Multiple-Gene Sequencing Shows Clinical Relevance in Cancer-Risk Assessment

Study findings point to the clinical benefits of a multiple-gene sequencing panel for assessing cancer risk in appropriately selected groups of patients

medwireNews: Researchers have shown that screening for multiple pathogenic mutations using a customised germline-DNA sequencing panel has clinical relevance in women referred for evaluation of hereditary breast and ovarian cancer.

The screening revealed 15 pathogenic variants in 10.6% of women without BRCA1 or BRCA2 mutations that warranted more intensive screening or prevention.

“This is a significant yield of potentially actionable results, comparable to the 5% to 10% probability threshold endorsed by guidelines and payers for BRCA1/2 and Lynch syndrome testing”, note the researchers, led by James Ford, from Stanford University School of Medicine in California, USA.

The 198 participants, 174 of whom had breast cancer, were referred for clinical BRCA1/2 testing from 2002 to 2012, at which time they also donated blood samples for research purposes.

Testing of DNA extracted from these blood samples using a sequencing panel of 42 cancer-associated genes confirmed 57 of the women were carrying germline BRCA1/2 mutations. But it also identified 16 pathogenic variants (in ATM, BLM, CDH1, CDKN2A, MUTYH, MLH1, NBN, PRSS1 and SLX4) in 11.4% of women without BRCA1/2 mutations. Fifteen of these mutations were deemed “potentially actionable”.

gene panels offer a middle ground between sequencing just a single gene like BRCA1 that we are certain is involved in disease risk, and sequencing every gene in the genome. It’s a focused approach that should allow us to capture the most relevant information”, James Ford commented in a press release.

The researchers were able to contact 11 of the 14 women carrying the 15 mutations warranting attention who, in consultation with a genetic counsellor and an oncologist, were advised on further preventative options.

Six women (carrying ATM, BLM, CDH1, NBN and SLX4 variants) were advised to undergo annual breast magnetic resonance imaging because of an estimated doubling of breast cancer risk, while six (carrying CDH1, MLH1 and MUTYH variants) were advised to consider frequent colonoscopy and/or endoscopic gastroduodenoscopy due to an increased risk of gastrointestinal cancer.

One woman, who had triple-negative breast cancer at 35 years of age and a hysterectomy for endometrial cancer at 46 years of age, was found to be carrying a frameshift MLH1 mutation consistent with Lynch syndrome. She underwent risk-reducing salpingo-oophorectomy and early colonoscopy, which identified a tubular adenoma that was then removed.

The researchers note that this woman would have been offered Lynch syndrome screening according to current practice guidelines because she had early endometrial cancer, but at the time she was assessed this was not routine practice.

Testing also identified that each woman carried an average of 2.1 variants of uncertain significance, but due to a lack of practical implications these were not followed up.

“These findings provide an early signal for the clinical relevance of multiple-gene sequencing in cancer-risk assessment”, say the researchers in the Journal of Clinical Oncology.


Kurian A, Hare E, Mills M, et al. Clinical Evaluation of a Multiple-Gene Sequencing Panel for Hereditary Cancer Risk Assessment. J Clin Oncol 2014; Advance online publication 14 April. doi: 10.1200/JCO.2013.53.6607

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