GENETICS OF PANCREATIC CANCER

n what is believed to be the largest pancreatic cancer genome-wide association study to date, researchers at the Johns Hopkins Kimmel Cancer Center, the National Cancer Institute, and collaborators from over 80 other institutions worldwide discovered changes to 5 new regions in the human genome that may increase the risk of pancreatic cancer. These findings were published by Klein et al in Nature Communications.

The new outcomes represent one more step toward fully capturing all of the genetic changes that lead to pancreatic cancer risk, which could lead to more targeted treatments and methods of early detection screening, researchers said.

Identified Variants

The newly identified genetic variants—located on human chromosomes 1 (position 1p36.33), 7 (position 7p12), 8 (position 8q21.11), 17 (position 17q12) and 18 (position 18q21.32)—may increase the risk of pancreatic cancer by 15% to 25% for each copy present in the genome, said Alison Klein, PhD, MHS, the study leader and a member of the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins. The group previously reported 17 variants in 13 genetic regions.

The findings included genetic information from 9,040 patients with pancreatic cancer and 12,946 healthy individuals of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). The scientists analyzed more than 11.3 million variants in 21,536 people.

“On an individual level, having one of these variants isn't very predictive of cancer, in that they're only associated with a modest change in risk, but when taken together, they help to create the fuller picture of how pancreatic cancer develops,” said Dr. Klein, Professor of Oncology, Pathology, and Epidemiology.

One of the new variants was found in NOC2L, a protein that binds directly to TP53, a major driver gene in pancreatic cancer, Dr. Klein said. It also binds with another tumor-suppressor gene called TP63—in previous work, Dr. Klein and colleagues identified that variants in the TP63 gene are associated with increased pancreatic cancer risk.

Variants in the HNF4G and HNF1B genes—hepatocyte growth factors that are involved in the regulation of cell growth—have been shown to play a role in regulation of the pancreas and in the development of cancer. Variation in HNF1B has also been linked to maturity-onset diabetes of the young, a familial form of diabetes that develops in people aged 25 years or younger, Dr. Klein said.

The additional variants were found near the GRP gene, which is involved in the release of gastrointestinal hormones, and on TNS3, a gene involved with the regulation of cell adhesion and migration and possibly metastasis.

Continuing studies will delve deeper into the genetics of pancreatic cancer, Dr. Klein said: “There is still a lot more that we don't know about hereditary factors in pancreatic cancer risk.”