An international team of researchers has uncovered multiple new germline mutations that may influence the development of sarcomas. Notably, they found that variants in several DNA damage sensing and repair genes contribute greatly to sarcoma risk, including BRCA2, ATM, ATR, and ERCC2.

An international team led by the Garvan Institute of Medical Research in New South Wales, Australia, has uncovered multiple new germline mutations that may influence the development of sarcomas. Their findings suggest “a large, clinically significant, and under-recognized burden of genetic risk” in these connective-tissue cancers (Lancet Oncol 2016;17:1261–71).

The researchers obtained blood or saliva samples from 1,162 patients with 32 sarcoma subtypes, and carried out targeted exon sequencing of 72 genes selected for potential associations with cancer risk. They discovered that 55% of patients carried known or likely pathogenic germline mutations in at least one gene. However, only 155 (13.3%) patients fulfilled criteria for a family history of known cancer-predisposing disorders such as Li-Fraumeni syndrome, which is driven by germline TP53 mutations and characterized by early-onset soft-tissue sarcomas, among other cancers.

“This suggests that sarcomas are more hereditary than previously thought, but familial patterns alone may be insufficient to determine risk,” says senior author David Thomas, MD, PhD.

Germline variants in several DNA damage sensing and repair genes, including BRCA2, ATM, ATR, and ERCC2, contributed greatly to sarcoma risk, the researchers reported. Among patients given radiation for their primary cancer, which results in treatment-induced DNA damage, the high probability of developing a secondary sarcoma is well established. Therefore, “in retrospect, our finding makes sense,” Thomas says. “These genes were not previously linked with sarcomas, however, other than anecdotally in the case of BRCA2. And ERCC2 was a total surprise; until now it's only been associated with risk for skin cancers.”

The team also found that approximately one fifth of study patients carried germline variants in multiple genes—two to six, on average. These individuals received their first cancer diagnosis at a median age of 25 years, compared with 32 years for those with mutant TP53, “the strongest known sarcoma gene,” Thomas says. “This suggests a polygenic contribution to sarcoma risk, and more variants in a given individual appear to be associated with earlier onset of cancer.”

To Gary Schwartz, MD, deputy director of the Herbert Irving Comprehensive Cancer Center at Columbia University in New York, NY, “this study shows the absolute importance of conducting not only somatic, but also germline mutation analyses, in patients with sarcoma.”

Schwartz notes that many of the implicated genes are already druggable: PARP inhibitors may be effective against BRCA2 variants, for instance, whereas ATM and ATR variants may benefit from drugs targeting cell-cycle checkpoints such as WEE1 or CHK1. Mutations in ERCC2 render cells more sensitive to cisplatin, he adds, so this drug—not commonly used to treat sarcomas—may be another therapeutic option.

“Germline mutations are still greatly underappreciated as a source of biomarkers for targeted therapy,” Thomas agrees.

The next steps for Thomas's team include evaluating still more patients with different sarcomas to better parse the genetic signals specific to each subtype. Acknowledging that targeted exon sequencing is inherently biased, he says they'll use a whole-genome approach instead, which could reveal many more pathogenic germline variants. –Alissa Poh

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