Gala Manish K, Austin Thomas, Ogino Shuji, Chan Andrew T
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Cancer Prev Res (Phila). 2015 Jul;8(7):614-9. doi: 10.1158/1940-6207.CAPR-14-0444. Epub 2015 Apr 21.
Oncogene-induced senescence (OIS), a tumor-suppressive mechanism that is induced by the replicative and metabolic stress of oncogene activation, is a key barrier in the development of BRAF V600E colon cancer. Inhibition of this mechanism has been observed through epigenetic changes observed in sporadic serrated polyps, as well as through the germline mutations associated with those who develop serrated polyposis. We hypothesize that upregulated autocrine factors exist that are specific to the serrated pathway and also promote bypass of oncogene-induced senescence. To identify such autocrine factors, we integrate analyses of microarrays of sessile serrated polyps and two large colon cancer cohorts, the Cancer Genome Atlas (TCGA; n = 153), and French national Cartes d'Identité des Tumeurs (CIT) program (n = 462), with enhanced gene annotation through natural language processing techniques of the existing medical corpus. We reproducibly associate higher expression of the ligand-receptor axis of TFF2 and CXCR4 with BRAF V600E-mutant colon cancer (P = 3.0 × 10(-3) and 0.077, respectively for TCGA; P = 3.0 × 10(-8) and 5.1 × 10(-7) for CIT). Given well-described oncogenic roles of TFF2 and CXCR4 in colon cancer, and availability of CXCR4 inhibitors for other clinical indications, this ligand-receptor axis may represent an actionable target for prevention and treatment of this molecular subtype of colorectal cancer.
癌基因诱导的衰老（OIS）是一种由癌基因激活的复制和代谢应激所诱导的肿瘤抑制机制，是BRAF V600E结肠癌发生发展中的关键障碍。在散发性锯齿状息肉中观察到的表观遗传变化以及与发生锯齿状息肉病的患者相关的种系突变，均已证实存在对这种机制的抑制作用。我们推测，存在特定于锯齿状通路的上调自分泌因子，这些因子也能促进癌基因诱导衰老的旁路形成。为了鉴定此类自分泌因子，我们整合了对无蒂锯齿状息肉微阵列以及两个大型结肠癌队列（癌症基因组图谱（TCGA；n = 153）和法国国家肿瘤识别卡（CIT）计划（n = 462））的分析，并通过对现有医学语料库采用自然语言处理技术增强基因注释。我们反复发现，TFF2和CXCR4的配体 - 受体轴的高表达与BRAF V600E突变型结肠癌相关（对于TCGA，P分别为3.0×10⁻³和0.077；对于CIT，P分别为3.0×10⁻⁸和5.1×10⁻⁷）。鉴于TFF2和CXCR4在结肠癌中已明确的致癌作用，以及CXCR4抑制剂可用于其他临床适应症，这种配体 - 受体轴可能是预防和治疗这种分子亚型结直肠癌的一个可行靶点。
