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Sarcoma Patient Targeted Sequencing IDs Germline Mutations in Known Cancer Genes

NEW YORK (GenomeWeb) – Germline mutations in several known cancer genes appear to boost individuals' susceptibility to a rare form of bone and soft-tissue cancer called sarcoma, according to a paper published online last night in the Lancet Oncology.

As part of the International Sarcoma Kindred Study (ISKS), an international team led by researchers in Australia did targeted gene panel sequencing on more than 1,000 individuals with sarcoma. Along with mutations in genes already implicated in sarcoma, the sequence data revealed recurrent mutations in genes related to other cancer types such as TP53, ERCC2, ATR, BRCA2, and ATM.

Across the individuals tested, the team found that more than half carried mutations to at least one of the cancer-related genes — and the risk of early-onset sarcoma was ratcheted up in those with mutations affecting more than one of these genes, which was the case about one-fifth of the cohort.

"We can now see that the risk for developing sarcoma is increased through the combined effect of multiple genes, and that the more mutations someone carries, the earlier the onset of cancer," senior author David Thomas, head of the Kinghorn Cancer Centre and the Garvan Institute of Medical Research cancer division, said in a statement.

"We've never been able to identify these at-risk individuals, and their families, before. Now we can," Thomas explained. "That means we can manage risk better, and help those people to get the care they need, when they need it."

Focusing on 72 potential cancer risk genes, he and his colleagues did targeted gene panel sequencing in DNA from blood or saliva samples from 1,162 individuals older than 15 years who had been diagnosed with sarcoma. Nearly three-quarters self-identified as Caucasian and around 15 percent had been diagnosed with multiple primary cancers.

Compared with more than 6,500 Caucasian controls from three large cohorts such as the National Heart, Lung, and Blood Institute's Exome Sequencing Project, the researchers noted that roughly 55 percent of the sarcoma patients showed a boost in suspicious germline variants that appeared to be pathogenic. Those mutations were particularly over-represented in the TP53, BRCA2, ATM, ATR, and ERCC2 genes.

Along with clues to cancer risk, the "genetic drivers that give a person an increased risk of cancer also helps us understand how best to treat that person's cancer," Thomas said in a statement, noting that "for about a third of the individuals we studied, the gene mutations they carry give us important information about how regularly they should be monitored and how they should or should not be treated."

For example, 28 individuals with sarcoma had germline mutations affecting the breast and ovarian cancer risk genes BRCA1 or BRCA2. And nearly two-dozen individuals had rare, pathogenic mutations in ERCC2, Thomas explained, a gene coding for a protein that typically helps to reduce toxicity associated with chemotherapy.

The team plans to continue expanding on its current findings by doing whole-genome sequencing on germline samples from individuals who are at risk of sarcoma. The effort is being done with help from the Sydney Genomics Collaborative program and the New South Wales government's NSW Cancer Genomic Medicine Program.

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