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Testing for the presence of cancer predisposition genes may help identify individuals who could benefit from screening, prevention, and early detection of breast, ovarian, colorectal, and potentially pancreatic cancer. Enhanced cancer screening and prevention strategies might also benefit relatives of persons with such gene mutations.
Although persons genetically predisposed to pancreatic cancer may benefit from early detection, genes that predispose to pancreatic cancer and the risks for pancreatic cancer associated with mutations in these genes were previously undetermined. The goal of this case-control study by Hu and colleagues was to examine the possible association of inherited germline mutations in cancer predisposition genes with increased risks for pancreatic cancer.
The association between inherited germline mutations and a more than 10-fold increased risk for pancreatic ductal adenocarcinoma (PDAC) has been "re-demonstrated" in what could be the largest case-control study to date.
"Overall, genetic testing guidelines for patients with pancreatic cancer and for their unaffected relatives must be developed," said author Fergus J. Couch, PhD, of the department of laboratory medicine and pathology at the Mayo Clinic, in Rochester, Minnesota, and colleagues.
The new study was published online June 19 in the Journal of the American Medical Association(JAMA).[1]
The case-control study compared data from 3030 patients with PDAC and 123,136 reference control participants.
The team found mutations in 6 genes (CDKN2A, TP53, MLH1, BRCA2, ATM, and BRCA1) in 167 patients with pancreatic cancer (5.5% of the total cohort of patients with pancreatic cancer).
The corrected odds ratios (ORs) ranged from 2.58 to 12.33. The highest risk for pancreatic cancer was associated with mutations in CDKN2A.
In patients with genetic mutations in at least 1 of the 6 cancer predisposition genes, 7.9% had a family history of PDAC, and 5.2% had no family history of pancreatic cancer (P =.06).
Although the frequency of predisposing mutations in the series was greater than 5%, the specificity for mutations was too low for effective selection of patients for clinical genetic testing, the study authors acknowledged.
"The best predictors of mutations in patients with pancreatic cancer in the current study were a personal history of another primary cancer, a personal history of breast cancer, and a family history of one or more first- or second-degree relatives with epithelial cancers (pancreatic, breast, ovarian, endometrial, or colorectal)," they wrote.
The researchers noted that these results are consistent with a recent study of 854 patients with PDAC that identified mutations in the same 6 cancer predisposition genes, as well as in PALB2, in 3.5% of families of patients with pancreatic cancer.[2] Although mutations in PALB2 were frequently observed in the current study, no significant association with pancreatic cancer was found, they pointed out.
In an accompanying editorial, Sapna Syngal, MD, MPH, and C. Sloane Furniss, PhD, both from the division of population sciences at Dana-Farber Cancer Institute in Boston, Massachusetts, noted that "discussion about genetic testing needs to happen at or shortly after diagnosis as part of the standard management of newly diagnosed PDAC."[3]
Clinicians should also discuss genetic testing and surveillance in at-risk relatives at the time of diagnosis, they said.
Precedents for this approach have been established in ovarian and colon cancer, the editorialists noted. In ovarian cancer, the estimated prevalence of genetic mutations is 25%. The National Comprehensive Cancer Network guidelines currently recommend genetic testing in all cases.[4]
Similarly, multiple guidelines recommend universal screening for Lynch syndrome for all colorectal cancers, even though the 3% prevalence of gene mutations is "lower than even the most conservative estimates reported in the pancreatic cancer studies," they said.
"If genetic testing reveals a pathogenic mutation, at-risk relatives may elect to be tested for that mutation and benefit from cancer prevention strategies to decrease their own risk of developing pancreatic cancer as well as other related malignancies," Dr Syngal told Medscape Medical News.
When approached for comment, Igor Astsaturov, MD, PhD, associate professor of hematology/oncology at Fox Chase Cancer Center in Philadelphia, Pennsylvania, said "[t]he current study re-demonstrates the more than 10-fold increased risk for pancreatic cancer from previously established pancreatic cancer genetic mutations. I don't think there are many studies like this in terms of the sheer number of patients."
In patients who have already been diagnosed with pancreatic cancer, genetic testing "can make a world of difference," Dr Astsaturov told Medscape Medical News. "Almost every patient diagnosed with pancreatic cancer has aggressive, incurable disease, so go after the tumor material and get the DNA sequencing. It's a no-brainer."
