Cancer Research UK, Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK.
Breast Cancer Res. 2010;12(1):R10. doi: 10.1186/bcr2476. Epub 2010 Feb 10.
The risk of breast cancer to first degree relatives of breast cancer patients is approximately twice that of the general population. Breast cancer, however, is a heterogeneous disease and it is plausible that the familial relative risk (FRR) for breast cancer may differ by the pathological subtype of the tumour. The contribution of genetic variants associated with breast cancer susceptibility to the subtype-specific FRR is still unclear.
We computed breast cancer FRR for subtypes of breast cancer by comparing breast cancer incidence in relatives of breast cancer cases from a population-based series with known estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (HER2) status with that expected from the general population. We estimated the contribution to the FRR of genetic variants associated with breast cancer susceptibility using subtype-specific genotypic relative risks and allele frequencies for each variant.
At least one marker was measured for 4,590 breast cancer cases, who reported 9,014 affected and unaffected first-degree female relatives. There was no difference between the breast cancer FRR for relatives of patients with ER-negative (FRR = 1.78, 95% confidence intervals (CI): 1.44 to 2.11) and ER-positive disease (1.82, 95% CI: 1.67 to 1.98), P = 0.99. There was some suggestion that the breast cancer FRR for relatives of patients with ER-negative disease was higher than that for ER-positive disease for ages of the relative less than 50 years old (FRR = 2.96, 95% CI: 2.04 to 3.87; and 2.05, 95% CI: 1.70 to 2.40 respectively; P = 0.07), and that the breast cancer FRR for relatives of patients with ER-positive disease was higher than for ER-negative disease when the age of the relative was greater than 50 years (FRR = 1.76, 95% CI: 1.59 to 1.93; and 1.41, 95% CI: 1.08 to 1.74 respectively, P = 0.06). We estimated that mutations in BRCA1 and BRCA2 explain 32% of breast cancer FRR for relatives of patients with ER-negative and 9.4% of the breast cancer FRR for relatives of patients with ER-positive disease. Twelve recently identified common breast cancer susceptibility variants were estimated to explain 1.9% and 9.6% of the FRR to relatives of patients with ER-negative and ER-positive disease respectively.
FRR for breast cancer was significantly increased for both ER-negative and ER-positive disease. Including receptor status in conjunction with genetic status may aid risk prediction in women with a family history.
乳腺癌患者一级亲属的乳腺癌风险约为普通人群的两倍。然而，乳腺癌是一种异质性疾病，肿瘤的病理亚型可能导致家族相对风险（FRR）的差异。与乳腺癌易感性相关的遗传变异对特定亚型 FRR 的贡献仍不清楚。
我们通过比较基于人群的系列中乳腺癌病例的亲属的乳腺癌发病率与一般人群中预期的发病率，计算了不同亚型乳腺癌的 FRR。我们使用特定亚型的基因型相对风险和每个变体的等位基因频率来估计与乳腺癌易感性相关的遗传变体对 FRR 的贡献。
至少为 4590 例乳腺癌病例测量了一个标记物，这些病例报告了 9014 例受影响和未受影响的一级女性亲属。ER 阴性（FRR=1.78，95%置信区间[CI]：1.44 至 2.11）和 ER 阳性疾病（1.82，95%CI：1.67 至 1.98）患者亲属的乳腺癌 FRR 无差异，P=0.99。有一些证据表明，ER 阴性疾病患者亲属的乳腺癌 FRR 高于 ER 阳性疾病患者亲属的乳腺癌 FRR，年龄小于 50 岁的亲属（FRR=2.96，95%CI：2.04 至 3.87；和 2.05，95%CI：1.70 至 2.40；P=0.07），年龄大于 50 岁的亲属的乳腺癌 FRR 高于 ER 阴性疾病患者（FRR=1.76，95%CI：1.59 至 1.93；和 1.41，95%CI：1.08 至 1.74，P=0.06）。我们估计，BRCA1 和 BRCA2 中的突变分别解释了 ER 阴性患者亲属乳腺癌 FRR 的 32%和 ER 阳性患者亲属乳腺癌 FRR 的 9.4%。最近确定的 12 个常见乳腺癌易感性变体分别估计解释了 ER 阴性和 ER 阳性疾病患者亲属 FRR 的 1.9%和 9.6%。
ER 阴性和 ER 阳性疾病的乳腺癌 FRR 均显著增加。结合受体状态和遗传状态可能有助于有家族史的女性进行风险预测。
