Gaffin Center for Neuro-Oncology, Sharett Institute for Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center, Kiryat Hadassa, 91120, Jerusalem, Israel.
Breast Cancer Res Treat. 2023 Apr;198(2):197-205. doi: 10.1007/s10549-022-06851-6. Epub 2023 Feb 2.
BRCA1/2 genes are the two main genes associated with hereditary breast cancers (BC). In the present study, we explore clinical and molecular characteristics of BRCA-associated BC in relation to estrogen receptor (ER) status.
Three BC databases (DB) were evaluated: (i) Hadassah oncogenetics (n = 4826); (ii) METABRIC (n = 1980), and (iii) Nick-Zainal (n = 560). We evaluated age at diagnosis in BRCA positive (BP) and BRCA negative (BN) patients, and tested for mutational signature differences in cohort iii. mRNA differential expression analysis (DEA) and pathway analysis were performed in cohort ii.
Age at diagnosis was lower in BP vs. BN tumors in all cohorts in the ER- group, and only in cohort i for the ER + group. Signature 3 was universal in BP BC, whereas several signatures were associated with ER status. Pathway analysis was performed between BP&BN, and was significant only in ER- tumors: the major activated pathways involved cancer-related processes and were highly significant. The most significant pathway was estrogen-mediated S-phase entry and the most activated upstream regulator was ERBB2.
Signature 3 was universal for all BP BC, while other signatures were associated with ER status. ER + BP& BN show similar genomic characteristics, ER- BP differed markedly from BN. This suggests that the initial carcinogenic process is universal for all BRCA carriers, but further insults lead to the development of two genomically distinct subtypes ER- and ER + . This may shed light on possible mechanisms involved in BP and carry preventive and therapeutic implications.
BRCA1/2 基因是与遗传性乳腺癌（BC）相关的两个主要基因。本研究探讨了与雌激素受体（ER）状态相关的 BRCA 相关 BC 的临床和分子特征。
评估了三个 BC 数据库（DB）：（i）哈达萨肿瘤遗传学（n=4826）；（ii）METABRIC（n=1980）；和（iii）Nick-Zainal（n=560）。我们评估了 BRCA 阳性（BP）和 BRCA 阴性（BN）患者的诊断时年龄，并在队列 iii 中测试了突变特征的差异。在队列 ii 中进行了 mRNA 差异表达分析（DEA）和途径分析。
在所有 ER-组的队列中，BP 与 BN 肿瘤的诊断年龄均低于 BN 肿瘤，而在 ER+组中仅在队列 i 中。签名 3 在所有 BP BC 中都是普遍存在的，而其他签名与 ER 状态相关。在 BP&BN 之间进行了途径分析，仅在 ER-肿瘤中具有统计学意义：主要激活的途径涉及癌症相关过程，且具有高度显著性。最重要的途径是雌激素介导的 S 期进入，最活跃的上游调节剂是 ERBB2。
签名 3 对所有 BP BC 都是普遍存在的，而其他签名则与 ER 状态相关。ER+BP&BN 显示出相似的基因组特征，而 ER-BP 与 BN 明显不同。这表明初始致癌过程对所有 BRCA 携带者都是普遍存在的，但进一步的损伤导致了两种基因组上截然不同的亚型 ER-和 ER+的发展。这可能揭示了 BP 中可能涉及的机制，并具有预防和治疗意义。
