Background: The predictive and prognostic role ofBRAFalterations has been evaluated in colorectal cancer (CRC); however,BRAFalterations have not been fully characterized in non-CRC gastrointestinal (GI) malignancies. In the present study, we report the frequency and spectrum ofBRAFalterations among patients with non-CRC GI malignancies. Methods: Patients with CRC and non-CRC GI malignancies who underwent somatic tumor profiling via a tissue-based or liquid-based assay were included in this study. Gain-of-functionBRAFalterations were defined as pathogenic/likely pathogenic somatic short variants (SVs), copy number amplifications ≥8, or fusions (RNA or DNA). Results: Among 51,560 patients with somatic profiling, 40% had CRC and 60% had non-CRC GI malignancies.BRAFGOF alterations were seen more frequently in CRC (8.9%) compared to non-CRC GI malignancies (2.2%) (p< 0.001). Non-CRC GI malignancies with the highest prevalence ofBRAFGOF alterations were bile duct cancers (4.1%) and small intestine cancers (4.0%). AmongBRAFGOF alterations, class II (28% vs. 6.8%,p< 0.001) and class III (23% vs. 14%,p< 0.001) were more common in non-CRC GI malignancies. Among class II alterations, rates ofBRAFamplifications (3.1% vs. 0.3%,p< 0.001) andBRAFfusions (12% vs. 2.2%,p< 0.001) were higher in non-CRC GI malignancies compared to CRC. Conclusions: Non-CRC GI malignancies demonstrate a distinctBRAFalteration profile compared to CRC, with a higher frequency of class II and III mutations, and more specifically, a higher incidence ofBRAFfusions. Future studies should evaluate clinical implications for the management of non-CRC GI patients withBRAFalterations, especially BRAF fusions.
背景：BRAF基因改变在结直肠癌（CRC）中的预测和预后作用已有评估；然而，其在非结直肠癌胃肠道（GI）恶性肿瘤中的特征尚未完全阐明。本研究旨在报告非结直肠癌胃肠道恶性肿瘤患者中BRAF基因改变的频率与谱系特征。方法：本研究纳入了通过组织或液体检测进行体细胞肿瘤谱分析的确诊结直肠癌及非结直肠癌胃肠道恶性肿瘤患者。功能性BRAF基因改变定义为致病性/可能致病性体细胞短变异（SVs）、拷贝数扩增≥8或融合（RNA或DNA）。结果：在51,560例接受体细胞谱分析的患者中，40%为结直肠癌患者，60%为非结直肠癌胃肠道恶性肿瘤患者。与结直肠癌（8.9%）相比，非结直肠癌胃肠道恶性肿瘤中功能性BRAF基因改变的发生率显著更低（2.2%）（p<0.001）。在非结直肠癌胃肠道恶性肿瘤中，胆管癌（4.1%）和小肠癌（4.0%）的功能性BRAF基因改变发生率最高。在功能性BRAF基因改变中，II类（28% vs. 6.8%，p<0.001）和III类（23% vs. 14%，p<0.001）改变在非结直肠癌胃肠道恶性肿瘤中更为常见。在II类改变中，与结直肠癌相比，非结直肠癌胃肠道恶性肿瘤的BRAF扩增率（3.1% vs. 0.3%，p<0.001）和BRAF融合率（12% vs. 2.2%，p<0.001）更高。结论：与结直肠癌相比，非结直肠癌胃肠道恶性肿瘤呈现出独特的BRAF基因改变谱，其II类和III类突变发生率更高，尤其是BRAF融合的发生率显著增高。未来研究应评估BRAF基因改变（特别是BRAF融合）对非结直肠癌胃肠道恶性肿瘤患者临床管理的意义。
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