Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, North Carolina.
Cancer Epidemiol Biomarkers Prev. 2022 Dec 5;31(12):2136-2147. doi: 10.1158/1055-9965.EPI-22-0590.
Aberrant expression of DNA repair pathways such as homologous recombination (HR) can lead to DNA repair imbalance, genomic instability, and altered chemotherapy response. DNA repair imbalance may predict prognosis, but variation in DNA repair in diverse cohorts of breast cancer patients is understudied.
To identify RNA-based patterns of DNA repair expression, we performed unsupervised clustering on 51 DNA repair-related genes in the Cancer Genome Atlas Breast Cancer [TCGA BRCA (n = 1,094)] and Carolina Breast Cancer Study [CBCS (n = 1,461)]. Using published DNA-based HR deficiency (HRD) scores (high-HRD ≥ 42) from TCGA, we trained an RNA-based supervised classifier. Unsupervised and supervised HRD classifiers were evaluated in association with demographics, tumor characteristics, and clinical outcomes.
: Unsupervised clustering on DNA repair genes identified four clusters of breast tumors, with one group having high expression of HR genes. Approximately 39.7% of CBCS and 29.3% of TCGA breast tumors had this unsupervised high-HRD (U-HRD) profile. A supervised HRD classifier (S-HRD) trained on TCGA had 84% sensitivity and 73% specificity to detect HRD-high samples. Both U-HRD and S-HRD tumors in CBCS had higher frequency of TP53 mutant-like status (45% and 41% enrichment) and basal-like subtype (63% and 58% enrichment). S-HRD high was more common among black patients. Among chemotherapy-treated participants, recurrence was associated with S-HRD high (HR: 2.38, 95% confidence interval = 1.50-3.78).
HRD is associated with poor prognosis and enriched in the tumors of black women.
RNA-level indicators of HRD are predictive of breast cancer outcomes in diverse populations.
DNA 修复途径（如同源重组[HR]）的异常表达可导致 DNA 修复失衡、基因组不稳定和化疗反应改变。DNA 修复失衡可能预测预后，但不同乳腺癌患者群体中 DNA 修复的变化仍研究不足。
为了确定 DNA 修复表达的基于 RNA 的模式，我们对癌症基因组图谱乳腺癌（TCGA BRCA[n=1,094]）和卡罗莱纳乳腺癌研究（CBCS[n=1,461]）中 51 个与 DNA 修复相关的基因进行了无监督聚类。利用 TCGA 中已发表的基于 DNA 的 HR 缺陷（HRD）评分（高-HRD≥42），我们训练了一个基于 RNA 的有监督分类器。无监督和有监督的 HRD 分类器与人口统计学、肿瘤特征和临床结果相关联进行了评估。
对 DNA 修复基因的无监督聚类鉴定了四个乳腺癌肿瘤簇，其中一组 HR 基因表达较高。大约 39.7%的 CBCS 和 29.3%的 TCGA 乳腺癌肿瘤具有这种无监督的高-HRD（U-HRD）特征。基于 TCGA 训练的有监督 HRD 分类器（S-HRD）检测 HRD 高样本的灵敏度为 84%，特异性为 73%。CBCS 中的 U-HRD 和 S-HRD 肿瘤的 TP53 突变样状态频率更高（分别为 45%和 41%富集），基底样亚型也更丰富（分别为 63%和 58%富集）。S-HRD 高在黑人患者中更为常见。在接受化疗治疗的参与者中，复发与 S-HRD 高相关（HR：2.38，95%置信区间=1.50-3.78）。
HRD 与不良预后相关，并且在黑人女性的肿瘤中富集。
HRD 的 RNA 水平指标可预测不同人群的乳腺癌结局。
