SEATTLE (GenomeWeb) – A team led by researchers at Children's Hospital of Philadelphia is identifying more germline cancer susceptibility variants than anticipated in analyses of tumor sequences generated to find somatic mutations, according to research presented at the American College of Medical Genetics and Genomics annual meeting last week.
During a session on cancer genetics and therapeutics on Friday, CHOP's Suzanne MacFarland reported that she and her colleagues uncovered germline cancer susceptibility candidate variants in about 14 percent of the more than 1,200 pediatric patients assessed by tumor sequencing at CHOP over less than two years. Though not all of the risk variants were validated by subsequent germline testing, their results hinted that it may be particularly important to pay attention to potential germline variants in genes related to a patient's cancer type in tumor sequence data.
Between January 2016 and October 2018, the CHOP team assessed 1,425 tumor samples from 1,239 pediatric cancer patients using OncoMark Heme or OncoMark Solid panels as part of their somatic tumor sequencing program, MacFarland explained.
An estimated 79 percent of the patients got a clinical benefit from insights gained through somatic analyses of their tumor sequence data, she noted.
But the data also provided an opportunity to look for germline pathogenic or likely pathogenic variants in cancer susceptibility genes using sequence features such as variant allele frequency, small insertions or deletions, and larger deletions or duplications. That germline analysis also flagged known founder mutations and pathogenic glitches in genes previously implicated as causal in the tumor type at hand.
Across the pediatric cohort, the researchers unearthed 179 patients with 245 suspected germline variants between them. The patients most often carried pathogenic germline variants in Li-Fraumeni syndrome-related tumor suppressor gene TP53, MacFarland noted, though the researchers also saw apparent cancer-related variants in NF1, SMARCB1, MUTYH, and APC genes.
Nearly half of the variants referred for germline testing were found in genes linked to a patient's cancer type. And in a subset of 60 variants already sent for germline sequencing validation, MacFarland noted, 30 variants were confirmed as pathogenic or likely pathogenic germline changes. Again, tumor type appeared to be particularly informative, leading to more than 73 percent of those verified germline variants.
"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," MacFarland and her co-authors wrote in the abstract accompanying her ACMG presentation.
Although germline variants identified through tumor sequencing can add a layer of complexity to tumor sequencing analyses and to the information genetic counselors convey to cancer patients and their family members, such analyses can also uncover hereditary cancer risk factors that impact a patient's management as well as testing and screening recommendations for his or her family members.
In her presentation, for example, MacFarland shared details from two of the pediatric cases with germline mutations that were detected through tumor sequencing at CHOP. Those alterations — in TP53 and PTCH1, respectively — offered insights into current cancer risk and cancer histories for members of one family. Cascade testing is currently underway in the other family.
It remains to be seen how many of the germline risk candidates unearthed by tumor sequencing at that center hold up after confirmatory testing is done in additional cases. Even so, the frequency of possible germline variants that the CHOP team is finding in the pediatric cases is higher than anticipated from past studies.
A 2015 paper in the New England Journal of Medicine, for example, described germline variants in 8.5 percent of pediatric cancer cases. There, researchers from St. Jude Children's Research Hospital and elsewhere performed genome or exome sequencing on samples from 1,120 cancer patients under the age of 20, identifying pathogenic or likely pathogenic germline variants in 95 cases after specifically analyzing cancer predisposition and other genes in these sequences.
For another adult cancer study published in Cell last year, Washington University researchers Li Ding, Feng Chen, and their colleagues analyzed data for 10,389 adult patients with 33 cancer types assessed for the Cancer Genome Atlas project. Using a combination of tumor and matched normal sequence data, they unearthed cancer susceptibility germline variants in around 8 percent of cases.
Also, researchers at Nationwide Children's Hospital's Institute for Genomic Medicine have reportedly identified five children carrying germline cancer predisposition variants (and a child with a pathogenic variant in an ACMG59 gene not implicated in cancer) among 47 pediatric cancer patients enrolled and sequenced there between January 2018 and March 2019. That team has been working to consent parents for the return of validated germline risk variant information as they develop and validate a clinical pediatric cancer sequencing pipeline.