Berry D A, Parmigiani G, Sanchez J, Schildkraut J, Winer E
Institute of Statistics and Decision Sciences, Duke University, Durham, NC 27708-0251, USA.
J Natl Cancer Inst. 1997 Feb 5;89(3):227-38. doi: 10.1093/jnci/89.3.227.
Heritable mutations of the breast cancer gene BRCA1 are rare, occurring in fewer than 1% of women in the general population, and therefore account for a small proportion of cases of breast and ovarian cancers. Nevertheless, the presence of such mutations is highly predictive of the development of these cancers.
We developed and applied a mathematic model for calculating the probability that a woman with a family history of breast and/or ovarian cancer carries a mutation of BRCA1.
As a basis for the model, we use Mendelian genetics and apply Bayes' theorem to information on the family history of these diseases. Of importance are the exact relationships of all family members, including both affected and unaffected members, and ages at diagnosis of the affected members and current ages of the unaffected members. We used available estimates of BRCA1 mutation frequencies in the general population and age-specific incidence rates of breast and ovarian cancers in carriers and noncarriers of mutations to estimate the probability that a particular member of the family carries a mutation. This probability is based on cancer statuses of all first- and second-degree relatives. We first describe the model by considering single individuals: a woman diagnosed with breast and/or ovarian cancer and also a woman free of cancer. We next considered two artificial and two actual family histories and addressed the sensitivity of our calculations to various assumptions. Particular relationships of family members with and without cancer can have a substantial impact on the probability of carrying a susceptibility gene. Ages at diagnosis of affected family members and their types of cancer are also important. A woman with two primary cancers can have a probability of carrying a mutation in excess of 80%, even with no other information about family history. The number and relationships of unaffected members, along with their current ages or ages at death, are critical determinants of one's carrier probability. An affected woman with several cancers in her family can have a probability of carrying a mutation that ranges from close to 100% to less than 5%.
Our model gives informative and specific probabilities that a particular woman carries a mutation.
This model focuses on mutations in BRCA1 and assumes that all other breast cancer is sporadic. With the cloning of BRCA2, we now know that this assumption is incorrect. We have adjusted the model to include BRCA2, but the use of this version must await publication of penetrance data for BRCA2, including those for male breast cancer that are apparently associated with BRCA2 but not with BRCA1. The current model is, nevertheless, appropriate and useful. Of principal importance is its potential and that of improved versions for aiding women and their health care providers in assessing the need for genetic testing.
乳腺癌基因BRCA1的遗传性突变较为罕见，在普通人群中发生的比例不到1%，因此在乳腺癌和卵巢癌病例中所占比例较小。然而，此类突变的存在对这些癌症的发生具有高度预测性。
我们开发并应用了一种数学模型，用于计算有乳腺癌和/或卵巢癌家族史的女性携带BRCA1突变的概率。
作为该模型的基础，我们运用孟德尔遗传学，并将贝叶斯定理应用于这些疾病的家族史信息。重要的是所有家庭成员的确切关系，包括患病和未患病成员，以及患病成员的诊断年龄和未患病成员的当前年龄。我们利用普通人群中BRCA1突变频率的现有估计值以及突变携带者和非携带者中乳腺癌和卵巢癌的年龄特异性发病率，来估计家族中特定成员携带突变的概率。此概率基于所有一级和二级亲属的癌症状况。我们首先通过考虑个体来描述该模型：一名被诊断患有乳腺癌和/或卵巢癌的女性以及一名未患癌症的女性。接下来我们考虑了两个虚构的和两个实际的家族史，并探讨了我们的计算对各种假设的敏感性。有癌和无癌家庭成员的特定关系会对携带易感基因的概率产生重大影响。患病家庭成员的诊断年龄及其癌症类型也很重要。一名患有两种原发性癌症的女性携带突变的概率可能超过80%，即使没有关于家族史的其他信息。未患病成员的数量和关系，以及他们的当前年龄或死亡年龄，是一个人携带突变概率的关键决定因素。一名家族中有多种癌症的患病女性携带突变的概率范围可能从接近100%到低于5%。
我们的模型给出了特定女性携带突变的信息丰富且具体的概率。
该模型聚焦于BRCA1突变，并假设所有其他乳腺癌都是散发性的。随着BRCA2的克隆，我们现在知道这个假设是不正确的。我们已对模型进行调整以纳入BRCA2，但该版本的使用必须等待BRCA2外显率数据的公布，包括那些显然与BRCA2相关但与BRCA1无关的男性乳腺癌的数据。然而，当前模型仍然是合适且有用的。其主要重要性在于其潜力以及改进版本在帮助女性及其医疗保健提供者评估基因检测需求方面的潜力。
