancer metastasis. Matched normal samples were sequenced to 48-fold average genome coverage to get a look at germline variant patterns.

When they sorted through SNPs, small insertions and deletions, and structural variants in the tumor and matched normal genomes, the researchers uncovered loss-of-function alterations to both copies of BRCA2 in three of the 10 tumors. One of those tumors came from an individual with both germline and somatic truncations in BRCA2.

To better understand the significance and frequency of BRCA2 mutations in prostate cancer, the team profiled the broader mutation patterns in the original tumor set before searching for comparable BRCA2 changes in other prostate cancer tumors.

When biallelic BRCA2 mutations were present, the overall somatic mutation rate was nearly three times higher than that in the other seven tumors, for example, with 2.9-fold more single nucleotide changes and 3.1-fold more indels. And while cytosine and thymine swaps were common in the non-BRCA2-mutated tumors, these substitutions did not appear to be enriched when biallelic BRCA2 loss occurred.

The BRCA2-mutated prostate cancers appeared to be more aggressive than other prostate cancers, both in the original sample set and in a group of 50 more prostate tumors previously profiled by whole-genome sequencing.

The team saw similar patterns when it did BRCA2 targeted analyses on another 150 metastatic prostate cancers. That set included 18 tumors with biallelic BRCA2 mutations — nine had a combination of germline and somatic changes and nine contained somatic mutations in both copies of BRCA2. 

"Our analysis … highlights the need to evaluate all variant types for both germline and somatic mutations in BRCA2, because half of the deficient tumors have somatic-only disruptions," the study's authors wrote, noting that the work "implicates BRCA2 status and the [homologous recombination]-deficiency-associated molecular signature as potentially important prognostic and treatment selection biomarkers in aggressive and metastatic [prostate cancer]."