Phelan C M, Rebbeck T R, Weber B L, Devilee P, Ruttledge M H, Lynch H T, Lenoir G M, Stratton M R, Easton D F, Ponder B A, Cannon-Albright L, Larsson C, Goldgar D E, Narod S A
Division of Medical Genetics, Montreal General Hospital, Quebec, Canada.
Nat Genet. 1996 Mar;12(3):309-11. doi: 10.1038/ng0396-309.
Women who carry a mutation in the BRCA1 gene (on chromosome 17q21), have an 80% risk of breast cancer and a 40% risk of ovarian cancer by the age of 70 (ref. 1). The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors play a role in tumourigenesis in these individuals. The HRAS1 variable number of tandem repeats (VNTR) polymorphism, located 1 kilobase (kb) downstream of the HRAS1 proto-oncogene (chromosome 11p15.5) is one possible genetic modifier of cancer penetrance. Individuals who have rare alleles of the VNTR have an increased risk of certain types of cancers, including breast cancer (2-4). To investigate whether the presence of rare HRAS1 alleles increases susceptibility to hereditary breast and ovarian cancer, we have typed a panel of 307 female BRCA1 carriers at this locus using a PCR-based technique. The risk for ovarian cancer was 2.11 times greater for BRCA1 carriers harbouring one or two rare HRAS1 alleles, compared to carriers with only common alleles (P = 0.015). The magnitude of the relative risk associated with a rare HRAS1 allele was not altered by adjusting for the other known risk factors for hereditary ovarian cancer (5). Susceptibility to breast cancer did not appear to be affected by the presence of rare HRAS1 alleles. This study is the first to show the effect of a modifying gene on the penetrance of an inherited cancer syndrome.
携带BRCA1基因（位于17号染色体q21区域）突变的女性，到70岁时患乳腺癌的风险为80%，患卵巢癌的风险为40%（参考文献1）。BRCA1基因的可变外显率表明，其他遗传和非遗传因素在这些个体的肿瘤发生过程中发挥作用。HRAS1可变串联重复序列（VNTR）多态性位于HRAS1原癌基因（11号染色体p15.5）下游1千碱基（kb）处，是癌症外显率的一种可能的遗传修饰因子。具有VNTR罕见等位基因的个体患某些类型癌症的风险增加，包括乳腺癌（2 - 4）。为了研究罕见HRAS1等位基因的存在是否会增加遗传性乳腺癌和卵巢癌的易感性，我们使用基于PCR的技术对307名女性BRCA1携带者在该位点进行了分型。与仅携带常见等位基因的携带者相比，携带一个或两个罕见HRAS1等位基因的BRCA1携带者患卵巢癌的风险高2.11倍（P = 0.015）。通过对遗传性卵巢癌的其他已知风险因素进行校正后，与罕见HRAS1等位基因相关的相对风险大小并未改变（5）。罕见HRAS1等位基因的存在似乎并未影响患乳腺癌的易感性。本研究首次表明了一个修饰基因对遗传性癌症综合征外显率的影响。
