Format

Send to

Choose Destination
JAMA Oncol. 2017 Nov 1;3(11):1546-1553. doi: 10.1001/jamaoncol.2017.1051.

Genomic Profiling of Small-Bowel Adenocarcinoma.

Author information

1
Foundation Medicine, Inc, Cambridge, Massachusetts.
2
Northwell Health, The Monter Cancer Center, Lake Success, New York.
3
Department of Oncology, Mayo Clinic, Rochester, Minnesota.
4
Gastroenterology and Digestive Oncology, Centre Hospitalo-Universitaire Avicenne, Assistance Publique Hôpitaux de Paris, University Paris 13, Bobigny, France.
5
Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York.
6
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland.
7
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Abstract

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; and CDKN2A: 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; and SMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889], P < .001). BRAF was 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) of BRAF-mutated cases. The ERBB2/HER2 point 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, including PIK3CA and MEK1, 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.

PMID:
28617917
PMCID:
PMC5710195
DOI:
10.1001/jamaoncol.2017.1051
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center