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At AACR, Broad Researcher Describes Search for Cancer-related Germline Mutations Using TCGA Exomes

By Andrea Anderson

CHICAGO (GenomeWeb News) – Researchers at the Broad Institute are bringing together reams of exome sequence data generated for the Cancer Genome Atlas to get a closer look at germline mutations at play in cancer.

During a presentation at the American Association for Cancer Research annual meeting here yesterday, the Broad's Adam Kiezun said TCGA team members at that center are currently working with more than 100 terabases of exome sequence data.

Using exome sequences that have been generated for some 2,800 individuals with cancer and around 4,000 population controls, they plan to do both case-control studies as well as an integrated germline and somatic variant analysis, Kiezun said.

Together, the approaches should make it possible to not only find inherited coding variants that elevate cancer risk, but also germline mutations working in conjunction with somatic mutations to influence or modify cancer-related processes.

Beyond trying to figure out which yet-undetected germline mutations might increase an individual's risk of developing disease, Kiezun explained, the search is expected to help uncover some low frequency cancer-related germline mutations that could help in untangling cancer biology or finding potential drug targets.

To find such cancer-relevant mutations, though, the team first needs to figure out the overall set of variants present within the exomes — no small task given the size of the data set at hand.

Kiezun noted that more than 1 million variants have turned up so far, including many rare or low frequency variants at sites that appear to be functionally relevant based on PolyPhen2 analysis.

The researchers are also finding evidence that the frequency and nature of germline mutations varies depending on the population tested, underscoring the need for ancestry-matched controls when doing mutation analyses. Case-control studies may also be muddled by a failure to account for hidden relatedness between individuals being tested, Kiezun noted.

Along with their search for somatic cancer-related mutations, the germline analysis has helped spur the development of tools for doing everything from the annotation of cancer-related point mutations or small insertions to analyses that consider combined information on both germline and somatic variants.

Additional information on that suite of tools, developed by the Broad Institute's Cancer Genome Analysis group, is available online.