PO.PS01.07 · 人群科学
利用相反关联的遗传变异研究ER+和ER-乳腺癌亚型的分歧风险
Investigating divergent ER + and ER - breast cancer subtype risks by using oppositely associated genetic variants
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
乳腺癌是美国女性癌症相关死亡的第二大常见原因，其发病率逐年上升。雌激素受体阴性（ER-）乳腺癌相较于雌激素受体阳性（ER+）类型尤为侵袭，对常规治疗的反应也较差，尽管其表现出更高的免疫原性和对免疫治疗更好的反应。本研究着重于识别在ER+和ER-乳腺癌之间呈相反关联的单核苷酸多态性（SNP），即某个SNP的存在会增加一种亚型的风险而降低另一种亚型的风险。我们从乳腺癌协会联盟（BCAC）中识别出481个在亚型间呈相反关联（p<0.1）的SNP，并使用来自癌症基因组图谱（TCGA）乳腺癌患者的数据（通过TOPMED填补服务器进行填补）对这些关联进行交叉验证。我们的发现揭示了45个与ER+风险增加但ER-风险降低相关的SNP，以及2个与ER-风险增加但ER+风险降低相关的SNP，这些SNP在BCAC和TCGA数据集之间一致。在增加ER+风险的一致SNP中，大多数定位于11号染色体上已知抑癌基因ATM附近的区域；然而，10号染色体上的一个SNP（10:21471086:C/T）此前已被证明可增加循环IGF-1并降低结直肠癌风险，且在女性中的作用程度大于男性。使用CIBERSORTx工具的进一步分析显示，该SNP与肿瘤微环境中血管周样未成熟细胞浸润增加相关。在增加ER-风险的SNP中，一个定位于DLX2基因一个描述不充分的反义非编码转录本，该基因与乳腺癌有关；另一个定位于PTPRN2基因的内含子，该基因与1型糖尿病和多种癌症有关。虽然本研究受限于其聚焦于欧洲女性以及ER-病例样本量较小，但结果为可能差异性影响ER+和ER-疾病的遗传变异提供了初步见解，支持未来旨在阐明促成亚型特异性风险、免疫浸润和治疗反应的通路的工作。
查看英文原文 English abstract
Breast cancer is the second most common cause of cancer-related deaths among women in the United States, with its incidence increasing each year. Estrogen receptor-negative (ER - ) breast cancers are particularly aggressive and less responsive to conventional treatments compared to estrogen receptor-positive (ER + ) types, though they exhibit higher immunogenicity and better responses to immunotherapies. This study focuses on identifying single nucleotide polymorphisms (SNPs) that are oppositely associated between ER + and ER - breast cancers, meaning that the presence of a SNP increases the risk of one subtype while decreasing the risk of the other subtype. We identified 481 SNPs from the Breast Cancer Association Consortium (BCAC) that were oppositely associated between subtypes (p < 0.1) and cross-validated these associations using data from breast cancer patients in The Cancer Genome Atlas (TCGA), imputed using the TOPMED imputation server. Our findings revealed 45 SNPs associated with increased ER + risk but decreased ER - risk and 2 SNPs associated with increased ER - risk but decreased ER + risk that were concordant between the BCAC and TCGA datasets. Of the concordant SNPs that increased ER + risk, the majority mapped to a region of chromosome 11 near the known tumor suppressor gene ATM; however, one SNP on chromosome 10 (10:21471086:C/T) has been previously shown to increase circulating IGF-1 and decrease colorectal cancer risk to a greater extent in women than men. Further analysis using the CIBERSORTx tool showed that this SNP was associated with increased infiltration of perivascular-like immature cells in the tumor microenvironment. Of the SNPs that increased ER - risk, one localized to a poorly described antisense non-coding transcript of the DLX2 gene which has been implicated in breast cancer, while the other localized to an intron of the PTPRN2 gene that is implicated in type 1 diabetes mellitus and many cancers. While this study is limited by its focus on European women and the small sample size of ER - cases, the results offer preliminary insight into inherited variants that may differentially influence ER + and ER - disease, supporting future work aimed at clarifying the pathways that contribute to subtype-specific risk, immune infiltration, and treatment response.
利益披露 Disclosure
P. Schofield, None.