Chang-Claude J
Division of Clinical Epidemiology, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
IARC Sci Publ. 2001;154:177-90.
Inherited genetic susceptibility to breast cancer can be due both to genes which confer a high degree of risk and to polygenes which have a smaller effect on disease risk. An estimated 5-10% of breast cancer is considered to be due to mutations in genes conferring high risk which results in hereditary patterns of disease. Two major breast cancer susceptibility genes, BRCA1 and BRCA2, which were identified using linkage analysis in large extended breast and/or ovarian cancer pedigrees, are estimated to account for the majority of large families with breast/ovarian cancer predisposition and about two-thirds of large breast cancer families. The associated lifetime risk for breast cancer in mutation carriers ranges from 40% to 90%, depending on the extent of family history and the population. Other genetic factors, such as HRAS or CAG repeats of AR, as well as reproductive and hormonal factors may therefore modify cancer risk. Women at particularly high risk of developing breast cancer represent a group in whom expensive and rigorous screening programmes are cost-effective and who may benefit from trials of chemoprevention. There are only preliminary data on the efficacy of increased surveillance and on risk reduction due to prophylactic surgery. However, for chemoprevention to be equivalent to prophylactic mastectomy, it will be necessary to strive for an equivalent reduction. The efficacy of chemoprevention in this high-risk population is unknown. Existing and new agents for chemoprevention need to be carefully assessed in properly designed clinical trials among such women. In the process, other factors modifying the penetrance in mutation carriers need to be taken into account in order to evaluate the true effect of the chemopreventive agents. Polygenes confer much lower levels of risk and may be relevant for risk assessment when the effects of multiple loci, possibly in conjunction with environmental factors, are understood and quantified. At present, it seems unlikely that the genetic information at single polygenes will be clinically relevant for risk assessment and management.
乳腺癌的遗传易感性既可能源于赋予高风险的基因，也可能源于对疾病风险影响较小的多基因。据估计，5%至10%的乳腺癌被认为是由赋予高风险的基因突变所致，这会导致疾病的遗传模式。两个主要的乳腺癌易感基因BRCA1和BRCA2，是通过对大型扩展性乳腺癌和/或卵巢癌家系进行连锁分析确定的，据估计，它们在大多数有乳腺癌/卵巢癌易感性的大家族以及约三分之二的大型乳腺癌家族中起作用。突变携带者患乳腺癌的终生风险在40%至90%之间，具体取决于家族病史的程度和人群。因此，其他遗传因素，如HRAS或AR的CAG重复序列，以及生殖和激素因素可能会改变癌症风险。患乳腺癌风险特别高的女性群体，实施昂贵且严格的筛查项目具有成本效益，她们可能会从化学预防试验中受益。关于加强监测的效果以及预防性手术降低风险的效果，目前仅有初步数据。然而，要使化学预防等同于预防性乳房切除术，就必须努力实现同等程度的降低。在这一高风险人群中，化学预防的效果尚不清楚。需要在这类女性中进行精心设计的临床试验，仔细评估现有的和新的化学预防药物。在此过程中，为了评估化学预防药物的真实效果，需要考虑影响突变携带者外显率的其他因素。多基因赋予的风险水平要低得多，当多个位点的作用（可能与环境因素共同作用）得到理解和量化时，它们可能与风险评估相关。目前，单个多基因的遗传信息在临床上似乎不太可能与风险评估和管理相关。
