Sequencing Finds Germline Risk Variants in Pediatric Cancer Cases

Somatic panel sequencing is increasingly used in pediatric oncology to aid in cancer diagnosis, risk classification, identification of targetable biomarkers, and treatment planning. As tumor tissues contain both somatic and germline variants, tumor profiling can uncover potential germline changes incidentally.

An analysis of thousands of variants detected in a large pediatric cancer cohort through tumor sequencing can identify potential pathogenic germline variants that may have predisposed the individuals to cancer and to evaluate factors that affect germline variant prediction has been reported.


A team of scientists at the Children's Hospital of Philadelphia (Philadelphia, PA, USA) analyzed data from 1,425 tumors in 1,239 individuals for potential cancer-predisposing germline variants over the period of January 2016 to October 2018. The team used the somatic sequencing panels CHOP OncoMark Heme and OncoMark Solid. Variants were considered potentially germline if they met one of the following criteria: 1) pathogenic/likely pathogenic variants in genes known to be associated with cancer predisposition with variant allele frequency (VAF) between 0.4-1.0; 2) large indels or gross deletions/duplications affecting capture of potential germline variants, regardless of VAF; 3) known founder mutations, regardless of VAF; and/or 4) pathogenic variants in a gene that could be causal for the patient’s tumor type, regardless of VAF.

The scientists reported that a total of 245 variants identified in 179 individuals were concerning presence in the germline, which accounted for a total of 14% of the patients evaluated with somatic testing. The gene in which variants concerning for germline origin was most commonly identified was TP53, followed by NF1, SMARCB1, MUTYH, and APC. Of the 60 variants that underwent confirmatory germline sequencing at the time of the report, 30 (50%) of them were confirmed to be germline. Of variants confirmed to be germline, 73.3% were referred due to patient’s tumor type regardless of VAF, three-fold higher than those due to VAF alone (23.3%). However, 76.7% of the confirmed germline variants have VAF >0.4, compared to 53.3% of non-germline variants. There is no significant difference regarding the rates of loss of heterozygosity between the two groups (53.3% versus 40.0%).

The authors concluded that the frequency of potential germline variants incidentally uncovered during somatic tumor sequencing was higher than expected based on other large sequencing studies. Half of the variants undergoing confirmatory testing were confirmed in the germline. Identification of these variants is crucial for the appropriate clinical management of these patients as well as at-risk family members.

Suzanne P. MacFarland, MD, an Oncologist and lead author of the study, said, “Patient tumor type appeared to be the best predictor of an underlying germline variant, and variant allele frequency and loss of heterozygosity were less sensitive but still helpful in identifying patients with potential cancer predisposition.” The study was presented at the American College of Medical Genetics and Genomics annual meeting held April 2-6, 2019, in Seattle, WA, USA.

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Children's Hospital of Philadelphia