DataSheet_1_Association of genetic ancestry with HER2, GRB7 AND estrogen receptor expression among Colombian women with breast cancer.docx

BackgroundOur previous study reported higher mRNA levels of the human epidermal growth factor receptor 2 (HER2)-amplicon genes ERBB2 and GRB7 in estrogen receptor (ER)-positive breast cancer patients with relatively high Indigenous American (IA) ancestry from Colombia. Even though the protein expression of HER2 and GRB7 is highly correlated, they may also express independently, an event that could change the patients’ prognosis. In this study, we aimed to explore the differences in ER, HER2 and GRB7 protein expression according to genetic ancestry, to further assess the clinical implications of this association.
MethodsWe estimated genetic ancestry from non-tumoral breast tissue DNA and assessed tumoral protein expression of ER, HER2, and GRB7 by immunohistochemistry in a cohort of Colombian patients from different health institutions. We used binomial and multinomial logistic regression models to test the association between genetic ancestry and protein expression. Kaplan-Meier and log-rank tests were used to evaluate the effect of HER2/GRB7 co-expression on patients’ survival.
ResultsOur results show that patients with higher IA ancestry have higher odds of having HER2+/GRB7- breast tumors, compared to the HER2-/GRB7- subtype, and this association seems to be stronger among ER-positive tumors (ER+/HER2+/GRB7-: OR=3.04, 95% CI, 1.47-6.37, p<0.05). However, in the multivariate model this association was attenuated (OR=1.80, 95% CI, 0.72-4.44, p=0.19). On the other hand, it was observed that having a higher European ancestry patients presented lower odds of ER+/HER2+/GRB7- breast tumors, this association remained significant in the multivariate model (OR=0.36, 95% CI, 0.13 - 0.93, p= 0.0395). The survival analysis according to HER2/GRB7 co-expression did not show statistically significant differences in the overall survival and recurrence-free survival.
ConclusionsOur results suggest that Colombian patients with higher IA ancestry and a lower European fraction have higher odds of ER+/HER2+/GRB7- tumors compared to ER+/HER2-/GRB7- disease. However, this association does not seem to be associated with patients’ overall or recurrence-free survival.

研究背景
本团队此前的研究显示，在来自哥伦比亚、美洲原住民（Indigenous American，IA）祖先占比较高的雌激素受体（estrogen receptor，ER）阳性乳腺癌患者中，人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）扩增子基因ERBB2与GRB7的mRNA水平更高。尽管HER2与GRB7的蛋白表达高度相关，但二者亦可独立表达，该现象可能会改变患者的预后情况。本研究旨在探究不同遗传祖先背景下ER、HER2及GRB7的蛋白表达差异，以进一步评估该关联的临床意义。

研究方法
本研究从哥伦比亚多家医疗机构的乳腺癌患者队列中，提取非肿瘤乳腺组织的DNA以估算遗传祖先背景，并通过免疫组化（immunohistochemistry）检测肿瘤组织中ER、HER2及GRB7的蛋白表达水平。本研究采用二项及多项逻辑回归模型，检验遗传祖先背景与蛋白表达之间的关联。采用卡普兰-迈耶（Kaplan-Meier）法与对数秩检验（log-rank test），评估HER2与GRB7共表达对患者生存情况的影响。

研究结果
本研究结果显示，与HER2-/GRB7-亚型乳腺癌相比，美洲原住民祖先占比更高的患者罹患HER2+/GRB7-型乳腺癌的比值比（odds ratio，OR）更高；且该关联在雌激素受体阳性（ER+）肿瘤中更为显著（ER+/HER2+/GRB7-：OR=3.04，95%置信区间（confidence interval，CI）：1.47~6.37，p<0.05）。但在多变量模型中，该关联被弱化（OR=1.80，95%CI：0.72~4.44，p=0.19）。另一方面，研究观察到欧洲祖先占比更高的患者罹患ER+/HER2+/GRB7-型乳腺癌的比值比更低，且该关联在多变量模型中仍具有统计学显著性（OR=0.36，95%CI：0.13~0.93，p=0.0395）。针对HER2/GRB7共表达的生存分析显示，患者的总生存期与无复发生存期均未出现具有统计学显著性的差异。

研究结论
本研究结果表明，与ER+/HER2-/GRB7-型乳腺癌患者相比，哥伦比亚患者中美洲原住民祖先占比更高、欧洲祖先占比更低的群体，罹患ER+/HER2+/GRB7-型肿瘤的比值比更高。但该关联似乎与患者的总生存期及无复发生存期均无显著相关性。