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 solid tumor patients who underwent prospective matched tumor-normal DNA sequencing and 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 13% (99/751) in moderate and high penetrance dominant genes. 34% of high or moderate penetrance variants were unexpected based on the patient's diagnosis and previous history. 76% 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 use of targeted therapies. Germline testing should be considered for all children with cancer.

Figure 1.

(A) Cancer types represented in the current study (blue) compared to the Annual International Childhood Cancer Classification (AICCC) distribution (red). Current study data is based on n=751 patients and shown with 95% confidence intervals. US census data (https://www.census.gov/quickfacts/fact/table/US/PST0452190) was used with AICCC data to calculate population percentages. (B) Germline P/LP variants and biallelic inactivation across 138 patients in the cohort. Bottom, the heat map shows the occurrence of germline P/LP variants across genes and cancer types. The color indicates the proportion of patients with a particular cancer type and germline alteration, and the number on the tiles indicate the absolute count. The total number of patients in the cohort for each of the cancer types is displayed on the left. Top, the absolute count of patients with biallelic inactivation in the genes shown on the x-axis. Biallelic inactivation includes loss of heterozygosity and second somatic hits. Patients for whom the allele status in tumor could not be assessed due to insufficient tumor purity, unavailability of sufficient tumor tissue, or low sequencing coverage in the tumor are indicated as indeterminate for biallelic inactivation.

Figure 2:

(A) Universal germline sequencing in 751 patients undergoing tumor-normal sequencing using MSK-IMPACT with tumor status of alternate allele if available, screening recommendations when indicated, cascade testing in relatives and examples of clinical translation. One family reported back undergoing IVF/PGT which resulted in a pregnancy and birth of a child unaffected with LFS. While using germline results in this manner was counseled on by the Clinical Genetics team, the number of families using this information for reproductive purposes was not systematically followed. Examples of clinical use of germline results. (B) A proband with embryonal rhabdomyosarcoma was detected to have a germline TP53 mutation which was subsequently found in her father through cascade testing. He was found through screening to have thyroid cancer and a meningioma. (C) A proband with a teratoma was found to have a germline PMS2 mutation and was started on immunotherapy. Cascade testing has not been performed in this family.