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BRCA 1/2, COMT Variant Co-Occurrence Associated With Cancer Resistance

NEW YORK (GenomeWeb) – A George Washington University research team has found evidence that individuals harboring both BRCA 1/2 and COMT variants may be resistant to cancer.

"Highly penetrant BRCA 1/2 pathogenic mutations are the best-studied genetic risk factor of breast cancer," the researchers wrote in a correspondence published yesterday in the New England Journal of Medicine. "Although the penetrance of BRCA 1/2 mutations is high, it is incomplete and cancer does not develop in some carriers." They also note that while it is unclear why some people with these disease risk variants do not develop cancer, it may imply that some cancer resistance also has a genetic component.

The findings are a result of the researchers' first attempt to search for protective genetic signatures and are based on genome- or exome-wide analysis of participants in the Exome Sequencing Project of the National Heart, Lung, and Blood Institute.

The GWU team screened 3,914 participants in the cohort and identified 15 women with nonsense and frameshift BRCA 1/2 mutations. The researchers ran a series of analyses on these women's genomes or exomes and within a population control cohort of 60,418 persons from the ExAct Consortium to determine the presence of a rare variant that may be responsible for cancer resistance.

"The single top-ranked variant for differential distribution was synonymous substitution p.L203 (rs165631) in the gene COMT encoding catechol O-methyltransferase," the researchers wrote. "It was present in five of the 15 women with BRCA 1/2 mutations and in none of the 25 patients with germline BRCA 1/2-positive breast cancer in the Cancer Genome Atlas."

The COMT gene is a key player in the inactivation of catechol estrogens. In previous studies, researchers have examined the role of its missense variant p.V158M in the genetic risk of breast cancer, however, these studies produced conflicting results. "This finding highlights a new focus to assess the genetic role of COMT in cancer, possibly executed through noncoding mechanisms," the researchers wrote.

In an interview, Anelia Horvath, director of the McCormick Genomic and Proteomic Center at GWU and lead author on the study, elaborated that "The reason that we believe it is unlikely that they have cancer is because they participated in population studies and their age range as requested by the study in which they participated is usually overlapping or after the age of early-onset breast cancer." However, she clarified that because they were looking at publicly available data that was anonymized, they can't make the statement that the individuals that they identified definitely did not have cancer.

Hovarth also noted that this was a fairly limited study of only 15 individuals, but said the findings warranted further investigation and validation.

"We just wanted to send out the message that our genomes may contain naturally occurring protective variants and now that we have ever-so-growing access to population genomes that could be a very useful strategy to look into that," she added.

The group now plans to perform similar studies for other cancers. "Using an expanded group population of individuals we will look for cancers that have strong genetic components and depending on how many individuals we find in the populations, we will perform similar analyses to what we did with BRCA 1/2," Horvath said.