Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors

Abstract

The spectrum of germline predisposition in pediatric cancer continues to be realized. Here we report 751 patients with solid tumors who underwent prospective matched tumor–normal DNA sequencing with downstream clinical use (ClinicalTrials.gov NCT01775072). Germline pathogenic and likely pathogenic (P/LP) variants were reported. One or more P/LP variants were found in 18% (138/751) of individuals when including variants in low-, moderate- and high-penetrance dominant or recessive genes or in 13% (99/751) of individuals in moderate- and high-penetrance dominant genes. Thirty-four percent of high- or moderate-penetrance variants were unexpected based on the patient’s diagnosis and previous history. Seventy-six percent of patients with positive results completed a clinical genetics visit, and 21% had at least one relative undergo cascade testing as a result of this testing. Clinical actionability additionally included screening, risk reduction in relatives, reproductive use and targeted therapies. Germline testing should be considered for all children with cancer.