Adding more genes to existing multi-gene panels that test for breast and ovarian cancer risk offers little clinical benefit, a study says.
The findings may serve as a note of caution against the trend to add ever more mutations of unknown significance to multi-gene sequencing tests.
'Adding on the additional cancer susceptibility genes to [specifically] breast-cancer susceptibility genes opened up more questions than it answered,' said Professor Katherine Nathanson of the University of Pennsylvania's Abramson Cancer Center. 'This study demonstrates little incremental utility to testing non-breast cancer susceptibility genes in breast cancer families.'
The study, which was published in the American Journal of Human Genetics, evaluated the clinical benefit of including genes with ill-defined links to breast or ovarian cancer risk in gene-sequencing tests.
Whole-exome sequencing was performed on 404 individuals from 253 families at high risk of breast or ovarian cancer. They examined a panel of 180 medically relevant cancer and non-cancer associated genes – including 25 genes linked to breast and ovarian cancer, 123 genes linked to other cancers, and 32 genes linked to cardiovascular disease.
They found over 1600 genetic variants – of these, 11 percent of patients who did not have BRCA1 or BRCA2 mutations had clinically relevant mutations in other cancer-risk genes that were already linked to a moderately increased risk of breast and ovarian cancer. Only two families had mutations in cancer-risk genes that had not been linked to breast cancer.
In addition to variants known to be clinically relevant, the panel also included variants of unknown significance (VUS). Adding these variants offered little useful information – 12 percent of participants had VUSs in known breast-cancer genes, but when other cancer-risk genes were added this jumped to 78 percent with VUSs. When all 180 disease-risk genes were added together, 95 percent of individuals had at least one VUS, and 30 percent had five or more.
'These findings add layers of complexity in counselling for cancer risk,' said the study's first author Dr Kara Maxwell, also at the University of Pennsylvania. 'A patient would now be expected to understand not only that a genetic finding could be found that may or may not be related to the cancer in their family, but that genetic variants could be found that may or may not put themselves and their family members at risk for a disease they weren't even thinking about at the time.'
Sources and References
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Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer
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Testing Non-Breast/Ovarian Cancer Genes in High-Risk Women Leaves More Questions than Answers, Penn Study Finds
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Families at Risk for Breast Cancer Gain Little Benefit, More Uncertainty From Expanded Gene Panel
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