Svrcek Magali, El-Bchiri Jamila, Chalastanis Alexandra, Capel Emilie, Dumont Sylvie, Buhard Olivier, Oliveira Carla, Seruca Raquel, Bossard Céline, Mosnier Jean-François, Berger Françoise, Leteurtre Emmanuelle, Lavergne-Slove Anne, Chenard Marie-Pierre, Hamelin Richard, Cosnes Jacques, Beaugerie Laurent, Tiret Emmanuel, Duval Alex, Fléjou Jean-François
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Antoine, Service d'Anatomie Pathologique, Paris, France.
J Clin Oncol. 2007 Sep 20;25(27):4231-8. doi: 10.1200/JCO.2007.10.9744.
Microsatellite instability (MSI) due to mismatch repair (MMR) deficiency has been reported to occur at variable frequencies in inflammatory bowel disease-associated intestinal neoplasias (IBD-Ns). We investigated a large series of IBD-N for associations between MSI and several biologic and clinical parameters related to tumors, patients, and their treatment.
A total of 277 IBD-Ns in 205 patients were screened for MSI. Biologic and clinical variables of patients with high levels of DNA microsatellite instability high (MSI-H) were collected and compared with those associated with 33 MSI-H non-IBD colorectal cancers (CRCs).
A total of 27 IBD-Ns from 17 patients were found to be MSI-H. Compared with sporadic MSI-H CRCs, patients presented with a younger age at diagnosis, and there was no female predominance and no right-sided predominance. Unlike sporadic MSI-H CRCs, MSI-H IBD-Ns presented with heterogeneous mismatch repair defects involving MLH1, MSH2, MSH6, or PMS2, and a low frequency of MLH1 promoter methylation. They exhibited frequent BRAF mutations and frameshift mutations in genes containing coding repeat sequences.
The mechanisms underlying MMR deficiency in MSI-H IBD-Ns are different from those in sporadic MSI-H tumors and seem to be more related to those observed in hereditary MSI-H tumors. However, BRAF mutations were observed in MSI-H IBD-Ns, similar to sporadic MSI-H tumors, but unlike hereditary MSI-H tumors. Finally, the mutational events in target genes for instability are the same in MSI-H IBD-N tumors as in non-IBD sporadic and hereditary colorectal MSI-H cancers, indicating a colon-related repertoire of target gene alterations.
据报道，在炎症性肠病相关肠道肿瘤（IBD-N）中，因错配修复（MMR）缺陷导致的微卫星不稳定性（MSI）出现频率各异。我们研究了一大系列IBD-N，以探讨MSI与肿瘤、患者及其治疗相关的若干生物学和临床参数之间的关联。
对205例患者的277个IBD-N进行了MSI筛查。收集DNA微卫星高度不稳定（MSI-H）患者的生物学和临床变量，并与33例MSI-H非IBD结直肠癌（CRC）相关变量进行比较。
在17例患者的27个IBD-N中发现为MSI-H。与散发性MSI-H CRC相比，患者诊断时年龄较轻，无女性优势，也无右侧优势。与散发性MSI-H CRC不同，MSI-H IBD-N表现出涉及MLH1、MSH2、MSH6或PMS2的异质性错配修复缺陷，且MLH1启动子甲基化频率较低。它们在含有编码重复序列的基因中频繁出现BRAF突变和移码突变。
MSI-H IBD-N中MMR缺陷的潜在机制与散发性MSI-H肿瘤不同，似乎与遗传性MSI-H肿瘤中观察到的机制更为相关。然而，在MSI-H IBD-N中观察到BRAF突变，这与散发性MSI-H肿瘤相似，但与遗传性MSI-H肿瘤不同。最后，MSI-H IBD-N肿瘤中不稳定靶基因的突变事件与非IBD散发性和遗传性结直肠癌MSI-H中的相同，表明存在与结肠相关的靶基因改变谱。
