Dunlop M G, Farrington S M, Carothers A D, Wyllie A H, Sharp L, Burn J, Liu B, Kinzler K W, Vogelstein B
University of Edinburgh, Department of Surgery, Royal Infirmary, UK.
Hum Mol Genet. 1997 Jan;6(1):105-10. doi: 10.1093/hmg/6.1.105.
The autosomal dominant syndrome of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is due to germline DNA mismatch repair gene mutations in most cases. However, the penetrance of such mutations outwith classical HNPCC kindreds is unknown because families studied to date have been specifically selected for research purposes. Using a population-based strategy, we have calculated the lifetime cancer risk associated with germline DNA mismatch repair gene mutations, irrespective of their family history. We identified 67 gene carriers whose risk to age 70 for all cancers was 91% for males and 69% for females. The risk of developing colorectal cancer was significantly greater for males than for females (74% versus 30%, P= 0.006). The risk of uterine cancer (42%) exceeded that for colorectal cancer in females, emphasising the need for uterine screening. Our findings give further insight into the biological effect of defective DNA mismatch repair. We have demonstrated a systematic approach to identifying individuals at high risk of cancer but who may not be part of classical HNPCC families. The risk estimates derived from these analyses provide a rational basis on which to guide genetic counselling and to tailor clinical surveillance.
遗传性非息肉病性结直肠癌（HNPCC）的常染色体显性综合征在大多数情况下是由种系DNA错配修复基因突变引起的。然而，由于迄今为止所研究的家族都是专门为研究目的而挑选的，所以此类突变在非典型HNPCC家族中的外显率尚不清楚。我们采用基于人群的策略，计算了与种系DNA错配修复基因突变相关的终生癌症风险，而不考虑其家族病史。我们识别出67名基因携带者，他们到70岁时患所有癌症的风险男性为91%，女性为69%。男性患结直肠癌的风险显著高于女性（74%对30%，P = 0.006）。女性患子宫癌的风险（42%）超过了结直肠癌，这凸显了子宫筛查的必要性。我们的研究结果进一步深入了解了有缺陷的DNA错配修复的生物学效应。我们展示了一种系统的方法来识别癌症高危个体，这些个体可能不属于典型的HNPCC家族。从这些分析中得出的风险估计为指导遗传咨询和定制临床监测提供了合理依据。
