Research Pilot Project

摘要--研究试点 乳腺癌是全世界女性中最常见的恶性肿瘤，但在 不同种族/民族之间的发病率和死亡率。拉美裔/拉丁裔(H/L)是一个成长中的、研究不足的 以欧洲人、美洲土著人和非洲人血统的可变混血儿为特征的群体。乳房 癌症在基因和生物上是异质性的，由多种不同的分子亚型组成。 预后和治疗反应方面的条件。PAM50基因表达面板区分了五个主要 乳腺癌的固有亚型：管腔A、管腔B(均为ERα阳性)、HER2/Neu富集型、基底样癌 而且是正常的。B亚型预后较A亚型差，核低表达 激素受体和高表达的增殖标记物。这些肿瘤从内分泌中获益较少。 治疗，并且仍然是导致乳腺癌死亡的最大原因。在301名经临床注释的H/L的队列中 在乳腺癌患者中，我们发现在西班牙裔/拉丁裔混血患者中， 腔内B型肿瘤非常高(&gt；42%)。在这些H/L患者中，以腔B肿瘤为特征 通过比腔A肿瘤更具侵袭性的临床表现，表明 腔B瘤与严重的健康结局差异有关。一种较高的B型肠腔发病率 据报道，美国H/L患者中存在肿瘤，但研究中的H/L患者数量太少，无法得出结论 明确的结论。使用RNAseq，我们发现H/L腔B瘤的特征通常是 ERBB2(Her2/Neu)受体、GRB7受体表达增加与肿瘤的迁移和侵袭 增强器，MIEN1。这三个基因的表达与土著美国人(IA)血统和ALL有关 位于Ch17q12。ERBB2和GRB7在Her2/Neu富集型肿瘤中共扩增，且相互关联 ERα阳性肿瘤具有内分泌抵抗和预后差的特点。基因祖先和 腔型B型乳腺癌有助于确定预后的生物标志物以及特定肿瘤的分子特征 H/L的治疗方法(精确医学)我们的主要假设是H/L种族/IA血统 与B腔肿瘤的高发病率以及ERBB2、GRB7和ERBB2、GRB7和ERBB2的表达增加有关 MIEN1。此外，我们认为这三个基因的表达升高可能是结果。 与IA血统相关的改变的启动子或增强子甲基化。为了检验这些想法，我们将考察一部小说 H/L乳腺癌患者队列的两个特定目的：(1)确定PAM50-1的分子图谱 利用RNAseq技术从H/L乳腺癌患者中证实管腔B瘤，并与这些发现进行相关性分析 与临床病理参数和预后的关系；(2)建立ERBB2、GRB7和ERBB2与GRB7和ERBB2之间的关系 MIEN1与启动子甲基化、祖先、临床病理参数和临床结果的关系。

ABSTRACT – Research Pilot Breast cancer is the most frequent malignancy in women worldwide, yet there are pronounced differences in incidence and mortality between racial/ethnic groups. Hispanics/Latinas (H/L) are a growing and understudied group characterized by a variable admixture of European, Indigenous American, and African ancestry. Breast cancer is genetically and biologically heterogeneous, consisting of multiple molecular subtypes which differ in terms of prognosis and response to treatment. The PAM50 gene expression panel distinguishes five main intrinsic subtypes of breast cancer: Luminal A, Luminal B (both ERα-positive), Her2/Neu enriched, Basal-like and Normal-like. The Luminal B subtype has a poorer prognosis than Luminal A, lower expression of nuclear hormone receptors, and higher expression of proliferation markers. These tumors benefit less from endocrine therapy, and remain the largest cause of breast cancer mortality. In a cohort of 301 clinically annotated H/L breast cancer patients, we found that among mixed-ancestry Hispanic/Latina patients, the frequency of Luminal B tumors is remarkably high (>42%). Among these H/L patients, Luminal B tumors are characterized by a more aggressive clinical presentation than Luminal A tumors, suggesting that the high frequency of Luminal B tumors is associated with a strong health outcomes disparity. A higher incidence of Luminal B tumors has been reported among US H/L patients, but the number of H/L in the study was too small to draw definite conclusions. Using RNASeq, we found that H/L Luminal B tumors are frequently characterized by increased expression of the ERBB2 (Her2/Neu) receptor, the GRB7 adaptor and the migration and invasion enhancer, MIEN1. Expression of these three genes was linked to Indigenous American (IA) ancestry and all are located at Ch17q12. ERBB2 and GRB7 are co-amplified in Her2/Neu enriched tumors, and are correlated with endocrine resistance and poor prognosis in ERα-positive tumors. A link between genetic ancestry and Luminal B breast cancer can help identify prognostic biomarkers as well as molecular features for specific therapeutic approaches (precision medicine) in H/L. Our primary hypothesis is that H/L ethnicity/IA ancestry are associated with a high incidence of Luminal B tumors and with increased expression of ERBB2, GRB7 and MIEN1. Furthermore, we propose that the elevated expression of these three genes may be the consequence of altered promoter or enhancer methylation linked to IA ancestry. To test these ideas, we will examine a novel cohort of H/L breast cancer patients in two specific aims: (1) to determine the molecular portraits of PAM50- confirmed Luminal B tumors from H/L breast cancer patients utilizing RNASeq, and to correlate these findings with clinicopathological parameters and outcomes, and (2) to establish the relationship of ERBB2, GRB7 and MIEN1 with promoter methylation, ancestry, clinicopathological parameters and clinical outcomes.