Study Finds Genetic Risk Variants in Half of Patients With Sarcoma


Key Points

  • Overall, 55% of sarcoma probands carried an excess of pathogenic variants.
  • Enrichment for pathogenic variants was observed in TP53, ATM, ATR, BRCA2, and ERCC2.

In an international genetic study (International Sarcoma Kindred Study) reported in The Lancet Oncology, Ballinger et al found that approximately half of all patients with sarcoma harbored potentially pathogenic monogenic and polygenic variation in known and novel cancer genes.

Study Details

The study included 1,162 patients with sarcoma aged ≥ 15 years from 4 cohorts. Targeted exon sequencing using blood (n = 1,114) or saliva (n = 48) was performed for 72 genes selected on the basis of association with increased cancer risk. A case-control rare variant burden analysis included 6,545 white controls from 3 cohorts. Rare variants were classified as known, expected, or predicted.

Excess of Pathogenic Variants

Median age at cancer diagnosis was 46 years in the sarcoma probands. Multiple primary cancers were found in 170 patients (15%), and 155 (17%) of 911 families with informative pedigrees fitted recognizable cancer syndromes. On case-control rare variant burden analysis, 638 (55%) of the probands exhibited an excess of pathogenic germline variants (combined odds ratio [OR] = 1.43, P < .0001); 227 known or expected pathogenic variants were identified in 217 probands. The presence of known, expected, or predicted pathogenic variants was associated with an earlier age of cancer onset.

Genes Affected

Significant enrichment for pathogenic variants was observed in TP53, ATM, and ATR (implicated in DNA-damage sensing and BRCA2 (implicated in homologous recombination) in probands vs controls. An unexpected excess of pathogenic variants was also observed in ERCC2 (implicated in DNA binding, DNA-damage sensing, helices activity, and basal transcription). Probands were significantly more likely than controls to have multiple pathogenic variants (OR = 2.21, P < .0001). The cumulative burden of multiple variants was significantly associated with earlier age at cancer diagnosis (P = .0032). Notifiable variants were identified in 66 (5.7%) of the probands, and variants with potentially actionable therapeutic significance were found in 293 (25%) of the probands.

The investigators concluded: “About half of patients with sarcoma have putatively pathogenic monogenic and polygenic variation in known and novel cancer genes, with implications for risk management and treatment.”

The study was funded by the Rainbows for Kate Foundation, Johanna Sewell Research Foundation, Australian National Health and Medical Research Council, Cancer Australia, Sarcoma UK, National Cancer Institute, and Liddy Shriver Sarcoma Initiative.

David M. Thomas, FRACP, of The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, Australia, is the corresponding author of The Lancet Oncology article.

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