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Cancer Heritability Gene Set Expanded With Common Variant Analysis

NEW YORK – Relatively common germline variants across many genes may combine to influence an individual's inherited cancer risk beyond the risk associated with rarer, more penetrant germline changes in notorious cancer-related genes such as BRCA1 or BRCA2, according to a new analysis by a University of Edinburgh-led team.

"It is reasonable to think that inherited mutations in certain genes, even those frequently observed in the broader population, can give an advantage to malignant cells to escape the tumor defenses in our cells," senior author Giovanni Stracquadanio, a senior lecturer in synthetic biology and quantitative biology researcher at the University of Edinburgh, explained in an email.

In a paper published in Cancer Research on Wednesday, the researchers tracked down more than 1,100 proposed cancer heritability genes — genes containing germline SNPs related to dozens of cancer types — using genotyping data for UK Biobank participants and a gene-focused computational tool dubbed "Bayesian Gene Heritability Analysis" (BAGHERA). Their subsequent analyses suggested that some 5 percent of those genes overlapped with known cancer driver genes found through the Cancer Genome Atlas, Pan-Cancer Analysis of Whole Genomes, or other tumor sequencing efforts.

Based on these and other results, Stracquadanio and his colleagues suspect that it will eventually be possible to tailor cancer patient treatment strategies by integrating germline variant clues with tumor mutational profiles. They noted that the findings also point to the possibility of developing improved prevention strategies.

"Our results suggest that germline and somatic mutation information could be exploited to identify subgroups of individuals at higher risk of cancer in the broader population and could prove useful to establish strategies for early detection and cancer surveillance," the authors wrote.

After validating the approach with simulated data, the investigators used BAGHERA to search for gene-level heritability for 38 cancer types with genome-wide association study summary statistics for nearly 361,200 UK Biobank participants, expanding from the resulting cancer heritability gene set to explore its overlap with genes that are altered within tumors.

"BAGHERA was specifically designed for low heritability traits such as cancer," the authors explained, "and provides robust heritability estimates under different genetic architectures."

With this approach, the team tracked down 1,146 proposed cancer heritability genes at more than 780 loci that appear to collectively impact individuals' risk of developing 16 cancer types, including forms of disease that develop relatively late in life. That collection encompassed 60 genes that are prone to somatic driver mutations, based on prior tumor sequencing analyses, pointing to the possibility of refining cancer detection and treatment methods with a combination of germline and somatic mutation insights.

"Taken together, our study provides new insights on the genetic architecture of cancer with gene-level resolution," the authors concluded. "We expect that integrating heritability information on cancer genes, along with other cancer heritability genes linked to environmental risk factors and somatic information, will help define more effective early detection and surveillance strategies for the broader population."

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