Froggatt N J, Green J, Brassett C, Evans D G, Bishop D T, Kolodner R, Maher E R
Cambridge University, Department of Pathology, UK.
J Med Genet. 1999 Feb;36(2):97-102.
The frequency, origin, and phenotypic expression of a germline MSH2 gene mutation previously identified in seven kindreds with hereditary non-polyposis cancer syndrome (HNPCC) was investigated. The mutation (A-->T at nt943+3) disrupts the 3' splice site of exon 5 leading to the deletion of this exon from MSH2 mRNA and represents the only frequent MSH2 mutation so far reported. Although this mutation was initially detected in four of 33 colorectal cancer families analysed from eastern England, more extensive analysis has reduced the frequency to four of 52 (8%) English HNPCC kindreds analysed. In contrast, the MSH2 mutation was identified in 10 of 20 (50%) separately identified colorectal families from Newfoundland. To investigate the origin of this mutation in colorectal cancer families from England (n=4), Newfoundland (n=10), and the United States (n=3), haplotype analysis using microsatellite markers linked to MSH2 was performed. Within the English and US families there was little evidence for a recent common origin of the MSH2 splice site mutation in most families. In contrast, a common haplotype was identified at the two flanking markers (CA5 and D2S288) in eight of the Newfoundland families. These findings suggested a founder effect within Newfoundland similar to that reported by others for two MLH1 mutations in Finnish HNPCC families. We calculated age related risks of all, colorectal, endometrial, and ovarian cancers in nt943+3 A-->T MSH2 mutation carriers (n=76) for all patients and for men and women separately. For both sexes combined, the penetrances at age 60 years for all cancers and for colorectal cancer were 0.86 and 0.57, respectively. The risk of colorectal cancer was significantly higher (p<0.01) in males than females (0.63 v 0.30 and 0.84 v 0.44 at ages 50 and 60 years, respectively). For females there was a high risk of endometrial cancer (0.5 at age 60 years) and premenopausal ovarian cancer (0.2 at 50 years). These intersex differences in colorectal cancer risks have implications for screening programmes and for attempts to identify colorectal cancer susceptibility modifiers.
对先前在7个遗传性非息肉病癌症综合征（HNPCC）家族中鉴定出的种系MSH2基因突变的频率、起源及表型表达进行了研究。该突变（第943 + 3位核苷酸处A→T）破坏了外显子5的3'剪接位点，导致该外显子从MSH2 mRNA中缺失，是迄今为止报道的唯一常见的MSH2突变。尽管该突变最初在来自英格兰东部的33个结直肠癌家族中的4个中检测到，但更广泛的分析已将频率降低至在分析的52个（8%）英国HNPCC家族中的4个。相比之下，在来自纽芬兰的20个单独鉴定的结直肠癌家族中的10个（50%）中鉴定出了MSH2突变。为了研究来自英格兰（n = 4）、纽芬兰（n = 10）和美国（n = 3）的结直肠癌家族中该突变的起源，使用与MSH2连锁的微卫星标记进行了单倍型分析。在英国家族和美国家族中，大多数家族中几乎没有证据表明MSH2剪接位点突变有近期的共同起源。相比之下，在纽芬兰的8个家族中的两个侧翼标记（CA5和D2S288）处鉴定出了一个共同的单倍型。这些发现表明纽芬兰存在奠基者效应，类似于其他人报道的芬兰HNPCC家族中的两个MLH1突变。我们计算了nt943 + 3 A→T MSH2突变携带者（n = 76）中所有癌症、结直肠癌、子宫内膜癌和卵巢癌的年龄相关风险，分别针对所有患者以及男性和女性进行了计算。对于男女合计，60岁时所有癌症和结直肠癌的外显率分别为0.86和0.57。男性患结直肠癌的风险显著高于女性（50岁和60岁时分别为0.63对0.30以及0.84对0.44，p < 0.01）。对于女性，患子宫内膜癌（60岁时为0.5）和绝经前卵巢癌（50岁时为0.2）的风险较高。结直肠癌风险中的这些性别差异对筛查计划以及识别结直肠癌易感性修饰因子的尝试具有影响。
