Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
Breast Cancer Res. 2010;12(3):R28. doi: 10.1186/bcr2576. Epub 2010 May 18.
INTRODUCTION: Mutations in BRCA1 and BRCA2 confer high risks of breast cancer and ovarian cancer. The risk prediction algorithm BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) may be used to compute the probabilities of carrying mutations in BRCA1 and BRCA2 and help to target mutation screening. Tumours from BRCA1 and BRCA2 mutation carriers display distinctive pathological features that could be used to better discriminate between BRCA1 mutation carriers, BRCA2 mutation carriers and noncarriers. In particular, oestrogen receptor (ER)-negative status, triple-negative (TN) status, and expression of basal markers are predictive of BRCA1 mutation carrier status. METHODS: We extended BOADICEA by treating breast cancer subtypes as distinct disease end points. Age-specific expression of phenotypic markers in a series of tumours from 182 BRCA1 mutation carriers, 62 BRCA2 mutation carriers and 109 controls from the Breast Cancer Linkage Consortium, and over 300,000 tumours from the general population obtained from the Surveillance Epidemiology, and End Results database, were used to calculate age-specific and genotype-specific incidences of each disease end point. The probability that an individual carries a BRCA1 or BRCA2 mutation given their family history and tumour marker status of family members was computed in sample pedigrees. RESULTS: The cumulative risk of ER-negative breast cancer by age 70 for BRCA1 mutation carriers was estimated to be 55% and the risk of ER-positive disease was 18%. The corresponding risks for BRCA2 mutation carriers were 21% and 44% for ER-negative and ER-positive disease, respectively. The predicted BRCA1 carrier probabilities among ER-positive breast cancer cases were less than 1% at all ages. For women diagnosed with breast cancer below age 50 years, these probabilities rose to more than 5% in ER-negative breast cancer, 7% in TN disease and 24% in TN breast cancer expressing both CK5/6 and CK14 cytokeratins. Large differences in mutation probabilities were observed by combining ER status and other informative markers with family history. CONCLUSIONS: This approach combines both full pedigree and tumour subtype data to predict BRCA1/2 carrier probabilities. Prediction of BRCA1/2 carrier status, and hence selection of women for mutation screening, may be substantially improved by combining tumour pathology with family history of cancer.
简介：BRCA1 和 BRCA2 基因突变可导致乳腺癌和卵巢癌的高风险。BOADICEA（乳腺癌和卵巢疾病发病和携带者估计算法）风险预测算法可用于计算 BRCA1 和 BRCA2 基因突变的携带概率，并有助于靶向突变筛查。BRCA1 和 BRCA2 突变携带者的肿瘤显示出独特的病理特征，可用于更好地区分 BRCA1 突变携带者、BRCA2 突变携带者和非携带者。特别是，雌激素受体（ER）阴性状态、三阴性（TN）状态和基底标志物的表达可预测 BRCA1 突变携带者状态。
方法：我们通过将乳腺癌亚型视为不同的疾病终点来扩展 BOADICEA。从乳腺癌连锁协会的 182 名 BRCA1 突变携带者、62 名 BRCA2 突变携带者和 109 名对照者的一系列肿瘤中，以及从监测、流行病学和最终结果数据库中获得的 30 多万例普通人群肿瘤中，检测到特定年龄的表型标志物的表达，用于计算每个疾病终点的特定年龄和基因型的发生率。根据家族史和家族成员的肿瘤标志物状态，计算个体携带 BRCA1 或 BRCA2 突变的概率。
结果：BRCA1 突变携带者的 ER 阴性乳腺癌累积风险在 70 岁时估计为 55%，ER 阳性疾病的风险为 18%。BRCA2 突变携带者的相应风险分别为 ER 阴性和 ER 阳性疾病的 21%和 44%。在所有年龄组中，ER 阳性乳腺癌病例中预测的 BRCA1 携带者概率均小于 1%。对于 50 岁以下诊断为乳腺癌的女性，在 ER 阴性乳腺癌、三阴性疾病和同时表达 CK5/6 和 CK14 细胞角蛋白的三阴性乳腺癌中，这些概率上升至 5%以上、7%和 24%。通过将 ER 状态和其他信息性标志物与家族史相结合，观察到突变概率的巨大差异。
结论：该方法结合了全系谱和肿瘤亚型数据来预测 BRCA1/2 携带者的概率。通过将肿瘤病理学与癌症家族史相结合，BRCA1/2 携带者状态的预测，从而选择女性进行突变筛查，可能会得到显著改善。
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