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.

重要性  小肠腺癌 (SBA) 是一种罕见的癌症，与其他肠源性癌症相比，其发病率显着降低、诊断较晚，总体生存期更差。迄今为止，缺乏对 SBA 的全面基因组分析。

目的  对大量 SBA 和其他胃肠道肿瘤进行深入的基因组表征，以进行比较并确定潜在的临床可操作改变。

设计、设置和参与者  对 2012 年 8 月 24 日至 2 月 3 日期间收集的 SBA (n = 317)、结直肠癌 (n = 6353) 和胃癌 (n = 889) 患者的临床样本进行了前瞻性分析， 2016 年，应个体治疗医师在临床护理过程中的要求，使用基于混合捕获的基因组分析，以做出治疗决策。

结果  纳入分析的7559例患者中，男性4138例（54.7%）；中位年龄为56（范围，12-101）岁。在 SBA 中观察到的基因组改变的频率与任何一种结直肠癌相比都有明显差异（APC：26.8% [317 中的 85] 对 75.9% [6353 中的 4823]，P  < .001；和CDKN2A：14.5% [317 中的 46 ] vs 2.6% [165 of 6353], P  < .001) 或胃癌 ( 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；和SMAD4：17.4% [55 of 317] vs 5.2% [46 of 889]，P  < .001)。BRAF在 7.6%（6353 例中的 484 例）结直肠癌和 9.1%（317 例中的 29 例）的 SBA 样本中发生突变，但 V600E 突变在 SBA 中不太常见，仅占BRAF突变病例的 10.3%（29 例中的 3 例） . ERBB2/HER2点突变（8.2% [26 of 317]）、微卫星不稳定性（7.6% [13 of 170]）和高肿瘤突变负荷（9.5% [30 of 317]）都富含 SBA。与十二指肠腺癌相比，未明确 SBA 的分子谱以及炎症性肠病相关的 SBA 存在显着差异。在所有 3 个系列中也鉴定了几个其他基因的可靶向改变，包括PIK3CA和MEK1，以及受体酪氨酸激酶融合。

结论和相关性  本研究向我们介绍了 SBA 与结直肠癌和胃癌的首次大规模基因组比较。不同的基因组差异使 SBA 成为一种分子独特的肠癌。此外，基因组分析可以识别大多数 SBA 病例 (91%) 中潜在的可靶向基因组改变，并且 SBA 中微卫星不稳定性和肿瘤突变负担的较高发生率表明免疫治疗的潜在作用。