Genomic Analysis Finds Large Burden of Genetic Risk in Sarcoma Patients


A comprehensive genomic analysis of more than a thousand sarcoma patients found that about half had putatively pathogenic variations in either known or novel cancer genes.

A comprehensive genomic analysis of more than a thousand sarcoma patients found that about half had putatively pathogenic variations in either known or novel cancer genes. Among the most common variations were those seen in TP53, ATM, ATR, BRCA2, and ERCC2.

“Several lines of evidence suggest a strong genetic basis to sarcomas,” wrote study authors led by David M. Thomas, MD, PhD, of the Kinghorn Cancer Centre in Darlinghurst, Australia. Sarcomas disproportionately affect younger people, and early age of diagnosis is associated with a genetic basis for disease; also, sarcoma survivors are at increased risk of second cancers, and several rare genetic syndromes such as Li-Fraumeni syndrome are linked to sarcoma.

The new study aimed to elucidate the specific genetic underpinnings of bone and soft-tissue sarcoma, using samples from 1,162 sarcoma patients in four different cohorts. These were compared with 6,545 control subjects from three different cohorts. The results were published online ahead of print in Lancet Oncology.

The median age at sarcoma diagnosis was 46 years, and 15% of patients had multiple primary cancers. A total of 638 patients (55%) had a total of 956 rare genetic variants; 122 individuals had 127 variants known to be disease causing. Those carrying a variant had a younger age at diagnosis than those without any variant (43 years vs 50 years; P = .0010). Those carrying more dangerous variants had even younger age at diagnosis.

Compared to the control cohort, patients with sarcoma had an odds ratio for having any class 3, 4, or 5 variant (roughly similar to the International Agency for Research on Cancer’s classification of genetic variation) of 1.43 (95% CI, 1.24–1.64; P < .0001).

The researchers found that variants in TP53, as well as in genes implicated in DNA damage sensing such as ATM and ATR, were often present in sarcoma patients. BRCA2 variants were also more common in patients compared with controls, as were variants in ERCC2, which can affect DNA binding, damage sensing, and other processes. A total of 240 patients carried multiple variants, “suggesting a polygenic contribution to sarcoma risk,” according to the authors.

“A substantial fraction of the cohort carried variants that could affect risk counseling, management, or drug therapy,” the authors wrote. “The frequency of potentially actionable monogenic and polygenic germline variants in patients affected by sarcoma warrants attention as personalized medicine evolves, with particular relevance to other young-onset cancers.”

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