与白人/白种人相比,黑人/非裔美国人(B/AA)乳腺癌患者往往具有更具侵略性的肿瘤生物学特性。在这项研究中,研究了来自两个种族分组的患者的各种乳腺肿瘤分子表达谱。乳腺浸润性癌样本数据(RNASeq版本2,反相蛋白阵列,突变,和miRSeq数据)来自癌症基因组图谱。结果证实,B/AA患者比白种人患者更有可能携带侵袭性基底样或不良预后相关HER2富集的乳腺癌分子亚型。B/AA患者中三阴性乳腺癌(TNBC)的发病率也高于普通人群,这一事实反映在PIK3CA和TP53等基因的突变模式中。此外,永生化签名基因集,富含B/AA患者的样品。在III期患者中,TERT,DRAP1和PQBP1,永生化基因签名集的所有成员,是B/AA患者活性增加的主调节因子之一。驱动两组之间表达谱差异的主调节因子包括永生化标记,衰老标记,免疫反应和氧化还原基因产物。表达差异,在B/AA和白种人患者之间,RB1,hsa-let-7a,E2F1,c-MYC,TERT,和其他生物分子似乎协作以增强B/AA患者进入细胞周期的S期。miR-221的较高表达,这是一种促进进入细胞周期S期的oncomiR,受C-MYC调控,在B/AA患者的乳腺癌样品中表达更多。此外,促进细胞迁移和侵袭的miRNA,miR-135b,在B/AA患者中相对表达增加。敲低永生化标记物TERT抑制三阴性乳腺癌细胞系(MDA-MB-231和MDA-MB-468)细胞活力和TERT表达降低,MYC和WNT11。对于那些有生存数据的患者,诊断时年龄为50岁或更小的II期患者的预后,B/AA患者明显较差。与该B/AA患者亚组相关的还有HUWE1和PTEN表达缺失中的错义突变。相对于高加索人对内分泌治疗的无应答者,B/AA无反应者显示标记基因集的表达受抑制,该标记基因集的生物学过程包括白细胞介素的信号传导,生物钟,PPARα对脂质代谢的调节,FOXO介导的转录,和TP53降解的调节被过度代表。因此,我们确定了分子表达模式,表明对氧化应激的反应减弱,肿瘤抑制因子/促进因子调节的变化,在B/AA患者中增强的永生化对定义B/AA患者中报道的更具侵袭性的分子肿瘤表型可能很重要。
Black/African-American (B/AA) breast cancer patients tend to have more aggressive tumor biology compared to White/Caucasians. In this study, a variety of breast tumor molecular expression profiles of patients derived from the two racial groupings were investigated. Breast invasive carcinoma sample data (RNASeq version 2, Reverse Phase Protein Array, mutation, and miRSeq data) from the Cancer Genome Atlas were examined. The results affirm that B/AA patients are more likely than Caucasian patients to harbor the aggressive basal-like or the poor prognosis-associated HER2-enriched molecular subtypes of breast cancer. There is also a higher incidence of the triple-negative breast cancer (TNBC) among B/AA patients than the general population, a fact reflected in the mutation patterns of genes such as PIK3CA and TP53. Furthermore, an immortalization signature gene set, is enriched in samples from B/AA patients. Among stage III patients, TERT, DRAP1, and PQBP1, all members of the immortalization gene signature set, are among master-regulators with increased activity in B/AA patients. Master-regulators driving differences in expression profiles between the two groups include immortalization markers, senescence markers, and immune response and redox gene products. Differences in expression, between B/AA and Caucasian patients, of RB1, hsa-let-7a, E2F1, c-MYC, TERT, and other biomolecules appear to cooperate to enhance entry into the S-phase of the cell cycle in B/AA patients. Higher expression of miR-221, an oncomiR that facilitates entry into the cell cycle S-phase, is regulated by c-MYC, which is expressed more in breast cancer samples from B/AA patients. Furthermore, the cell migration- and invasion-promoting miRNA, miR-135b, has increased relative expression in B/AA patients. Knock down of the immortalization marker TERT inhibited triple-negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) cell viability and decreased expression of TERT, MYC and WNT11. For those patients with available survival data, prognosis of stage II patients 50 years of age or younger at diagnosis, was distinctly poorer in B/AA patients. Also associated with this subset of B/AA patients are missense mutations in HUWE1 and PTEN expression loss. Relative to Caucasian non-responders to endocrine therapy, B/AA non-responders show suppressed expression of a signature gene set on which biological processes including signaling by interleukins, circadian clock, regulation of lipid metabolism by PPARα, FOXO-mediated transcription, and regulation of TP53 degradation are over-represented. Thus, we identify molecular expression patterns suggesting diminished response to oxidative stress, changes in regulation of tumor suppressors/facilitators, and enhanced immortalization in B/AA patients are likely important in defining the more aggressive molecular tumor phenotype reported in B/AA patients.