SARCOMA GENETICS

More than 50% of patients with sarcoma may carry single or multiple genetic variants that contribute to the development of their cancers, and about 25% of these patients may carry mutations that could influence treatment choice.

The findings come from the first study to quantify rare genetic variation that may contribute to the development of sarcomas. It was published online August 4 in The Lancet Oncology.

"In this genetic analysis of individuals with sarcoma, and consistent with recent studies, we observed a large, clinically significant, and under-recognised burden of genetic risk. The excess risk lies in both classic monogenic and previously unrecognised polygenic rare variation," write first author Mandy L. Ballinger, PhD, from the Garvan Institute of Medical Research (Darlinghurst, New South Wales, Australia), and colleagues with the International Sarcoma Kindred Study.

This study is "one of the most important studies on sarcomas in recent years." write Robert S. Benjamin, MD, and Andrew Futreal, PhD, from the University of Texas MD Anderson Cancer Centre, Houston, in a linked editorial.

The editorialists say the most "notable" finding is the high prevalence of genetic variants. Another noteworthy finding: the identification of multiple genes which could explain why some patients clinically appear to have Li-Fraumeni syndrome but do not carry TP53 mutations.

The study suggests that "genetic abnormalities, heretofore not considered reportable, may still have major clinical implications," they write.

"[O]ffering germline testing for all patients with sarcomas might be warranted, especially in the context of a comprehensive assessment of family history," they conclude. "Although precisely how these new genetic findings could lead to improved therapeutic outcomes is not yet clear, improved understanding of the complex interactions caused by multiple genetic abnormalities could help to identify new therapeutic targets."

Diverse Group of Cancers 

Previous research has suggested that genes may play a role in the development of sarcomas, they write. This diverse group of cancers often has an early age of onset, which is typical of heritable disorders. Though rare, they disproportionately affect young people: About 20% of childhood cancers and 10% of adolescent and young adult cancers are sarcomas. Survivors of sarcoma are at increased risk for secondary cancers, and survivors of other types of cancers (such as melanoma and leukemia) have an increased risk for sarcoma.

However, the genetics of sarcomas remain obscure outside of rare syndromes such as Li-Fraumeni syndrome, which is linked to mutations in the TP53 gene and increased risk for several other cancers. Most cases of sarcoma are sporadic, though, with unknown cause, the authors write.

The study included 1162 patients with sarcoma (73% white; mean age at cancer diagnosis, 46 years), who were part of four other studies: the International Sarcoma Kindred Study (n = 966), Project GENESIS (n = 48), Asan Bio-Resource Center (n = 138), and kConFab (n = 10). Participants were at least 15 years old and had histologically confirmed sarcoma.

To identify rare genetic variants, researchers performed targeted exon sequencing of 72 genes associated with increased cancer risk. Next, they classified rare variants according to their risk for disease. Finally, they looked at the disease burden of these variants by doing a case-control analysis using 6545 white controls without cancer. Researchers also evaluated families' cancer history.

Results showed that 1 in 6 patients belonged to families that fit criteria for hereditary cancer syndromes, though most had gone unrecognized. One in 10 patients belonged to families that had increased cancer burden without fitting into known cancer syndromes.

Over half of patients (n = 638 [55%]) carried germline genetic variants that appeared capable of causing disease (combined odds ratio, 1.43; 95% confidence interval, 1.24 - 1.64; P < .0001). One in 5 had known or expected pathogenic variants.

All pathogenic variants were linked to earlier age of cancer onset.

A pooled analysis of all patients with sarcoma revealed that 240 carried multiple variants, suggesting that multiple genes may contribution to sarcoma risk.

The analysis also showed an excess of variants in TP53 (as expected), as well as new, unexpected genes: BRCA2, ATM, ATR, and ERCC2.

Mutations in TP53, ATM, and ATR are linked to ionizing radiation, the strongest environmental risk factor for sarcoma. ATM and ATR are implicated in sensing DNA damage. BRCA2 mutations are involved in homologous recombination and have also been reported in Li-Fraumeni syndrome, according to the authors.

They added that ERCC2 may be a new sarcoma susceptibility gene. ERCC2 is involved in nucleotide excision repair and linked to the autosomal recessive syndrome xeroderma pigmentosium type D, which increases the risk for some cancers. Mutations in ERCC2 may enhance sensitivity to cisplatin, which is often used to treat osteosarcomas.

One in 15 patients had germline variants considered to be clinically significant, about which patients should be notified. Twenty-five percent of patients had mutations that can affect response to available therapies, or to therapies currently being developed.

The authors concluded: "This study represents an important first step in mapping the heritability of sarcoma in human beings…. Sarcoma families found to be carrying high-risk genetic variants might benefit from surveillance and prevention strategies."

The study was funded by Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, the National Cancer Institute, and the Liddy Shriver Sarcoma Initiative. Dr Ballinger and coauthors have disclosed no relevant financial relationships; coauthor Dr Mitchell reports advisory board membership for AstraZeneca for ovarian cancer research. Editorialists Dr Benjamin and Dr Futreal have disclosed no relevant financial relationships.