Marra G, D'Atri S, Corti C, Bonmassar L, Cattaruzza M S, Schweizer P, Heinimann K, Bartosova Z, Nyström-Lahti M, Jiricny J
Institute of Medical Radiobiology of the University of Zürich, August Forel-Strasse 7, CH-8008 Zürich, Switzerland.
Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7164-9. doi: 10.1073/pnas.121136498.
Members of hereditary nonpolyposis colon cancer (HNPCC) families harboring heterozygous germline mutations in the DNA mismatch repair genes hMSH2 or hMLH1 present with tumors generally two to three decades earlier than individuals with nonfamilial sporadic colon cancer. We searched for phenotypic features that might predispose heterozygous cells from HNPCC kindreds to malignant transformation. hMSH2(+/-) lymphoblastoid cell lines were found to be on average about 4-fold more tolerant than wild-type cells to killing by the methylating agent temozolomide, a phenotype that is invariably linked with impairment of the mismatch repair system. This finding was associated with an average 2-fold decrease of the steady-state level of hMSH2 protein in hMSH2(+/-) cell lines. In contrast, hMLH1(+/-) heterozygous cells were indistinguishable from normal controls in these assays. Thus, despite the fact that HNPCC families harboring mutations in hMSH2 or hMLH1 cannot be distinguished clinically, the early stages of the carcinogenic process in hMSH2 and hMLH1 mutation carriers may be different. Should hMSH2(+/-) colonocytes and lymphoblasts harbor a similar phenotype, the increased tolerance of the former to DNA-damaging agents present in the human colon may play a key role in the initiation of the carcinogenic process.
遗传性非息肉病性结直肠癌（HNPCC）家族中，DNA错配修复基因hMSH2或hMLH1存在杂合种系突变的成员，其患肿瘤的时间通常比非家族性散发性结直肠癌患者早二至三十年。我们寻找了可能使HNPCC家族的杂合细胞易发生恶性转化的表型特征。结果发现，hMSH2(+/-)淋巴母细胞系对甲基化剂替莫唑胺杀伤的耐受性平均比野生型细胞高约4倍，这种表型总是与错配修复系统受损有关。这一发现与hMSH2(+/-)细胞系中hMSH2蛋白稳态水平平均降低2倍有关。相比之下，hMLH1(+/-)杂合细胞在这些检测中与正常对照无差异。因此，尽管携带hMSH2或hMLH1突变的HNPCC家族在临床上无法区分，但hMSH2和hMLH1突变携带者致癌过程的早期阶段可能不同。如果hMSH2(+/-)结肠细胞和淋巴母细胞具有相似的表型，那么前者对人类结肠中存在的DNA损伤剂耐受性增加可能在致癌过程的启动中起关键作用。
