Mutations in Genomic Integrity Gene Increase Hereditary Pancreatic Cancer Risk

Inherited mutations in the ataxia telangiectasia mutated (ATM) gene increase the odds of developing pancreatic cancer according to a new study. While there is predisposition for pancreatic cancer with up to 10% of cases occurring among families with a history of the disease, the genetic basis for this had not been previously discovered.

The research team from Johns Hopkins University as well as other cancer centers based in the United States, including the Mayo Clinic, used whole-genome and whole-exome analyses to isolate heterozygous, ATM gene mutations from individuals affected with pancreatic cancer who had at least 3 family members with pancreatic ductal adenocarcinoma. The team analyzed whole-genome sequences of 16 subjects from 6 families as well as whole-exome sequences of another 22 individuals from 10 additional families.

The ATM gene encodes a serine/threonine kinase that has important functions in genomic integrity, both in DNA double-stranded break repair and cell-cycle checkpoint activation. The protein is required and activated by DNA double-stranded breaks and activates key proteins that initiate the DNA damage checkpoint that leads to cell cycle arrest and results in DNA repair or apoptosis such as p53.

As a follow-up, the sequence of the entire coding region of the ATM gene from an additional 166 individuals with familial pancreatic cancer patients was compared to 190 spouse controls. Of the 166 patients, 4 had a loss of function mutation in the ATM gene while none of the spouse controls had a similar mutation as analyzed by conventional sequencing. Among 87 severely affected families with 3 or more cases of the cancer, 4 harmful ATM mutations were found (P = .009).

The potential importance of this discovery is underscored by the very high morbidity of pancreatic cancer. Most patients diagnosed with pancreatic ductal adenocarcinomas have a less than 5% chance of surviving 5 years. Multiple family members are affected in 5% to 10% of pancreatic cancer patients in the United States, providing evidence that a causative genetic factor is involved.

The genes that are responsible for 85% to 90% of familial pancreatic cancer that have at least 2 affected first-degree relatives are unknown. This is the first study to show a heritable trait partly responsible for this predisposition. Other germline mutations in the BRCA2, PALB2, CDKN2A, and STK11 genes have previously been identified in the minority of families.

The new discovery will likely facilitate risk counseling, provide a novel way to screen individuals for pancreatic cancer, and create a novel screening method for patients undergoing clinical trials.  Currently there are no screening methods for pancreatic cancer. Endoscopy is currently being evaluated as a screening tool in clinical trials.

A pancreatic tumor tissue sample was available from one of the pancreatic cancer patients with a germline ATM mutation. Sequencing analysis showed that the patient harbored a heterozygous nonsense variant in the DNA from a peripheral blood sample and a loss of function at the ATM locus, the same nonsense allele as in the blood sample. The authors suggest, based on this evidence that in this patient, loss of ATM was driven by the classic 2-hit model of tumor suppressor genes.

Loss of ATM is quite uncommon in patients that have sporadic cases of pancreatic ductal adenocarcinoma. While pancreatic neuroendocrine tumors have shown to harbor somatic ATM mutations, these tumors have little in common with pancreatic ductal adenocarcinoma, according to the study authors. Additionally, the ATM mutations in the neuroendocrine tumors may have no functional basis as being drivers of oncogenesis as there is no genetic or biochemical evidence showing that these mutations functionally affect the ATM protein.

As ATM is a key component of the DNA repair pathway, this study may facilitate the development of novel ATM-directed therapeutics and therapeutics based on synthetic lethal interactions for pancreatic cancer.