A large study of pancreatic cancer patients has found that almost 10 percent harbored inherited genetic variations or mutations that may have increased their susceptibility to the disease. At the same time, some of these mutations were associated with more favorable responses to certain chemotherapy agents, according to the scientists from Dana-Farber Cancer Institute.
The findings, published online in Genetics in Medicine today, have prompted Dana-Farber physicians to recommend offering genetic testing to all pancreatic cancer patients at the time of diagnosis, regardless of their age or family history of cancer.
The researchers noted that the potential advantages are several-fold. If, as it appears, particular inherited mutations increase the cancer’s susceptibility to DNA-damaging agents such as platinum chemotherapy and PARP inhibitors, test results could help guide therapy. In addition, the presence of an inherited pancreatic cancer susceptibility mutation increases the chance that close relatives may carry a mutant gene for a familial cancer syndrome. Relatives may choose to have genetic testing for such syndromes and in some cases, can take advantage of risk-reducing surveillance and proactive treatment.
“Based on data from this and other studies, we are now offering genetic testing to all pancreatic cancer patients regardless of age and family history,” said Matthew Yurgelun, MD, one of three first authors of the paper. Until recently, he said, many estimates of inherited, or “germline,” mutations in pancreatic cancer were lower. It has also been thought that being diagnosed at an early age or with a family history of pancreatic cancer pointed to the likelihood of a germline mutation, but it is now recognized that those factors are not reliable indicators of an inherited mutation at work.
The new report is from a study designed to determine the prevalence of germline cancer susceptibility gene variants in pancreatic cancer. It included next-generation sequencing of germline DNA from 289 patients to look for variations in 24 genes linked to inherited cancer risk. Several of those genes, such as BRCA1, BRCA2, ATM, and others, are involved in cells’ ability to repair breaks in both strands of their DNA molecules (double-strand DNA damage repair genes, or dsDDR genes. Several other genes are associated with Lynch syndrome – a familial susceptibility to several cancers, including pancreatic cancer – or other cancer susceptibility syndromes. Such syndromes include familial adenomatous polyposis, familial atypical multiple mole/melanoma syndrome, Peutz-Jeghers syndrome and Li-Fraumeni syndrome.
Sequencing was carried out on 289 patients diagnosed with pancreatic cancer who underwent surgical resection of their tumors. The sequencing revealed that 28 of the 289 patients, or 9.7 percent, carried inherited alterations – mutations or DNA variations – in genes predisposing to cancer. Of those 28 patients, 6, or 21.4 percent, had a family history of pancreatic cancer.
Also, 21 patients, or 7.3 percent, of the 289 study participants carried alterations or variants in double-strand DNA damage repair genes, or dsDDR genes, such as BRCA1, BRCA2, and ATM. Patients with these gene alterations experienced significantly longer overall survival – a median of 34.4 months – than patients who did not carry such gene alterations, who had median survival of 19.1 months. There was a non-significant trend toward superior overall survival for patients harboring dsDDR variants who received oxaliplatin-based chemotherapy after disease recurrence.
In addition to sequencing the patients’ germline DNA to look for an inherited mutant or variant copy of a cancer susceptibility gene, the scientists sequenced DNA taken from the patients’ pancreatic tumors. This “somatic” DNA, they expected, would reveal a “second hit” – a mutation in the other copy of the germline susceptibility gene: the first hit would raise the inherited risk of pancreatic cancer, and the second hit, acquired sometime during the patient’s life, would initiate the growth of a pancreatic tumor. However, second hits were detected in only 44.4 percent of patient who had germline genetic variants – a finding the authors called “somewhat surprising.”
Co-senior authors of the study are Jonathan A. Nowak, MD, PhD of the Department of Pathology at Brigham and Women’s Hospital, and Brian M. Wolpin, MD, MPH, Director of the Gastrointestinal Cancer Center and the Hale Center for Pancreatic Cancer Research at Dana-Farber.
This research was supported in part by the Dana-Farber/Harvard Cancer Center SPORE in Gastrointestinal Cancer (P50 CA127003), the National Cancer Institute (U01 CA210171), the Lustgarten Foundation, and the Hale Center for Pancreatic Cancer Research.
Dana-Farber Cancer Institute