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Germline Cancer Risk Genes May Hold Rhabdomyosarcoma Survival Clues, Study Suggests

NEW YORK – The presence of germline pathogenic or likely pathogenic variants falling in known cancer risk genes may help predict overall and event-free survival in children with a relatively common soft tissue sarcoma type known as rhabdomyosarcoma, according to new research from the Children's Oncology Group.

Baylor College of Medicine researcher Bailey Martin-Giacalone, who presented the findings at the American Society of Human Genetics annual meeting on Wednesday, noted that the burden of germline cancer risk has been characterized for RMS patients in the past.

For a paper published in the Journal of the National Cancer Institute in July, for example, she and her co-authors found pathogenic or likely pathogenic variants in cancer risk genes in 45 of 615 — or just over 7 percent — of exome-sequenced RMS patients considered in a Children's Oncology Group consortium analysis of germline cancer predisposition.

The analysis focused on two-dozen genes linked to RMS risk in the past, as well as 63 genes with ties to the risk of other cancer types. Variant frequencies in RMS cases were compared with those from 9,963 RMS-free adult control individuals, who carried risky variants in the same gene set just 1.5 percent of the time.

More than 70 percent of risk variants found in the RMS patient germlines fell in genes such as TP53, NF1, or HRAS that have been linked to RMS, a cancer that forms in skeletal muscle precursor cells. But the team also saw pathogenic or likely pathogenic germline variants in other cancer predisposition genes as well.

For the latest study, the team went a step further, searching for ties between such germline variants and RMS patient outcomes.

Indeed, exome sequence and clinical outcomes data for 580 newly diagnosed RMS cases revealed an overrepresentation of pathogenic or likely pathogenic variants in cancer predisposition genes in patients with shorter overall survival and event-free survival times, Martin-Giacalone reported.

While the overall survival and event-free survival differences were not statistically significant when the researchers included all cancer predisposition genes, both measures of survival dipped in cases carrying risky germline variants in RMS-associated genes — an effect that appeared to be even more enhanced when those germline variants turned up in the TP53 or HRAS genes.

The presence of germline variants in RMS-associated genes was also linked to lower-than-usual survival and event-free survival times when the team focused on RMS cases with embryonal histology, Martin-Giacalone explained, a subtype subgroup that normally has a survival edge of cases from the rarer alveolar RMS, or ARMS, subtype.

Embryonal RMS, or ERMS, tumors generally lack PAX3-FOXO1 or PAX7-FOXO1 fusions found in some 80 percent of ARMS tumors, she noted, and the PAX3/7-FOXO1 fusions typically presage poorer event-free survival outcomes.

On the other hand, germline cancer risk variants appear to be more common in ERMS tumors than in ARMS tumors, based on data in the team's JNCI paper, and the ARMS cases linked to such germline variants so far all occurred in individuals with PAX3/7-FOXO1 fusion-free tumors.

Together, these and other findings hint that germline testing might provide clues to RMS patient outcomes in cases that lack prognostically informative gene fusions, though Martin-Giacalone noted that additional studies on patients with RMS are anticipated, including whole-genome sequencing analyses on matched tumor-normal samples to look at potential interactions between germline and somatic variants.

"Currently, children diagnosed with RMS do not routinely undergo genetic testing, however, our findings suggest that germline genetic testing should be considered in novel risk stratification protocols and surveillance strategies," the authors suggested in an abstract for the ASHG presentation.