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WUSTL Team Finds Inherited Mutations Common Across Cancer Types

NEW YORK (GenomeWeb) – Researchers from Washington University in St. Louis have found that inherited mutations may play a larger role in certain cancer types than was previously known.

Reporting their work today in Nature Communications, the researchers analyzed germline and tumor sequence data from 4,034 samples representing 12 cancer types that had been sequenced as part of the Cancer Genome Atlas project.

"In general, we have known that ovarian and breast cancers have a significant inherited component, and others, such as acute myeloid leukemia and lung cancer, have a much smaller inherited genetic contribution," Li Ding, a senior author of the study and associate professor of medicine and assistant director of the McDonnell Genome Institute at WUSTL, said in a statement. However, the authors were surprised to see that other cancers, particularly stomach cancer, appeared to have such a large genetic component — with 11 percent of stomach cancer cases harboring germline variants.

In addition, the study was one of the first times researchers have been able to pinpoint gene culprits outside of some well-established genes like BRCA1, BRCA2, and the Lynch syndrome genes.

The researchers analyzed 12 cancer types: breast adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, acute myeloid leukemia, low grade glioma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian carcinoma, prostate adenocarcinoma, stomach adenocarcinoma, and uterine corpus endometrial carcinoma.

The researchers focused their analyses on two gene sets: 114 known cancer-susceptibility genes and 47 DNA repair genes associated with the Fanconi anemia pathway. Fifteen genes overlapped between the two sets.

The team focused its analyses on rare mutations in these gene sets and looked to see if they were not only present in the same individual's tumor DNA, but enriched in the tumor DNA.

"If a mutation is present in the germline and amplified in the tumor, there is a high likelihood it is playing a role in the cancer," Ding said in the statement.

After identifying potential susceptibility mutations from the TCGA dataset, the researchers validated their findings against an additional 1,627 TCGA cases and also compared the cancer to control datasets from the National Heart Lung and Blood Institute's Women's Health Initiative Exome Sequencing Project.

The researchers found rare germline mutations that were enriched in the tumors across all 12 cancer types. Focusing on truncating mutations, which are most likely to impact gene function, the researchers found that 19 percent of ovarian cancer cases carried rare germline truncations in the 114 cancer susceptibility genes. By contrast, only 4 percent of AML cases had rare germline truncating mutations.

Somewhat surprisingly, the team found that 11 percent of stomach cancer cases had potential cancer predisposition variants. That percentage was higher than previously anticipated and slightly above what they found in breast cancer, which is known to have a strong genetic component.

Next, the team looked to see which genes were the most commonly mutated. Thirteen genes had a significantly elevated burden of mutations across all 12 cancer types: BRCA1, BRCA2, ATM, BRIP1, and PALB2. And an additional 21 genes had "suggestive evidence" of an increased burden, comprising 8.3 percent of the total number of cases.

BRCA1 had 53 rare truncation variants across seven different cancer types and BRCA2 had 50 variants across six cancer types. Most of the BRCA1 and BRCA2 variants were found in ovarian and breast cancer cases, however seven BRCA1 and six BRCA2 variants were detected in other cancer types: three each in endometrial, stomach and lung cancers, two in kidney cancer, and one each in prostate and head and neck cancer.

In addition, individuals carrying a BRCA1 or BRCA2 mutation had a significantly younger age of diagnosis than those without the mutations — 52.7 years versus 63.1 years — "providing support that these variants may contribute to younger onsets of these cancer types, though additional data is required for confirmation and to reach statistical significance," the authors wrote.

The team found significant loss of heterozygosity in nine genes: ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D.

Overall, "the scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumor development, a critical step toward precision medicine," the authors wrote. Despite analyzing over 4,000 cases, the authors noted that the sample size was still small and limited primarily to individuals of European background, "emphasizing the need for the development of a reference source of genomic data on germline cancer predisposition variants from ancestrally diverse population groups."

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