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Hereditary Cancer Panel Study Suggests Germline Mutations Missed in Some Pancreatic Cancers

CHICAGO (GenomeWeb) – Early results from a prospective study by investigators at Ambry Genetics, Beth Israel Deaconess Medical Center, the University of Pittsburgh, and HonorHealth/TGen suggest that the suite of genes that carry risky mutations in some pancreatic cancer patients may be broader than generally appreciated.

At the American Society of Clinical Oncology annual meeting this week, Beth Israel Deaconess Medical Center's Mary Linton Bounetheau Peters presented findings for the first 239 individuals with pancreatic ductal adenocarcinoma (PDAC) who were evaluated for the study. The team ultimately plans to search for cancer-related germline mutations in 300 unselected individuals with PDAC diagnoses and wrapped up enrollment for the study.

In an effort to uncover new germline risk variants associated with PDAC, researchers are using Ambry's CancerNext hereditary cancer gene sequencing panel to profile 32 genes previously implicated in pancreatic cancer and/or other cancer types in the PDAC patients using DNA extracted from blood or saliva samples. The resulting gene panel profiles are then considered alongside multi-generation pedigrees for the affected individuals, Peters explained.

"From a clinical standpoint, it's helpful because we don't know what we don't know about pancreatic cancer and genetics," she said. "So much of the work done to date has been retrospective and looking at people who have known genetic cancer syndromes."

During a session on cancer prevention, hereditary genetics, and epidemiology yesterday, Peters reported that the team has uncovered suspicious germline mutations in just over 11 percent of the initial group of 239 individuals with PDAC diagnoses. Another 26 percent of participants had variants of unknown significance, while 63 percent had no discernable mutations in the targeted genes.

Along with mutations in documented PDAC risk genes such as ATM, BRCA1, BRCA2, STK11, and CDKN2A, the data suggests more than 4 percent of the PDAC patients have germline mutations in BARD1, NF1, RAD50, and CHEK2 — genes that are not currently included in Ambry's hereditary cancer gene panel test for pancreatic cancer, PancNext. The pathogenic or likely pathogenic CHEK2 mutations turned up in nine of the PDAC patients so far.

Though a significant portion of the PDAC patients met hereditary cancer testing criteria set forth by the American College of Gastroenterology and National Comprehensive Cancer Network, Peters reported, the researchers identified six individuals with pathogenic mutations in cancer-related genes that did not.

"Existing testing criteria did not identify 30 percent of carriers," she and her co-authors wrote in the abstract accompanying the ASCO presentation. "Continued refinement of guidelines is necessary to align genetic testing with inherited PDAC risk."

The investigators are gearing up to test the remaining samples over the coming months. They are also investigating the newly discovered mutations, particularly those affecting CHEK2, to see if they are pathologic.

Those involved in the study hope the results will raise awareness about the subset of pancreatic cancer patients who have inherited risk variants, explained Ambry's clinical collaboration manager Virginia Speare, though she acknowledged that questions remain about how to manage these cases and when to offer germline testing in pancreatic cancer patients.

Past studies of pancreatic cancer suggest most cases arise spontaneously, she noted, and the condition has been linked to certain lifestyle features or exposures such as smoking. Still, the latest study supports the notion that a portion of pancreatic cancers involve the same sorts of germline alterations that would prompt enhanced screening if found in individuals with breast or ovarian cancer, for example.

That, in turn, raises questions about the best health management options for PDAC patients with pathogenic germline mutations in cancer risk genes, particularly since many different organ types may be affected.

When it comes to screening for tumors in the pancreas itself, the problem becomes even murkier: despite studies evaluating pancreatic cancer screening such as endoscopic ultrasound or magnetic resonance imaging, Peters explained, researchers and clinicians "haven't hit consensus yet" on what to do with individuals believed to be at high risk of pancreatic and/or other cancer types based on hereditary cancer test results.

Due to that lack of agreement over screening options and effectiveness, coupled with some lack of awareness about the possibility that pancreatic cancer patients carry risky germline mutations, hereditary cancer gene testing is still used inconsistently in individuals diagnosed with the disease.

"We're struggling a little bit to identify who we should be referring for genetic testing, and the use of genetic testing is much lower [than in breast or gynecological cancer]," Peters said.

Such issues are amplified as efforts in the clinic and research settings continue to unravel potential germline contributions to pancreatic and other cancers. For a study published in Nature in February, for example, an international team led by investigators in the UK, Australia, and Italy used whole-genome sequencing to unearth apparent germline mutations in BRCA2, CHEK2, and other genes in individuals with pancreatic neuroendocrine tumors as well — including changes described in individuals with inherited risk of gastric, colon, and/or other cancer types.

More broadly, analyses on samples from efforts such as the Cancer Genome Atlas Project have highlighted — and started to tally up — the contribution that germline mutations make to the risk of many different cancer types. Genetic testing company GeneDx also reported in 2015 on the prevalence of pathogenic or likely pathogenic germline variants identified when its hereditary cancer gene panel was used to test 10,000 patients referred to the company's testing lab, demonstrating that worrisome mutations in the germline may occur in a significant subset of individuals with cancer.