NEW YORK (GenomeWeb) – Inherited mutations affecting cancer-related genes — including the DNA repair gene BRCA2 — appear to be over-represented in individuals with pancreatic neuroendocrine tumors, new research suggests.
As they reported in Nature today, the researchers sequenced more than 100 primary, sporadic pancreatic neuroendocrine tumors, a type of tumor that can be malignant or benign, with variable clinical progression patterns. Based on the genome sequences, coupled with additional genomic profiles for these and other tumors, they estimated that some 17 percent of individuals with pancreatic neuroendocrine tumors carried germline mutations in genes previously implicated in cancer.
"One of the most provocative findings is that these cancers had a larger than expected inherited gene defect that likely contributed to their development, potentially raising challenges in the clinic and refocusing future studies in the area," co-corresponding author Andrew Biankin, a cancer sciences researcher affiliated with the University of Glasgow and the University of New South Wales, said in a statement.
Going into the study, he and his team knew that while high-grade pancreatic neuroendocrine tumors are typically deadly, low- and intermediate-grade forms of the disease, which are far more common, have much more variable clinical trajectories and outcomes.
"Our current understanding of the molecular pathology of [low-grade or intermediate-grade pancreatic neuroendocrine tumors] is insufficient for their clinical management, where the challenge is to predict the aggressiveness of individual tumors in order to identify patients who will benefit from early aggressive therapy and to minimize harm from the inadvertent overtreatment of patients with indolent disease," the authors wrote.
To get a better look at the molecular features that mark sporadic forms of the disease, the researchers used Illumina HiSeq 2000 instruments do whole-genome sequencing on matched tumor-normal samples from 98 individuals with pancreatic neuroendocrine tumors enrolled through the International Cancer Genome Consortium. All but five of the tumors had been classified as low- or intermediate-grade.
In addition to whole-genome sequencing, the team did SNP profiling on the full set of tumors, combined with c-tailing quantitative PCR on 86 of the tumors and RNA sequencing on a subset of 30 samples. Samples from 62 individuals with pancreatic neuroendocrine tumors were profiled using amplicon sequencing and fluorescence in situ hybridization to validate findings in the discovery set.
From these data, the researchers found that pancreatic neuroendocrine tumors tended to have lower somatic mutation or chromosomal rearrangement rates compared with exocrine tumors affecting the pancreas, such as pancreatic ductal adenocarcinomas. Nevertheless, they detected a handful of characteristic mutation signatures, along with recurrent mutations or copy number changes affecting genes from DNA damage repair, chromatin remodeling, telomere maintenance, and mTOR signaling pathways.
The team's analyses also led to the discovery of germline mutations in several genes suspected of increasing cancer risk, including inactivating mutations that dial down activity of MUTYH, which has been implicated in colon, gastric, and other cancers. A broader search for cancer-related germline variants led to potentially risky inherited mutations in genes such as BRCA2, CHEK2, or VHL in a higher-than-anticipated proportion of the pancreatic neuroendocrine tumors.
"By sequencing the genome of these tumours we have decrypted the landscape of genetic alterations of these tumours. This discovery will allow us to target the development of specific therapies that aim to counter the alterations identified," co-first author Also Scarpa, a pathology and diagnostics researcher affiliated with the University and Hospital Trust of Verona, said in a statement.