Genomic Profiling of Small-Bowel Adenocarcinoma

Importance

Small-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking.

Objective

To perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations.

Design, Setting, and Participants

Prospective analysis was performed of clinical samples from patients with SBA (n = 317), colorectal cancer (n = 6353), and gastric carcinoma (n = 889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture–based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions.

Results

Of the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% [85 of 317] vs 75.9% [4823 of 6353],P < .001; andCDKN2A: 14.5% [46 of 317] vs 2.6% [165 of 6353],P < .001) or gastric carcinoma (KRAS: 53.6% [170 of 317] vs 14.2% [126 of 889],P < .001;APC: 26.8% [85 of 317] vs 7.8% [69 of 889],P < .001; andSMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889],P < .001).BRAFwas mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) ofBRAF-mutated cases. TheERBB2/HER2point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease–associated SBAs. Targetable alterations in several additional genes, includingPIK3CAandMEK1, and receptor tyrosine kinase fusions, were also identified in all 3 series.

Conclusions and Relevance

This study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy.