Individuals suspected of being at increased risk for breast or ovarian cancer gain little clinically actionable information from an analysis of a large panel of medically relevant genes, while the interpretation of the test results becomes far more complex, according to a study appearing online today in theAmerican Journal of Human Genetics.
Researchers from the University of Pennsylvania, the Mayo Clinic at Rochester, and elsewhere sequenced the exomes of hundreds of individuals from more than 250 breast or ovarian cancer-affected families, focusing their analysis on 180 genes with previously described medical relevance. While their data uncovered pathogenic or likely pathogenic mutations in a dozen breast cancer susceptibility genes, it also yielded potentially pathogenic mutations in non-cancer related genes as well as a slew of variants of unknown significance.
“Adding on the additional cancer susceptibility genes to the ‘breast cancer susceptibility’ genes opened up more questions than it answered,” co-senior author Katherine Nathanson, associate director of the University of Pennsylvania’s Abramson Cancer Center and a researcher with the UPenn Division of Translational Medicine and Genetics, said in a statement. “This study therefore adds to prior findings of ours, and demonstrates little incremental utility to testing non-breast cancer susceptibility genes in breast cancer families.”
For their study, which was conducted through the Simplifying Complex Exomes (SIMPLEXO) consortium, the researchers used Illumina HiSeq 2000 or 2500 instruments to sequence protein-coding regions in the genomes of 404 individuals from 253 cancer-affected families.
Their analyses centered on 180 genes that were selected for their medical relevance, including cancer susceptibility genes described in several past studies and non-cancer disease risk genes included in the American College of Medical Genetics and Genomics (ACMG) list of genes for which incidental findings are reportable.
The team not only searched for disease-related alterations in these genes but also evaluated the ACMG’s guidelines for classifying variants. Based on the high concordance of variant calls with locus-specific databases and ClinVar, they concluded that the guidelines have good clinical utility.
From the 1,640 genetic variants detected in 167 of the genes, the researchers identified pathogenic or likely pathogenic variants in 12 cancer susceptibility genes, affecting individuals from 26 families — roughly 11 percent of individuals who did not carry cancer-related BRCA1 or BRCA2 mutations.
Two more families had pathogenic or likely pathogenic mutations in the autosomal-dominant cancer susceptibility genes ATR or MSH6, the researchers reported, while individuals from 23 families had mutations affecting one copy of an autosomal recessive cancer-related gene. Individuals from 10 families carried worrisome mutations in 32 genes linked to non-cancer-related diseases.
In addition, the team uncovered one or more variant of unknown significance in 95 percent of the individuals tested, with 13 percent of individuals carrying at least six VUS. A subset of those variants — around 12 percent — fell in well-known breast cancer susceptibility genes.
So while incidental findings in the families were relatively modest, the large proportion of variants of unknown significance “add layers of complexity in counseling for cancer risk,” according to the study’s first author Kara Maxwell, a hematology and oncology researcher at the University of Pennsylvania’s Perelman School of Medicine.
“Our data do not support the use of medical exome or whole-exome sequencing for evaluation of cancer susceptibility in individuals at high risk for breast and/or ovarian cancer at this time; the incremental benefit of potential mutation identification would be outweighed by the identification of multiple VUSs,” the researchers concluded in their study.
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