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Study Supports Clinical Utility of Gene Panel Sequencing Approach

NEW YORK (GenomeWeb News) – A new study suggests gene panels can pick up potentially pathogenic variants in hereditary, cancer-related genes in a clinical setting — in some cases leading to more aggressive screening and detection strategies.

Stanford University researchers reporting in the Journal of Clinical Oncology online last night took a crack at using a custom gene sequencing panel to test DNA from blood samples collected over a decade from almost 200 women previously tested for BRCA1 and BRCA2 gene mutations. The panel focused on BRCA1 and BRCA2, along with 40 other genes implicated in breast and other cancers and related risk conditions.

In addition to verifying known BRCA1 and BRCA2 in 57 women known to carry germline mutations in those breast and ovarian cancer risk genes, the team identified 16 potential risk mutations in other genes using the gene panel approach. Those included roughly two variants of unknown significance per person, on average.

But in some instances, the investigators unearthed mutations in the gene panel sequences that ultimately altered the care or follow-up screening that an individual received, including a genetic glitch in one patient that led to the detection and removal of a pre-cancerous colon polyp.

"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," senior author James Ford, director of Stanford University's Clinical Cancer Genetics Program, said in a statement. "It’s a focused approach that should allow us to capture the most relevant information."

Nevertheless, he and his co-authors explained, relatively little research has been done to test the clinical utility of the gene panel sequencing approach.

To that end, they set out to assess a custom 42-gene panel on blood samples from 198 women tested for BRCA1/BRCA2 mutations between 2002 and 2012 through Stanford's Clinical Cancer Genetics program who had given consent for other testing on their DNA. Of the participants, 174 had been diagnosed with breast cancer and 57 carried known germline glitches in their BRCA1 and/or BRCA2 genes.

After getting each participant's gene panel sequenced at the CLIA-approved InVitae lab in San Francisco using Illumina's MiSeq instrument, the group tapped the resulting sequence data to narrow in on an average of just over two variants of unknown significance per person.

All told, researchers found 57 of the 59 BRCA1 or BRCA2 mutations present in the participants. They also uncovered 16 potentially pathogenic variants in non-BRCA1/2 genes, including 15 variants with the potential to spur a rethink of patients' tests or treatment. For the 14 women carrying those potentially actionable pathogenic alterations, researchers returned these genetic findings to participants and their healthcare provider.

For instance, gene panel sequencing revealed a colon cancer risk mutation in one of the women that helped in finding and removing a pre-cancerous tubular adenoma. Several other women received recommendations for annual breast screening by MRI.

"Undoubtedly, multiple-gene sequencing raises many questions about results interpretation and patient counseling," Ford and co-authors concluded. "Our study demonstrates an early signal for the clinical relevance of multiple-gene sequencing and provides a strong rationale for future research to define its most effective use."