目的:克罗恩病(CrD)患者发生小肠腺癌(SBA)的风险升高。据报道,CrD-SBA中的可操作异柠檬酸脱氢酶1(IDH1)突变比散发性SBA更为频繁。本研究旨在探讨临床病理和免疫表型特征,以及甲基化谱,IDH1突变的CrD-SBAs。
结果:对国际多中心系列手术切除的CrD-SBAs进行IDH1突变检测。临床病理特征,比较了IDH1突变和IDH1野生型CrD-SBA之间的免疫表型标记表达和O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)和长散布核元件1(LINE-1)甲基化。所检查的49个CrD-SBA中的10个(20%)具有IDH1突变,并且所有突变的癌症具有R132C变体。与IDH1野生型病例相比,IDH1突变的CrD-SBA显示细胞角蛋白7表达率显着降低(P=0.005),p53过表达率(P=0.012)和MGMT甲基化率(P=0.012)更高。与IDH1突变的SBA相关的所有三种发育不良生长都具有相应浸润性癌症的相同IDH1变体(R132C),并且都是非常规亚型(两个锯齿状增生性病变和一个杯状细胞缺陷型增生)。特别是,非常规锯齿状发育不良与IDH1突变的CrD-SBA显著相关(P=0.029).在IDH1突变的CrD-SBA患者和IDH1野生型CrD-SBA患者之间没有发现显着癌症特异性生存差异(风险比=0.55,95%置信区间=0.16-1.89;P=0.313)。
结论:IDH1突变的CrD-SBAs,大约占总病例的五分之一,以独特的免疫表型特征和甲基化谱为特征,具有潜在的治疗意义。此外,IDH1突变的非常规,锯齿状发育不良可能代表此类CrD-SBA的前兆病变。
OBJECTIVE: Patients with Crohn\'s disease (CrD) have an elevated risk for the development of small bowel adenocarcinomas (SBAs). Actionable isocitrate dehydrogenase 1 (IDH1) mutations have been reported to be more frequent in CrD-SBAs than in sporadic SBAs. The present study aimed to investigate the clinicopathological and immunophenotypical features, as well as methylation profiles, of IDH1-mutated CrD-SBAs.
RESULTS: An international multicentre series of surgically resected CrD-SBAs was tested for IDH1 mutation. Clinicopathological features, immunophenotypical marker expression and O6-methylguanine-DNA methyltransferase (MGMT) and long interspersed nuclear element-1 (LINE-1) methylation were compared between IDH1-mutated and IDH1 wild-type CrD-SBAs. Ten (20%) of the 49 CrD-SBAs examined harboured an IDH1 mutation and all the mutated cancers harboured the R132C variant. Compared to IDH1 wild-type cases, IDH1-mutated CrD-SBAs showed significantly lower rates of cytokeratin 7 expression (P = 0.005) and higher rates of p53 overexpression (P = 0.012) and MGMT methylation (P = 0.012). All three dysplastic growths associated with IDH1-mutated SBAs harboured the same IDH1 variant (R132C) of the corresponding invasive cancer, and all were of non-conventional subtype (two serrated dysplastic lesions and one goblet cell-deficient dysplasia). In particular, non-conventional serrated dysplasia was significantly associated with IDH1-mutated CrD-SBAs (P = 0.029). No significant cancer-specific survival difference between IDH1-mutated CrD-SBA patients and IDH1 wild-type CrD-SBA patients was found (hazard ratio = 0.55, 95% confidence interval = 0.16-1.89; P = 0.313).
CONCLUSIONS: IDH1-mutated CrD-SBAs, which represent approximately one-fifth of total cases, are characterised by distinctive immunophenotypical features and methylation profiles, with potential therapeutic implications. Moreover, IDH1-mutated non-conventional, serrated dysplasia is likely to represent a precursor lesion to such CrD-SBAs.