Cancer Risk Variants Found in Significant Subset of Sarcoma Patient Germlines


New research from a Dana-Farber Cancer Institute and Harvard Medical School team suggests that genetic risk for cancer may be found in well over 1 in 10 individuals who develop sarcomas — a group of heterogeneous mesenchymal soft tissue or bone tumors that can fall into dozens of histological subtypes.

"There are many types of sarcomas, more than 70 histological types," noted Mersedeh Rohanizadegan, a clinical geneticist at the Dana-Farber Cancer Institute, adding that bone sarcomas are found most often in pediatric forms of the disease, while soft tissue sarcomas are typically diagnosed in adults and are slightly over-represented in males.

At the American College of Medical Genetics and Genomics annual meeting on Wednesday, Rohanizadegan shared findings from a retrospective analysis of germline multi-gene panel testing data on 343 adult sarcoma patients between the ages of 18 and 96 years old. Although most sarcomas occur sporadically, the researchers found pathogenic or likely pathogenic variants in germline samples from 16 percent of the sarcoma cases considered.

"We think that, based on our findings, it is wise to consider genetic testing among patients with soft tissue sarcoma," Rohanizadegan said.

"We are working to implement genetic testing more broadly in our own institution for bone and soft tissue sarcoma," she added. "We also think that cascade testing for the family members will be helpful in these cases."

The team's results fit with international data reported for nearly 1,200 sarcoma patients in Lancet Oncology in 2016, which pointed to an overrepresentation of pathogenic or likely pathogenic variants in sarcoma patients as well as ties between earlier-than-usual cancer diagnoses and risky variants in the germline.

Based on targeted testing on more than 20 genes Rohanizadegan and her colleagues tracked down pathogenic or likely pathogenic variants in the germlines of 56 sarcoma patients. And more than half of the cases with a positive germline finding — 61 percent — were in individuals younger than 50 years old.

Some of the cancer risk variants turned up in genes that have been linked to sarcoma-related cancer predisposition syndromes such as Li-Fraumeni syndrome, hereditary retinoblastoma, neurofibromatosis type 1, or familial adenomatous polyposis. Even so, past research suggests that such forms of the disease are rare and are more closely linked to childhood sarcomas than to sarcomas that appear in adults.

In the newly analyzed adult sarcoma cohort, germline variants in TP53 were most common, followed by the SDHB/SDHC genes, BRCA2, and CHEK2, Rohanizadegan reported, though the team also saw pathogenic or likely pathogenic variants in genes such as ATM, BRCA1, MSH2, MLH1, or RAD51D.

Across the entire retrospective cohort, more than 80 percent of the individuals had sarcoma as their primary diagnosis, Rohanizadegan noted, while 4 percent of the patients had more than one sarcoma diagnoses and 41 percent had multiple primary cancers besides sarcoma. Some 13 percent of study participants had one or more family members with sarcoma.

"Our findings suggest that genetic predisposition has a larger role than expected of sarcoma cases, therefore genetic testing should be offered to patients with sporadic or familial sarcoma as well as cascade testing for their family members," Rohanizadegan and her coauthors explained in an abstract for the presentation.


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