Clinical Germline Testing Evaluated for Pediatric Cancer Patients

Pediatric cancer is rare, with fewer than 10,000 solid tumors diagnosed in children annually in the USA. Previous studies interrogating germline predisposition broadly across pediatric cancer types have found heritable germline predisposition in 8%–12% of patients.

The yield of germline predisposition detected is dependent on the genes included for analysis and variant interpretation as well as the ascertainment biases found in each cohort. Iterative data are required to expand upon the understanding of susceptibility to pediatric cancer and determine the extent to which germline data may translate into clinical practice.


Pediatricians and their colleagues at Memorial Sloan Kettering Cancer Center (New York, NY, USA) conducted matched tumor-normal DNA sequencing on 751 pediatric cancer patients treated at the center from July 2015 to July 2020. Tumor and blood samples were obtained and sequenced using the MSK-IMPACT platform, a capture-based NGS assay capable of identifying sequence mutations, copy number alterations and select gene fusions in 468 genes. Germline data were analyzed in 88 genes and germline pathogenic and likely pathogenic (P/LP) variants were reported. The study covered several different cancer types, including sarcoma, neuroblastoma, central nervous system (CNS) tumors, retinoblastoma, and other rare solid tumors.

The team reported that one or more P/LP variants were found in 138/751 (18%) of individuals when including variants in low-, moderate- and high-penetrance dominant or recessive genes or in 99/751 (13%) of individuals in moderate- and high-penetrance dominant genes. The found 34% of high- or moderate-penetrance variants were unexpected based on the patient’s diagnosis and previous history and 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.

Germline variants were found in 49% of patients with retinoblastoma, 21% of patients with CNS tumors, 15% of patients with neuroblastoma, 12% of patients with sarcoma, and 19% of patients with other tumor types. The most common mutations in high- or moderate-penetrance genes were in RB1 (found in 4% of patients), NF1 (1%) and TP53 (1%) in patients with retinoblastoma and those with a prior clinical diagnoses of neurofibromatosis type 1 (NF1) - or Li Fraumeni syndrome (LFS)-associated tumors.

About 3% of patients had variants in DNA damage repair genes, 1.6 % had mutations in the RAS–MEK or mTOR–PTEN pathway, and 1% had variants in metabolic pathways related to cancer. Among genetic diseases that were not identified by MSK-IMPACT in this study was the growth disorder Beckwith–Wiedemann syndrome, identified in four patients. The authors suggested combining multiple tests in such cases, like next-generation sequencing (NGS) and RNA sequencing, to detect all types of genetic variants.

The authors noted that potential cost savings exist through cancer screening and early detection, prevention, pre-implantation genetic testing, and potentially more effective therapeutics; however, there are also significant costs associated with each of these in addition to the costs of sequencing and clinical genetics visits. The study was published on February 15, 2021 in the journal Nature Cancer.

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Memorial Sloan Kettering Cancer Center