Cancer Epidemiology Centre, Victorian Cancer Registry, Carlton, Victoria, Australia.
J Natl Cancer Inst. 2010 Feb 3;102(3):193-201. doi: 10.1093/jnci/djp473. Epub 2009 Dec 22.
Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.
We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.
For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7).
We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.
MSH6 种系突变导致的遗传性 DNA 错配修复基因突变引起的林奇综合征结直肠癌占 10%-20%。由于仅有少数关于突变携带者的研究，他们的癌症风险尚不确定。
我们从五个国家的 113 个 MSH6 突变携带者家族中确定了 MSH6 突变状态、性别、年龄以及癌症、息肉切除术和子宫切除术的病史，这些家族是通过家族癌症诊所和基于人群的癌症登记处确定的。我们从 3104 名亲属中获取了这些信息。使用改良的分离分析，并根据确认情况进行适当的条件处理，估计了携带者的特定年龄累积风险以及携带者的癌症风险比（HR）与同一国家一般人群的 HR 相比。
对于 MSH6 突变携带者，分别在 70 岁和 80 岁时估计的累积风险如下：结直肠癌男性为 22%（95%可信区间[CI] = 14%至 32%）和 44%（95% CI = 28%至 62%），女性为 10%（95% CI = 5%至 17%）和 20%（95% CI = 11%至 35%）；子宫内膜癌男性为 26%（95% CI = 18%至 36%）和 44%（95% CI = 30%至 58%），女性为 40%（95% CI = 32%至 52%）和 65%（95% CI = 53%至 78%）；与林奇综合征相关的任何癌症，男性为 24%（95% CI = 16%至 37%）和 47%（95% CI = 32%至 66%），女性为 40%（95% CI = 32%至 52%）和 65%（95% CI = 53%至 78%）。与一般人群的发病率相比，MSH6 突变携带者结直肠癌的发病率增加了 8 倍（HR = 7.6，95% CI = 5.4 至 10.8），这与性别和年龄无关。MSH6 突变携带者的女性子宫内膜癌发病率增加了 26 倍（HR = 25.5，95% CI = 16.8 至 38.7），与林奇综合征相关的其他癌症发病率增加了 6 倍（HR = 6.0，95% CI = 3.4 至 10.7）。
我们已经获得了 MSH6 突变携带者的绝对和相对癌症风险的精确和准确估计。
