Genomic Profiling of Small-Bowel Adenocarcinoma

Alexa B. Schrock, Craig E. Devoe, Robert R Mc Williams, James Sun, Thomas Aparicio, Philip J. Stephens, Jeffrey S. Ross, Richard Wilson, Vincent A. Miller, Siraj M. Ali, Michael J. Overman

Research output: Contribution to journalArticle

42 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1546-1553
Number of pages8
JournalJAMA oncology
Volume3
Issue number11
DOIs
StatePublished - Nov 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Schrock, A. B., Devoe, C. E., Mc Williams, R. R., Sun, J., Aparicio, T., Stephens, P. J., Ross, J. S., Wilson, R., Miller, V. A., Ali, S. M., & Overman, M. J. (2017). Genomic Profiling of Small-Bowel Adenocarcinoma. JAMA oncology, 3(11), 1546-1553. https://doi.org/10.1001/jamaoncol.2017.1051