In a small subset of 8% to 10% of patients with specific mutations, "those treated with new targeted approaches do better," he pointed out.
Nevertheless, Dr Astsaturov also emphasized that when it comes to pancreatic cancer, prevention strategies are lagging. "We're still in the dark when it comes to prevention, including how often we should scan, and whether we should scan at all. This is where the controversy lies."
This ambiguity can create a lot of anxiety in the family members of patients diagnosed with pancreatic cancer, he said.
Although the current study does not change the approach to surveillance or intervention for families who have no personal history of pancreatic cancer, it does shift the focus to persons with a family history of pancreatic cancer, Dr Astsaturov said.
"The surveillance procedures still need to be developed, and patients and clinicians should be attentive, particularly to those who develop unusual symptoms, such as loss of appetite, weight loss, persistent back pain, and a new diagnosis of diabetes," he advised.
Zev Wainberg, MD, associate professor of hematology/oncology at the University of California, Los Angeles (UCLA), agreed that genetic testing should be considered for all patients with newly diagnosed pancreatic cancer, particularly patients at higher risk.
"This study adds to the growing data on increased risk of certain populations for pancreatic cancer, and it really highlights the importance of DNA collection in these patients," said Dr Wainberg, who is codirector of the Gastrointestinal Oncology Program at the UCLA Jonsson Comprehensive Cancer Center. He was not affiliated with the study.
"It is clear that the group of patients with inherited germline mutations is larger than previously thought, particularly in certain higher-risk groups," Dr Wainberg told Medscape Medical News. "This may have important implications for further screening in these at-risk groups, and family members should be referred for genetic counseling."
For the study, patients were recruited into the Mayo Clinic Biospecimen Resource for Pancreas Research -- a prospective pancreatic cancer registry -- between October 12, 2000 and March 31, 2016. Most (95.6%) were non-Hispanic whites, 43.2% were female, and the mean age at diagnosis was 65.3 years.
The researchers extracted genomic DNA from peripheral blood lymphocyte samples and used a custom panel of 21 cancer predisposition genes to assess the prevalence of germline mutations.
DNA sequence data for the same predisposition genes were obtained from reference control groups registered in the Genome Aggregation Database and the Exome Aggregation Consortium.
In the comparative analysis of patients with pancreatic cancer and the reference control participants, significant associations were observed between pancreatic cancer and mutations in the following genes:
The study also demonstrated significant associations between mutations in the 6 predisposition genes and advanced stage of disease (P =.04); a personal history of breast, ovarian, colorectal, or nonovarian gynecologic cancer (OR=1.67; P =.009); a family history of breast cancer (OR=1.58; P =.01); and a family history of pancreatic, ovarian, gynecologic, or colorectal cancer (OR=1.40; P =.04).
In addition, patients with genetic mutations in any of the 6 genes were younger than noncarriers; the mean age at diagnosis was 62.5 years for patients with genetic mutations vs 65.5 years for noncarriers (P <.001). In patients who had mutations in BRCA2 only, the mean age at diagnosis was even younger than in noncarriers: 60.5 years vs 63.3 years (P =.01).
BRCA2 carriers were also more likely to have a family history of breast cancer (OR=2.07; adjusted P =.04). Patients with mutations in CDKN2A were more likely to have a family history of pancreatic cancer (OR=7.91; adjusted P =.005).
The study is limited by the fact that the study population consisted largely of white patients with PDAC, the researchers said. They noted that they also relied on public reference control participants matched for race and ethnicity.
This study was funded by the National Institutes of Health, the Mayo Clinic, the Rolfe Pancreatic Cancer Foundation, and the Vernon F. and Mae E. Thompson Charitable Fund. Dr Couch has disclosed no relevant financial relationships. Study coauthors John DiCarlo, PhD; Zhong Wu, PhD; and Raed Samara, PhD, have disclosed financial relationships with Qiagen Inc. Coauthor Robert R. McWilliams, MD, has relationships with Bristol-Myers Squibb Company, Ipsen, and Merrimack Pharmaceuticals, Inc. No other study coauthors have disclosed any relevant financial relationships. Dr Syngal has a relationship with Myriad Genetics, Inc. Dr Furniss and Dr Wainberg have disclosed no relevant financial relationships. Dr Astsaturov has a financial relationship with Caris Life Sciences, Inc.
JAMA. 2018;319:2401-2409.
