Vassileva Vessela, Millar Anna, Briollais Laurent, Chapman William, Bapat Bharati
Samuel Lunenfeld Research Institute, Toronto, Ontario, M5G 1X5 Canada.
Cancer Res. 2002 Jul 15;62(14):4095-9.
Microsatellite instability (MSI) is observed in a subset of endometrial cancers (ECs) and is attributed to defects in mismatch repair. Mismatch repair deficiency allows for accumulation of mutations in the coding repeats of key target genes, which may be involved in the initiation and progression of MSI+ EC. We examined genes implicated in DNA repair pathways in 38 MSI-high (MSI-H), 10 MSI-low, 25 microsatellite stable ECs, and a selected panel of associated premalignant hyperplasias. Genetic alterations were correlated to histopathological data, including tumor grade and stage. Somatic frameshift mutations were observed in hMLH3, hMSH3, hMSH6, CHK1, and BAX genes in MSI-H endometrial hyperplasias and cancers, whereas mutations in ATR and CDC25C were observed only in MSI-H ECs. Increased mutation frequency in DNA damage response pathway genes including ATR, CHK1, and BAX demonstrated a significant trend with advancing tumor grade (P < 0.05). Our observations of the same mutations at short coding mononucleotide repeats in both premalignant lesions and tumors and association of increased frequency of mutation accumulation with advancing tumor grade suggest that these alterations may play a role in the development and progression of MSI+ EC.
微卫星不稳定性（MSI）在一部分子宫内膜癌（EC）中被观察到，其归因于错配修复缺陷。错配修复缺陷使得关键靶基因编码重复序列中的突变得以积累，这些基因可能参与MSI+ EC的发生和发展。我们检测了38例微卫星高度不稳定（MSI-H）、10例微卫星低度不稳定、25例微卫星稳定的EC以及一组选定的相关癌前增生组织中与DNA修复途径相关的基因。基因改变与组织病理学数据相关，包括肿瘤分级和分期。在MSI-H子宫内膜增生和癌组织中，hMLH3、hMSH3、hMSH6、CHK1和BAX基因中观察到体细胞移码突变，而ATR和CDC25C的突变仅在MSI-H EC中观察到。包括ATR、CHK1和BAX在内的DNA损伤反应途径基因的突变频率增加，显示出随着肿瘤分级升高的显著趋势（P < 0.05）。我们在癌前病变和肿瘤的短编码单核苷酸重复序列中观察到相同的突变，以及突变积累频率增加与肿瘤分级升高的相关性，表明这些改变可能在MSI+ EC的发生和发展中起作用。
