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Reporting Germline Variants in Cancer Panels Could Provide Useful Info, but With Added Challenges

NEW YORK (GenomeWeb) – Cancer patients who undergo sequencing of their tumor genome may also benefit from an analysis of their germline DNA, although such analysis will also uncover clinically relevant findings not related to the patients' cancers and many variants of uncertain significance, according to researchers from Memorial Sloan Kettering Cancer Center.

The researchers analyzed 1,566 late-stage cancer patients using their clinically validated 341-gene cancer panel, which helps guide patients into clinical trials. Along with the standard tumor DNA analysis, the researchers also looked at germline variants in 187 genes in the panel that are related to Mendelian disease.

Reporting today in JAMA Oncology, the researchers found that nearly 16 percent, or 246 patients, had presumed pathogenic germline variants.

Of those patients, 198 individuals had mutations in genes associated with cancer susceptibility, however only 81 of those patients' cancer susceptibility mutations were concordant with their cancer.

The study demonstrates the potential utility of doing matched normal analysis with tumor sequencing, as 59 percent of patients with a potentially pathogenic variant in a cancer susceptibility gene had a cancer not known to be associated with that gene. "Finding unexpected mutations creates an opportunity to institute beneficial preventive measures for the patient's family, and possibly to use specific targeted treatments (such as PARP inhibitors) for the patient," the authors wrote.

Patients with advanced cancer at MSKCC are offered mutation profiling via a custom-designed panel called MSK-IMPACT, which analyzes 341 genes. The patients in the study underwent tumor profiling between March 2014 and October 2014. Anonymized germline sequencing was offered under an IRB-approved waiver.

In June, MSKCC researchers began reporting back germline variants and assessing MSK-IMPACT's clinical utility.

In the JAMA Oncology study, the researchers considered variants to 187 genes that overlapped with their panel and known Mendelian disease. Included in those 187 were 26 of the 56 genes in which the American College of Medical Genetics and Genomics advises clinical labs report variants. They found pathogenic or likely pathogenic variants in 246 out of 1,566 patients.

The majority of variants were SNVs or small indels, although there were 10 larger duplication or deletion events.

Patients had an average of six variants of unknown significance in a disease-associated gene, and every patient except one had at least one VUS.

Not surprisingly, genes associated with inherited cancer were the most commonly mutated in patients' germline DNA, with 12.6 percent of patients harboring one. Variants to BRCA2, CHEK2, MUTYH, and BRCA1 were the most common, and the germline mutations to these cancer genes were typically also found in patients' tumor DNA.

Interestingly, 55 patients harbored mutations in 18 genes associated with a Mendelian disease other than cancer. At the time of the study, only cancer-related data could be reported back to the patients, but the researchers acknowledged that going forward clinical labs would have to take into consideration how to appropriately do post-test counseling for Mendelian disease findings that may shed light on existing conditions and provide genetic information relevant for the patient's family.

Variants indicating carrier status for an autosomal recessive disorder were found in 125 individuals and variants for autosomal dominant disease were found in 192 individuals.

Looking specifically at the 26 genes that overlap with the ACMG recommended list, the researchers found that 101 individuals had at least one mutation in one of those genes.

"The significant prevalence of such unexpected germline mutations suggests that cancer susceptibility due to rare variation may be more common than previously believed," the authors wrote.

While including germline analysis in cancer panel tests has advantages in that it could help identify additional therapeutic information, it also adds an extra level of consideration that clinical centers will have to take into account, the authors wrote.

For instance, "it will not be uncommon to detect unexpected actionable variants," the authors wrote. "Even restricting reporting to the ACMG-endorsed gene set would identify potentially actionable mutations in at least 5 percent of our patients."

Patients will have to be informed about the possibility of uncovering "inherited susceptibility or previously undiagnosed genetic disease," they wrote, and medical centers will need to "develop appropriate post-test result communication protocols, as patients currently undergoing tumor mutation profiling may be difficult to engage in traditional post-test genetic counseling owing to their advanced disease."

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