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Six gene mutations linked to pancreatic cancer

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June 19, 2018

Fergus J. Couch

Researchers identified mutations in six genes associated with pancreatic cancer, according to study results published in JAMA.

“Cancer predisposition gene testing is useful for identifying individuals who may benefit from screening, prevention and early detection of breast, ovarian and colorectal cancer and may be beneficial for individuals at risk [for] pancreatic cancer,” Fergus J. Couch, PhD, consultant in the division of experimental pathology and laboratory medicine at Mayo Clinic in Rochester, Minnesota, and colleagues wrote. “Family members of those with germline predisposition gene mutations may also benefit from enhanced cancer screening and prevention strategies.”

The researchers performed a case-control analysis to identify genes associated with pancreatic cancer, and they conducted a longitudinal analysis of patients who had pancreatic cancer to determine prognosis.

A total of 3,030 adults with pancreatic cancer enrolled in the study at Mayo Clinic from Oct. 12, 2000, and March 31, 2016. Follow-up continued through June 22, 2017. The control cohort included 123,136 individuals who had exome sequence data from the Genome Aggregation Database, and 53,105 individuals from the Exome Aggregation Consortium Database.

When Couch and colleagues compared 3,030 patients with pancreatic cancer to controls, mutations in six genes appeared significantly associated with pancreatic cancer: CDKN2A (0.3% of cases vs. 0.2% of controls; OR = 12.33; 95% CI, 5.43-25.61), TP53 (0.2% vs. 0.02%; OR = 6.7, 95% CI, 2.52-14.95), MLH1 (0.13% vs. 0.02%; OR = 6.66; 95% CI, 1.94-17.53), BRCA2 (1.9% vs. 0.3%; OR = 6.2; 95% CI, 4.62-8.17); ATM (2.3% vs. 0.37%; OR = 5.71; 95% CI, 4.38-7.33) and BRCA1 (0.6% vs. 0.2%; OR = 2.58; 95% CI, 1.54-4.05).

Researchers observed a mutation in one of the six predisposition genes among 27 of 343 patients (7.9%; 95% CI, 5.3%-11.2%) with a family history of pancreatic cancer and 140 of 2,687 patients (5.2%; 95% CI, 4.4%-6.1%) with no family history, indicating family history of pancreatic cancer did not indicate the presence of 83.8% of mutations.

Also, 40 of 495 patients (8.1%; 95% CI, 5.8%-10.8%) with another prior primary cancer diagnosis harbored a mutation.

Researchers observed significant associations between mutations in the six predisposition genes and advanced stage of disease (P = .04), personal history of other cancers (OR = 1.67; 95% CI, 1.17-2.48), family history of breast cancer (OR = 1.58; 95% CI, 1.11-2.23) and family history of common epithelial cancers (OR = 1.4; 95% CI, 1.01-1.92).

Also, patients with a mutation in these one of these genes were diagnosed at a younger age (62.5 years vs. 65.5 years, P < .001), especially with a BRCA2 mutation alone (mean age, 60.5 years vs. 63.3 years; P = .01).

Median OS for patients with mutation in the six genes was 13.6 months, compared with 11.4 months among those without mutations, which did not represent a significant difference (HR = 0.86; 95% CI, 0.72-1.02).

These findings suggest it is appropriate to consider screening for inherited susceptibility for cases of pancreatic cancer, Sapna Syngal, MD, MPH, professor of medicine at Harvard Medical School, and C. Sloane Furniss, PhD, research scientist at Dana-Farber Cancer Institute, wrote in an accompanying editorial.

“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. “Because the window of opportunity is limited, discussion about genetic testing needs to happen at or shortly after diagnosis as part of the standard management of newly diagnosed pancreatic ductal adenocarcinoma.” – by Andy Polhamus

Disclosures: Couch reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures. Syngal reports personal fees from Myriad Genetics Inc. Furniss reports no relevant financial disclosures.

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Perspective

In this case-control study, Hu and colleagues report the germline analysis of 21 cancer predisposition genes among 3,030 patients with pancreatic cancer compared with 123,136 cancer-free controls for whom whole exome sequencing was available. The authors found that six genes were significantly more prevalent among patients with pancreatic cancer than controls, suggesting that these genes lead to a predisposition to the malignancy. These six mutations — BRCA2, ATM, BRCA1, TP53, MLH1 and CDKN2A — occurred at a combined rate of 5.5% among this patient population.

The best predictors of a mutation among patients with pancreatic cancer were personal history of another cancer, personal history of breast cancer, and family history of another epithelial cancer in a first- or second-degree relative. However, it was notable that family history of pancreatic cancer did not inform 83.8% of mutations and that 76% of mutation carriers did not have a personal cancer history.

Up until this point in management of patients with pancreatic cancer, we have relied heavily on clinical history to determine whether to recommend genetic evaluation. Family history of cancer, ethnic group (eg, Ashkenazi Jewish ancestry), personal cancer history and early age of pancreatic cancer onset historically have guided us toward testing. Indeed, National Comprehensive Cancer Network guidelines advise that individuals in whom a genetic predisposition syndrome is suspected should be referred to genetic counseling. Aside from several ongoing clinical trials, the majority of patients with pancreatic cancer are not routinely tested for heritable disorders. Therefore, perhaps the most important finding in this analysis is that family history and personal cancer history — although most predictive of a predisposition gene compared with other factors — were certainly not always positive in mutation carriers. It also is notable that there were significant associations between patients who carried a genetic mutation and later-stage disease at diagnosis compared with noncarriers.

The key implication from these findings is that we should consider extending testing for genetic predisposition genes to all patients with pancreatic cancer. For patients already diagnosed, there may be therapeutic benefit when a predisposition gene is identified. This potential benefit only will increase as we continue to identify additional pancreatic cancer predisposition genes and further develop targeted therapies. For the family members of a patient with an identified gene, targeted genetic testing and subsequent screening for those found to carry a mutation could be offered and has the potential to positively impact survival, though studies are ongoing.

Several questions remain. First, the panel used by Hu and colleagues only contained 21 cancer predisposition genes, so it is plausible that the rates of patients with a predisposition gene may be somewhat higher than this analysis suggests. Second, this particular analysis did not address rates or somatic alterations among patients with pancreatic cancer, the identification of which may influence treatment choices and have bearing on survival. Finally, researchers observed no statistically significant difference in OS between mutation carriers and noncarriers after adjustment for age, stage and sex. It would be interesting to see this separated out by specific mutations and therapies in order to learn more about the natural history of patients carrying specific pancreatic cancer predisposition genes, and how different treatment strategies might affect them.

Kim A. Reiss Binder, MD

HemOnc Today Next Gen Innovator
Hospital of the University of Pennsylvania
Abramson Cancer Center
Penn Medicine

Disclosure: Reiss Binder reports research funding from Bristol-Myers Squibb, Clovis Oncology, Lilly Oncology and Tesaro.