Huang J, Kuismanen S A, Liu T, Chadwick R B, Johnson C K, Stevens M W, Richards S K, Meek J E, Gao X, Wright F A, Mecklin J P, Järvinen H J, Grönberg H, Bisgaard M L, Lindblom A, Peltomäki P
Division of Human Cancer Genetics, Ohio State University, Columbus 43210, USA.
Cancer Res. 2001 Feb 15;61(4):1619-23.
A set of 90 nonpolypotic colon cancer families in which germ-line mutations of MSH2 and MLH1 had been excluded were screened for mutations in two additional DNA mismatch repair genes, MSH6 and MSH3. Kindreds fulfilling and not fulfilling the Amsterdam I criteria, showing early and late onset colorectal (and other) cancers, and having microsatellite stable and unstable tumors were included. Two partly parallel approaches were used: genetic linkage analysis (19 large families) and the protein truncation test (85, mostly smaller, families). Whereas MSH3 was not involved in any family, a large Amsterdam-positive, late-onset family showed a novel germ-line mutation in MSH6 (deletion of CT at nucleotide 3052 in exon 4). The mutation was identified through genetic linkage (multipoint lod score 2.4) and subsequent sequencing of MSH6. Furthermore, the entire MSH6 gene was sequenced exon by exon in families with frameshift mutations in the (C)8 tract in tumors, previously suggested as a predictor of MSH6 germ-line mutations; no mutations were found. We conclude that germ-line involvement of MSH6 and MSH3 is rare and that other genes are likely to account for a majority of MSH2-, MLH1-mutation negative families with nonpolypotic colon cancer.
对一组90个非息肉病性结肠癌家族进行筛查，这些家族已排除MSH2和MLH1的种系突变，以检测另外两个DNA错配修复基因MSH6和MSH3中的突变。纳入了符合和不符合阿姆斯特丹I标准、表现为早发和晚发结直肠癌（及其他癌症）以及具有微卫星稳定和不稳定肿瘤的家族。采用了两种部分平行的方法：基因连锁分析（19个大家系）和蛋白质截短试验（85个家系，大多为小家系）。虽然没有任何家族涉及MSH3，但一个大型的阿姆斯特丹阳性、晚发家系在MSH6中显示出一种新的种系突变（外显子4中第3052位核苷酸处的CT缺失）。该突变通过基因连锁分析（多点连锁分数为2.4）及随后的MSH6测序得以鉴定。此外，对肿瘤中（C）8序列存在移码突变的家族逐外显子对整个MSH6基因进行测序，此前认为这可作为MSH6种系突变的预测指标；但未发现突变。我们得出结论，MSH6和MSH3的种系参与很少见，其他基因可能是大多数MSH2、MLH1突变阴性的非息肉病性结肠癌家族的病因。
