Research Pilot Project

摘要-研究试点 乳腺癌是世界范围内女性最常见的恶性肿瘤，但在乳腺癌的发病率方面存在明显差异。 种族/族裔群体之间的发病率和死亡率。西班牙裔/拉丁裔（H/L）是一个不断增长和研究不足的群体， 以欧洲人、美洲土著人和非洲人血统的不同混合为特征的群体。乳腺 癌症在遗传和生物学上是异质的，由多种分子亚型组成， 预后和对治疗的反应。PAM 50基因表达组区分了五种主要的 乳腺癌的内在亚型：管腔A、管腔B（均为ERα阳性）、Her 2/Neu富集、基底样 和正常一样。Luminal B亚型的预后比Luminal A亚型差，核表达较低， 激素受体和增殖标记物的更高表达。这些肿瘤从内分泌中获益较少 乳腺癌是乳腺癌的主要病因之一。在301例临床标注的H/L队列中， 乳腺癌患者中，我们发现在混合血统的西班牙裔/拉丁裔患者中， 管腔型B类肿瘤的发生率非常高（>42%）。在这些H/L患者中，管腔B肿瘤的特征在于 比Luminal A肿瘤更具侵袭性的临床表现，这表明高频率的 管腔B肿瘤与强烈的健康结果差异相关。管腔B的发生率较高 在美国H/L患者中已经报道了肿瘤，但是研究中H/L的数量太少，无法得出 明确的结论。使用RNASeq，我们发现H/L Luminal B肿瘤通常具有以下特征： ERBB 2（Her 2/Neu）受体、GRB 7衔接子以及迁移和侵袭的表达增加 增强子，MIEN 1。这三个基因的表达与土著美国人（IA）的祖先有关， 位于Ch 17 q12。ERBB 2和GRB 7在Her 2/Neu富集的肿瘤中共扩增，并且相关 ERα阳性肿瘤存在内分泌抵抗，预后差。遗传祖先和 管腔型B乳腺癌可以帮助确定预后生物标志物以及特定的 治疗方法（精确医学）在H/L。我们的主要假设是H/L种族/IA血统 与管腔B肿瘤的高发病率以及ERBB 2、GRB 7和 MIEN1.此外，我们提出，这三个基因的表达升高可能是结果， 与IA祖先相关的启动子或增强子甲基化的改变。为了验证这些观点，我们将考察一部小说 H/L乳腺癌患者队列的两个具体目标：（1）确定PAM 50的分子画像- 使用RNASeq证实来自H/L乳腺癌患者的管腔B肿瘤，并将这些发现与 与临床病理参数和结果，以及（2）建立ERBB 2，GRB 7和 MIEN 1与启动子甲基化、祖先、临床病理参数和临床结局的关系

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.