Robles Ana I, Traverso Giovanni, Zhang Ming, Roberts Nicholas J, Khan Mohammed A, Joseph Christine, Lauwers Gregory Y, Selaru Florin M, Popoli Maria, Pittman Meredith E, Ke Xiquan, Hruban Ralph H, Meltzer Stephen J, Kinzler Kenneth W, Vogelstein Bert, Harris Curtis C, Papadopoulos Nickolas
Laboratory of Human Carcinogenesis, National Cancer Institute's Center for Cancer Research, National Institutes of Health, Bethesda, Maryland.
Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Department of Chemical Engineering, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Gastroenterology. 2016 Apr;150(4):931-43. doi: 10.1053/j.gastro.2015.12.036. Epub 2016 Jan 5.
BACKGROUND & AIMS: A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors.
We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies.
Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD.
Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer.
炎症性肠病（IBD）病程较长会增加患结直肠癌的风险。对有限数量基因的突变分析表明，IBD患者发生的结直肠肿瘤与非IBD患者的结直肠肿瘤不同。我们进行了全外显子组测序分析，以描绘这些肿瘤的基因图谱。
我们收集了31例IBD合并结直肠癌患者（15例溃疡性结肠炎、14例克罗恩病、2例未定型结肠炎）的结直肠肿瘤组织和非肿瘤组织，并对显微切割的肿瘤组织和匹配的非肿瘤组织进行全外显子组测序分析。通过比较匹配的标本，我们鉴定出体细胞改变。散发性结直肠肿瘤的突变发生率来自之前发表的外显子组测序研究。
两个标本在DNA校对或错配修复基因POLE、MLH1和MSH6中存在体细胞突变，肿瘤细胞具有高突变表型。其余肿瘤平均每个样本有71个改变。TP53是最常发生突变的基因，其发生率与散发性结直肠肿瘤相似（63%的病例）。然而，IBD患者的肿瘤具有不同的突变谱。IBD患者肿瘤中APC和KRAS的突变率明显低于散发性结直肠肿瘤（分别为13%和20%的病例）。几个基因在IBD患者的肿瘤中更频繁或独特地发生突变，包括SOX9和EP300（它们在WNT通路中编码蛋白质）、NRG1（它编码一种ERBB配体）和IL16（它编码一种细胞因子）。我们的研究还揭示了Rho和Rac GTPase网络成分中的复发性突变，表明非经典WNT信号在IBD患者结直肠肿瘤发生中起作用。
IBD患者发生结直肠肿瘤具有与散发性结直肠肿瘤不同的基因特征。这些发现可用于开发针对IBD合并结直肠癌患者诊断和治疗的疾病特异性标志物。
