PO.PS01.01 · 人群科学

LEPR 和 PTGS2 基因多态性有助于乳腺癌的预后评估

Gene polymorphisms in LEPR and PTGS2 contribute for prognostic evaluation in breast cancer

编号 2306 展板 5 时间 4/20 09:00–12:00 区域 Section 35 主讲 Alessandra de Souza, MS

分会场 Biomarkers of Endogenous or Exogenous Exposures, Early Detection, Biological Effects, and Prognosis

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作者与单位 Authors & Affiliations

Alessandra Brandão de Souza¹, Daniely Regina Freitas-Alves¹, Taiana Sousa Lopes da Silva², Mario da Silva Ramos³, Matheus de Oliveira Afonso³, Jéssica Vilarinho Cardoso⁴, Jamila Alessandra Perini⁴, Rosane Vianna-Jorge³

¹Fundação Oswaldo Cruz (Fiocruz), Rio de Janeiro, Brazil,²Instituto Nacional do Câncer, Rio de Janeiro, Brazil,³Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil,⁴Universidade Estadual da Zona Oeste, Rio de Janeiro, Brazil

摘要 Abstract

中文摘要

乳腺癌是全球第二常见的肿瘤，被认为是一种异质性疾病，具有不同的遗传背景和多样的组织学及分子表现，从而影响预后。除肿瘤特异性特征外，个体遗传变异也可能影响疾病结局，需要在预后模型中加以评估。在此，我们采用候选基因方法，聚焦于炎症等生物学相关通路，以研究单核苷酸多态性（SNP）对乳腺癌结局的影响。该研究涉及对一个巴西女性前瞻性队列（N = 1038）的 10 年随访，这些患者为单侧、非转移性乳腺癌，在国家癌症研究所接受治疗（CAAE 55929416.8.0000.5240）。采用实时 PCR 对血样进行 14 个来自五个基因（LEP、LEPR、PTGS2、VEGFA 和 EGFR）的 SNP 基因分型。采用 Haploview 评估连锁不平衡和单倍型。采用 Kaplan-Meier 法估计生存曲线。采用风险比（HR）和 95% 置信区间（95% CI）估计 SNP 对无病生存期（DFS）和乳腺癌特异性生存期（BCSS）的影响。通过 Cox 回归多变量模型获得校正风险比（HRadj）。在整个人群（HR = 0.45；95%CI 0.26 - 0.77）、绝经后女性（HR = 0.57；95%CI 0.37 - 0.88）以及腔面型肿瘤患者（HR = 0.44；95%CI 0.25 - 0.80）中，均检测到 LEPR rs1137101 与 DFS 改善相关。相比之下，PTGS2 rs689466 与绝经后女性（HR = 1.70；95%CI 1.21 - 2.37 的 DFS 和 HR = 1.67；95%CI 1.13 - 2.47 的 BCSS）以及肥胖患者（DFS 的 HR = 1.68；95%CI 1.08 - 2.64，BCSS 的 HR = 1.82；95%CI 1.08 - 3.04）中较差的结局相关。由于 LEPR rs1137100 和 LEPR rs1137101 显示出显著的连锁不平衡（R² = 0.89），因此也将它们与 PTGS2 rs689466 联合评估，考虑这三个 SNP（A>G、A>G、A>G）。在整个研究人群中，LEPR rs1137100 或 LEPR rs1137101 中任一存在至少两个变异等位基因，同时 PTGS2 rs689466 为参考基因型，显示出 DFS 改善（HR = 0.60；95%CI 0.37 - 0.96）。相比之下，PTGS2 rs689466 变异等位基因与 LEPR rs1137100 和 LEPR rs1137101 均为参考基因型的组合，即使在多变量模型中也显示出最差的结局，显著影响整个人群的 DFS（HRadj = 1.75；95%CI 1.18 - 2.60）和 BCSS（HRadj = 1.72；95%CI 1.07 - 2.75），以及绝经后女性的 DFS（HRadj = 2.09；95%CI 1.16 - 3.77）和 BCSS（HRadj = 2.60；95%CI 1.35 - 5.0）。本研究结果表明，在制定乳腺癌预后模型时，同时考虑肿瘤和个体生物标志物的重要性。

查看英文原文 English abstract

Breast cancer is the second most frequent neoplasm worldwide and is considered a heterogeneous disease, with distinct genetic backgrounds and diverse histological and molecular presentations that influence prognosis. Besides tumor-specific characteristics, individual genetic variations may also potentially impact disease outcomes, and need to be assessed in prognostic models. Here, we employed a candidate gene approach, focusing on biologically relevant pathways, such as inflammation, to investigate the effects of single nucleotide polymorphisms (SNPs) on breast cancer outcomes. The investigation involved a 10 year follow-up of a prospective cohort of Brazilian women (N = 1038) with unilateral, nonmetastatic breast cancer treated at the National Cancer Institute (CAAE 55929416.8.0000.5240). Blood samples were genotyped for 14 SNPs from five genes ( LEP , LEPR , PTGS2 , VEGFA and EGFR ) using Real-Time PCR. Linkage disequilibrium and haplotypes were evaluated using Haploview. Survival curves were estimated using the Kaplan-Meier method. The effects of SNPs on disease-free survival (DFS) and breast cancer specific survival (BCSS) were estimated using hazard ratios (HR) and 95% confidence intervals (95% CI). Adjusted hazard ratios (HRadj) were obtained through Cox regression multivariate models. Improved DFS was detected for LEPR rs1137101 when considering the whole population (HR = 0.45; 95%CI 0.26 - 0.77), post-menopausal women (HR = 0.57; 95%CI 0.37 - 0.88), or among patients with luminal tumors (HR = 0.44; 95%CI 0.25 - 0.80). In contrast, PTGS2 rs689466 was associated with worse outcomes of DFS (HR = 1.70; 95%CI 1.21 - 2.37) and BCSS (HR = 1.67; 95%CI 1.13 - 2.47) among post-menopausal women, as well as among obese patients (HR = 1.68; 95%CI 1.08 - 2.64 for DFS and HR = 1.82; 95%CI 1.08 - 3.04 for BCSS). Because LEPR rs1137100 and LEPR rs1137101 showed significant linkage disequilibrium (R 2 = 0,89), they were also evaluated together, in combination with PTGS2 rs689466, considering the three SNPs (A>G, A>G, A>G). The occurrence of at least two variant alleles in either LEPR rs1137100 or LEPR rs1137101, in combination with the reference genotype of PTGS2 rs689466 showed improved DFS (HR = 0.60; 95%CI 0.37 - 0.96) within the whole population of the study. In contrast, the occurrence of PTGS2 rs689466 variant alleles in combination with both LEPR rs1137100 and LEPR rs1137101 reference genotypes showed the worst outcomes even in multivariate models, significantly affecting both DFS (HRadj = 1.75; 95%CI 1.18 - 2.60) and BCSS (HRadj = 1.72; 95%CI 1.07 - 2.75) for the whole population, as well as for post-menopausal women, with DFS (HRadj = 2.09; 95%CI 1.16 - 3.77) and BCSS (HRadj = 2.60; 95%CI 1.35 - 5.0). The present results indicate the importance of tailoring prognostic models for breast cancer considering both tumor and individual biomarkers.

利益披露 Disclosure

A. B. de Souza, None.. D. Freitas-Alves, None.. T. S. da Silva, None.. M. Ramos, None.. M. Afonso, None.. J. Cardoso, None.. J. Perini, None.. R. Vianna-Jorge, None.

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