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Pancreatic Cancer Risk Linked to Germline Mutations in Six Cancer Predisposition Genes

NEW YORK (GenomeWeb) – Researchers have linked inherited germline mutations in six cancer predisposition genes to pancreatic cancer risk.

A team led by the Mayo Clinic's Fergus Couch examined the coding regions of 21 cancer-predisposing genes like TP53, BRCA1, or ATM in more than 3,000 pancreatic cancer patients, to search for mutations. Epidemiological studies have suggested that between 10 percent and 20 percent of pancreatic cancers have an inherited aspect, he and his colleagues noted.

As they reported today in the Journal of the American Medical Association, they found that mutations in six of these genes were associated with pancreatic cancer risk and could be found in 5.5 percent of patients in their cohort, including in patients without a family history of disease.

"Given the high case-fatality rate for pancreatic cancer, testing for inherited cancer susceptibility may identify candidates for participation in innovative approaches to screening and prevention," Couch and his colleagues wrote.

Pancreatic cancer has an 8.5 percent five-year survival rate, according to the National Cancer Institute.

The researchers recruited 3,030 individuals with pancreatic ductal adenocarcinoma and collected blood samples from them for DNA analysis. Using a custom multiplex PCR panel, the researchers targeted the coding regions and consensus splice sites of 21 cancer predisposition genes in this cohort, and then sequenced these samples on an Illumina HiSeq 4000 to a median depth read of 200X.

The researchers also used exome data from 123,136 individuals housed in the Genome Aggregation Database (gnomAD) database and exome data from 53,105 individuals in the Exome Aggregation Consortium database for controls, excluding samples from The Cancer Genome Atlas.

Couch and his colleagues uncovered mutations in 19 of the 21 genes they targeted within their pancreatic cancer cohort, and overall, they found 253 deleterious germline mutations in these genes in 249 patients.

When compared to controls, six genes — CDKN2A, TP53, MLH1, BRCA2, ATM, and BRCA1 — were significantly associated with pancreatic cancer and the researchers designated them pancreatic cancer predisposition genes. Mutations in CDKN2A were linked to the highest risk of pancreatic disease, though the researchers noted that their frequency was low. ATM harbored the highest number of mutations. Within the cohort, 167 of the 3,030 patients (5.5 percent) harbored a deleterious mutation in one of the six pancreatic cancer predisposition genes.

Of the 343 patients in the cohort with a family history of pancreatic cancer, 27 had a mutation in one of the predisposing genes, while 140 of the 2,687 patients with no family history of pancreatic cancer had a mutation in one of the predisposing genes. This, the researchers noted, means that for 83.8 percent of mutations, family history was not informative.

They also found significant associations between mutations in these six genes and advanced stage of disease, personal history of other cancers, family history of breast cancer, and family history of common epithelial cancers. However, their specificity was too low to be used to select patients for clinical genetic testing.

Because the frequency of predisposing mutations was more than 5 percent and as there were no other effective predictors of mutations, Couch and his colleagues argued that genetic testing of all pancreatic cancer patients using panel tests could be justified.

In an accompanying editorial in JAMA, the Dana-Farber Cancer Institute's Sapna Syngal and Sloane Furniss agreed with the research team's suggestion.

"Given the devastating outcomes of pancreatic cancer, the real potential benefit for targeted therapies, and, even more importantly, the potential for cancer prevention in at-risk relatives, it is time to consider implementation of germline genetic testing for all patients with pancreatic cancer," they wrote.

Couch and his colleagues cautioned that their cohort largely consisted of individuals of European ancestry and thus may lack generalizability.