Skip to main content
Premium Trial:

Request an Annual Quote

Small-Bowel Adenocarcinoma Is Molecularly Distinct From Colorectal, Gastric Cancers

NEW YORK (GenomeWeb) – Small-bowel adenocarcinoma is molecularly distinct from both colorectal cancer and gastric cancer, according to a new genomic profiling study.

An international team of researchers profiled the genomes of tumors from more than 7,500 people, including patients with small-bowel adenocarcinoma, colorectal cancer, and gastric cancer. Small-bowel adenocarcinoma is a rare cancer, occurring 50-fold to 100-fold less often than cancers of the large intestine.

As they reported today in JAMA Oncology, the researchers found that small-bowel adenocarcinomas harbored a suite of mutations that differed from those found in colorectal cancer and gastric cancer. In addition, the researchers uncovered a higher degree of microsatellite instability and mutational burden within small-bowel adenocarcinomas, though they also noted a number of potentially actionable mutations.

"To our knowledge, this project provides the largest genomic characterization of [small-bowel adenocarcinomas] to date and provides an improved biological insight into this cancer in relation to cancers of neighboring sites of the stomach and large intestine," the researchers led by MD Anderson's Michael Overman wrote in their paper. The team also included researchers from Foundation Medicine and other institutions.

Overman and his colleagues prospectively profiled samples from 7,559 patients, including 317 small-bowel adenocarcinoma, 6,353 colorectal cancer, and 889 gastric adenocarcinoma specimens that had been sent for analysis by treating physicians between 2012 and 2016.

Their hybrid capture-based genomic profiling approach examined either 236 or 315 cancer-related genes as well as introns from 19 or 28 genes that frequently undergo rearrangement. They reported a mean coverage depth of 651X.

Within their set of small-bowel adenocarcinomas, the researchers found that the most commonly mutated genes included TP53, KRAS, APC, SMAD4, PIK3CA, CDKN2A, and ARID1A. TP53, they noted, was mutated in nearly 60 percent of small-bowel adenocarcinomas. They also reported ERBB2/HER2 point mutations.

Rates of mutations in these genes differed between small-bowel adenocarcinomas and colorectal cancers or gastric adenocarcinomas. For instance, APC mutations were present in slightly more than a quarter of small-bowel adenocarcinomas, but were present in more than three-quarters of colorectal cancers and in fewer than 8 percent of gastric cancers.

Additionally, while BRAF mutations were present at about the same rate in small-bowel adenocarcinomas and colorectal cancers, the mutations weren't the same. Only 10 percent of small-bowel adenocarcinomas with BRAF mutations had V600E mutations, as compared to 73 percent of colorectal cancers with BRAF mutations. The BRAF mutations in small-bowel adenocarcinomas appeared to be inactivating, the researchers noted. BRAF mutations were present in less than 2 percent of gastric cancer patients.

This suggested to the researchers that small-bowel adenocarcinoma is a distinct disease.

The researchers also gauged microsatellite instability for a subset of tumors and found that a greater portion of small-bowel adenocarcinomas had high instability, as compared to colorectal cancers and gastric cancers. Of the 13 small-bowel adenocarcinomas with high microsatellite instability, 10 had one or more inactivating mutation in a mismatch repair gene.

They likewise reported that small-bowel adenocarcinomas had a higher mutational burden overall than did the colorectal cancers and gastric cancers they analyzed.

Overman and his colleagues also noted that a number of the alterations they found among small-bowel adenocarcinomas were potentially targetable. In particular, they highlighted PIK3CA, ERBB2/HER2, and BRAF mutations as potentially actionable.

"Identification of multiple clinically relevant genomic alterations and mutational profiles is encouraging in a population with limited treatment options and poor prognosis," the researchers added.