Oncogenic gene fusions represent attractive targets for therapy of cancer. However, the frequency of actionable genomic rearrangements in colorectal cancer (CRC) is very low, and universal screening for these alterations seems to be impractical and costly. To address this problem, several large scale studies retrospectivelly showed that CRC with gene fusions are highly enriched in groups of tumors defined by MLH1 DNA mismatch repair protein deficiency (MLH1d), and hypermethylation of MLH1 promoter (MLH1 ph), and/or the presence of microsatellite instability, and BRAF /KRAS wild‐type status (BRAFwt /KRASwt ). In this study, we used targeted next generation sequencing (NGS) to explore the occurence of potentially therapeutically targetable gene fusions in an unselected series of BRAFwt /KRAS wt CRC cases that displayed MLH1d/MLH1 ph. From the initially identified group of 173 MLH1d CRC cases, 141 cases (81.5%) displayed MLH1 ph. BRAFwt/RASwt genotype was confirmed in 23 of 141 (~16%) of MLH1d/MLH1 ph cases. Targeted NGS of these 23 cases identified oncogenic gene fusions in nine patients (39.1%; CI95: 20.5%‐61.2%). Detected fusions involved NTRK (four cases), ALK (two cases), and BRAF genes (three cases). As a secondary outcome of NGS testing, we identified PIK3K‐AKT‐mTOR pathway alterations in two CRC cases, which displayed PIK3CA mutation. Altogether, 11 of 23 (~48%) MLH1d/MLH1 ph/BRAFwt/RASwt tumors showed genetic alterations that could induce resistance to anti‐EGFR therapy. Our study confirms that targeted NGS of MLH1d/MLH1 ph and BRAFwt /RASwt CRCs could be a cost‐effective strategy in detecting patients with potentially druggable oncogenic kinase fusions.

中文翻译：

---

MLH1 缺陷、MLH1 启动子高甲基化和 BRAF/RAS 野生型结直肠腺癌的靶向下一代测序可有效检测具有可操作致癌基因融合的肿瘤。

致癌基因融合代表了治疗癌症的有吸引力的目标。然而，结直肠癌 (CRC) 中可操作的基因组重排的频率非常低，对这些改变的普遍筛查似乎不切实际且成本高昂。为了解决这个问题，几项大规模研究回顾性地表明，具有基因融合的 CRC 在由 MLH1 DNA 错配修复蛋白缺陷 (MLH1d) 和MLH1启动子的高甲基化( MLH1 ph)定义的肿瘤组中高度富集，和/或存在微卫星不稳定性和BRAF / KRAS野生型状态 ( BRAFwt / KRASwt）。在本研究中，我们使用靶向下一代测序 (NGS) 来探索显示 MLH1d/ MLH1 ph 值的一系列未选择的BRAFwt / KRAS wt CRC 病例中潜在治疗靶向基因融合的发生。从最初确定的 173 例 MLH1d CRC 病例组中，141 例 (81.5%) 显示MLH1 ph。BRAFwt/RASwt基因型在 141例MLH1d/ MLH1 ph 病例中的 23 例（~16%）中得到证实。这 23 例患者的靶向 NGS 鉴定了 9 名患者的致癌基因融合（39.1%；CI95：20.5%-61.2%）。检测到的融合涉及NTRK（4 例）、ALK（2 例）和BRAF基因（三种情况）。作为 NGS 检测的次要结果，我们在两个显示PIK3CA突变的CRC 病例中发现了 PIK3K-AKT-mTOR 通路改变。总的来说，23 个 (~48%) MLH1d/ MLH1 ph/ BRAFwt/RASwt肿瘤中的 11 个显示出可能诱导抗 EGFR 治疗耐药的基因改变。我们的研究证实，MLH1d/ MLH1 ph 和BRAFwt / RASwt CRC 的靶向 NGS可能是检测具有潜在可药物致癌激酶融合的患者的一种具有成本效益的策略。