Department of Public Health Sciences, The University of Chicago, Chicago, Illinois
Center for Clinical Cancer Genetics, Department of Medicine, The University of Chicago, Chicago, Illinois
JAMA Oncol. 2017 Dec 1;3(12):1654-1662. doi: 10.1001/jamaoncol.2017.0595.
African Americans have the highest breast cancer mortality rate. Although racial difference in the distribution of intrinsic subtypes of breast cancer is known, it is unclear if there are other inherent genomic differences that contribute to the survival disparities.
To investigate racial differences in breast cancer molecular features and survival and to estimate the heritability of breast cancer subtypes.
DESIGN, SETTING, AND PARTICIPANTS: Among a convenience cohort of patients with invasive breast cancer, breast tumor and matched normal tissue sample data (as of September 18, 2015) were obtained from The Cancer Genome Atlas.
Breast cancer–free interval, tumor molecular features, and genetic variants.
Participants were 930 patients with breast cancer, including 154 black patients of African ancestry (mean [SD] age at diagnosis, 55.66 [13.01] years; 98.1% [n = 151] female) and 776 white patients of European ancestry (mean [SD] age at diagnosis, 59.51 [13.11] years; 99.0% [n = 768] female). Compared with white patients, black patients had a worse breast cancer-free interval (hazard ratio, HR=1.67; 95% CI, 1.02-2.74; P = .043). They had a higher likelihood of basal-like (odds ratio, 3.80; 95% CI, 2.46-5.87; P < .001) and human epidermal growth factor receptor 2 (ERBB2 [formerly HER2])–enriched (odds ratio, 2.22; 95% CI, 1.10-4.47; P = .027) breast cancer subtypes, with the Luminal A subtype as the reference. Blacks had more TP53 mutations and fewer PIK3CA mutations than whites. While most molecular differences were eliminated after adjusting for intrinsic subtype, the study found 16 DNA methylation probes, 4 DNA copy number segments, 1 protein, and 142 genes that were differentially expressed, with the gene-based signature having an excellent capacity for distinguishing breast tumors from black vs white patients (cross-validation C index, 0.878). Using germline genotypes, the heritability of breast cancer subtypes (basal vs nonbasal) was estimated to be 0.436 (P = 1.5 × 10−14). The estrogen receptor–positive polygenic risk score built from 89 known susceptibility variants was higher in blacks than in whites (difference, 0.24; P = 2.3 × 10−5), while the estrogen receptor–negative polygenic risk score was much higher in blacks than in whites (difference, 0.48; P = 2.8 × 10−11).
On the molecular level, after adjusting for intrinsic subtype frequency differences, this study found a modest number of genomic differences but a significant clinical survival outcome difference between blacks and whites in The Cancer Genome Atlas data set. Moreover, more than 40% of breast cancer subtype frequency differences could be explained by genetic variants. These data could form the basis for the development of molecular targeted therapies to improve clinical outcomes for the specific subtypes of breast cancers that disproportionately affect black women. Findings also indicate that personalized risk assessment and optimal treatment could reduce deaths from aggressive breast cancers for black women.
非裔美国人的乳腺癌死亡率最高。尽管已知乳腺癌内在亚型的分布存在种族差异，但尚不清楚是否存在其他导致生存差异的内在基因组差异。
研究乳腺癌分子特征和生存的种族差异，并估计乳腺癌亚型的遗传性。
设计、地点和参与者：在一项便利队列的浸润性乳腺癌患者中，从癌症基因组图谱中获取了乳房肿瘤和匹配的正常组织样本数据（截至 2015 年 9 月 18 日）。
乳腺癌无复发生存期、肿瘤分子特征和遗传变异。
参与者包括 930 名乳腺癌患者，其中 154 名非裔黑人患者（诊断时的平均[SD]年龄，55.66 [13.01]岁；98.1%[n=151]为女性）和 776 名白种人欧洲血统患者（诊断时的平均[SD]年龄，59.51 [13.11]岁；99.0%[n=768]为女性）。与白人患者相比，黑人患者的乳腺癌无复发生存期更差（风险比，1.67；95%置信区间，1.02-2.74；P=0.043）。他们基底样（优势比，3.80；95%置信区间，2.46-5.87；P<0.001）和人表皮生长因子受体 2（ERBB2[以前称为 HER2]）丰富的乳腺癌亚型的可能性更高（优势比，2.22；95%置信区间，1.10-4.47；P=0.027），以 Luminal A 亚型为参考。黑人比白人有更多的 TP53 突变和更少的 PIK3CA 突变。虽然在调整内在亚型后消除了大多数分子差异，但研究发现了 16 个 DNA 甲基化探针、4 个 DNA 拷贝数片段、1 个蛋白质和 142 个差异表达的基因，基于基因的特征具有出色的区分黑人与白人患者的乳房肿瘤的能力（交叉验证 C 指数，0.878）。使用种系基因型，估计乳腺癌亚型（基底 vs 非基底）的遗传性为 0.436（P=1.5×10−14）。从 89 个已知易感性变异构建的雌激素受体阳性多基因风险评分在黑人中高于白人（差异，0.24；P=2.3×10−5），而雌激素受体阴性多基因风险评分在黑人中则高得多黑人比白人（差异，0.48；P=2.8×10−11）。
在分子水平上，在调整内在亚型频率差异后，本研究发现了一些基因组差异，但在癌症基因组图谱数据集的黑人与白人之间存在显著的临床生存结局差异。此外，超过 40%的乳腺癌亚型频率差异可以通过遗传变异来解释。这些数据可以为开发分子靶向疗法奠定基础，以改善特定的乳腺癌亚型的临床结局，这些亚型不成比例地影响黑人妇女。研究结果还表明，个性化风险评估和最佳治疗可以减少黑人妇女因侵袭性乳腺癌而死亡的人数。
