• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Genetic variation and protein expression of metastasis-related genes as markers of tumor aggressiveness, recurrence, and survival among breast cancer patients.
【24h】

Genetic variation and protein expression of metastasis-related genes as markers of tumor aggressiveness, recurrence, and survival among breast cancer patients.

机译：转移相关基因的遗传变异和蛋白质表达是乳腺癌患者肿瘤侵袭性，复发和生存的标志。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Lymph node (LN) metastases and tumor characteristics predict breast cancer prognosis but correlate imperfectly with likelihood of metastatic relapse. Discovery of biomarkers that are predictive of metastasis may improve identification of patients requiring aggressive adjuvant therapy to prevent recurrence. In this dissertation, two types of markers were explored.;First, inherited genetic variation could potentially contribute to inter-patient variability in successful metastatic dissemination and colonization. To investigate this possibility, relationships between single nucleotide polymorphisms (SNPs) in 12 metastasis-related genes (BRMS1, CDH1, CD82/KAI1, CTNNB1, KISS1, MTA1, MTA2, MTA3, NME1, SATB1, SIPA1, and SNAI1), prognosis, and tumor characteristics that predispose patients to poorer prognosis, such as high grade and aggressive tumor subtypes, were analyzed in two separate study populations: the DataBank and BioRepository (DBBR) at Roswell Park Cancer Institute (N=859) and the Women's Circle of Health Study (WCHS; N=2,671), a case-control study of European-American (EA) and African-American (AA) women. In the DBBR dataset, seven variants in the BRMS1 (rs11537993, rs3116068, and rs1052566) and SIPA1 (rs75894763, rs746429, rs3741378, and rs2306364) genes were measured using SequenomRTM iPLEX Gold and TaqmanRTM real-time PCR assays. Logistic and Cox proportional hazards regressions were used to estimate odds ratios (OR) and hazard ratios (HR), respectively, for associations with tumor characteristics and prognosis. When the variants were combined into a risk allele score, the presence of eight or more risk alleles was associated with an increased likelihood of having a node positive tumor (OR=2.14, 95% CI 1.18-3.36, Ptrend = 0.002), although there were no significant associations with survival. In the WCHS dataset, 154 variants in the 12 aforementioned genes were measured using Illumina GoldenGate assays. Logistic regression, Haploview and PLINK were used to investigate single-SNP and haplotype associations between variants and risk of breast cancer, stratified by estrogen receptor (ER) status and LN status, and likelihood of ER negative and LN positive tumors. Pathway analyses, using the adaptive rank truncated product (ARTP) method, were conducted to assess the combined effect of SNPs with these outcomes. For significant genes and/or pathways (p?0.10), multiallelic risk scores were created using SNPs in the significant gene(s). To explore the contribution of each SNP in the significant gene(s) identified via ARTP, the elastic net form of penalized logistic regression was used. P-values for single-SNP, haplotype, and risk score analyses were corrected using the false discovery rate method. None of the single-SNP or haplotype associations remained significant after p-value correction. However, several genes were significant in the ARTP analysis [AA -- CDH1 (risk of node positive disease, p=0.10) and SIPA1 (likelihood of ER negative tumor, p=0.09); EA -- MTA2 (risk of ER positive, ER negative, and node negative breast cancer), SNAI1/CD82/NME1/CTNNB1 (risk of node positive breast cancer), SATB1 (risk of ER negative tumors, p=0.03)]. Multiallelic risk scores computed from the SNPs in these significant genes were also strongly associated with their respective outcomes.;Second, proteins involved in metastasis-related processes, such as the epithelial-mesenchymal transition (EMT), may serve as useful biomarkers of recurrence for breast cancer patients. To investigate this hypothesis, expression of three EMT-related proteins, E-cadherin, N-cadherin, and SATB1, was measured in primary breast tumors and matched lymph node (LN) metastases in 151 women who received surgery at RPCI. Protein expression was measured in tissue microarrays using immunohistochemistry. Semi-quantitative and quantitative assessments were made, using 4-category intensity/extent scores and Aperio's Positive Pixel Count algorithm (Aperio, v9). Unconditional and multinomial logistic regression was used to examine associations between primary tumor expression and tumor grade and subtype. Expression in primary tumors and metastases was compared using paired t-tests and McNemar's test. Time to recurrence and disease-free survival analyses were conducted using Kaplan-Meier and Cox proportional hazards regression techniques. Positive N-cadherin expression was associated with increased likelihood of having a high grade tumor as well as the HER2-enriched and triple negative tumor subtypes. Reduced E-cadherin expression was also associated with increased likelihood of having the HER2-enriched and triple negative tumor subtypes. Higher average SATB1 pixel intensity, indicating weaker expression, was associated with reduced likelihood of the HER2-enriched (OR=0.91, 95% CI 0.84-0.98) and triple negative (OR=0.91, 95% CI 0.84-0.99) subtypes. Mean differences in expression variables between primary tumor and LN metastases were generally significant for E-cadherin and SATB1, but there were no significant differences for N-cadherin. Patients with negative E-cadherin expression in primary tumors had poorer disease-free survival (log-rank test, p=0.04; HR=2.30, 95% CI 1.01-5.23), compared to those with positive expression. Patients with positive N-cadherin expression in LN metastases were at higher risk of recurrence compared to those negative for this marker (HR=2.93, 95% CI 1.01-8.49). SATB1 expression in LN metastases was also associated with increased risk of recurrence (HR=2.69, 95% CI 1.14-6.36) and poorer disease-free survival (HR=2.27, 95% CI 1.10-4.70).;In conclusion, our results suggest that genetic variants in and expression of metastasis-related genes may be related to tumor characteristics associated with more aggressive behavior, as well as prognostic outcomes, although larger studies are needed to confirm these findings. Further investigation of metastasis-related genes is necessary to better understand the biology of metastasis as well as to identify additional biomarkers that can accurately stratify patients by risk of recurrence.
机译：淋巴结（LN）转移和肿瘤特征可预测乳腺癌的预后，但与转移性复发的可能性不完全相关。发现可以预测转移的生物标志物可以改善对需要积极辅助治疗以防止复发的患者的识别。本文探讨了两种类型的标记物：第一，遗传性遗传变异可能成功地促进了转移和定植过程中患者之间的变异。为了研究这种可能性，我们探讨了12个与转移相关的基因（BRMS1，CDH1，CD82 / KAI1，CTNNB1，KISS1，MTA1，MTA2，MTA3，NME1，SATB1，SIPA1和SNAI1）之间的单核苷酸多态性（SNP）之间的关系，在两个独立的研究人群中分析了易导致患者预后较差的肿瘤特征，例如高级别和侵袭性肿瘤亚型：罗斯韦尔公园癌症研究所（N = 859）的数据库和生物存储库（DBBR）和女性健康圈研究（WCHS； N = 2,671），这是一项针对欧美（EA）和非洲裔美国（AA）妇女的病例对照研究。在DBBR数据集中，使用SequenomRTM iPLEX Gold和TaqmanRTM实时PCR测定法测量了BRMS1（rs11537993，rs3116068和rs1052566）和SIPA1（rs75894763，rs746429，rs3741378和rs2306364）基因的七个变体。 Logistic和Cox比例风险回归分别用于估计比值比（OR）和风险比（HR），以与肿瘤特征和预后相关。当将变体组合成风险等位基因得分时，存在八个或更多风险等位基因与淋巴结阳性肿瘤的可能性增加相关（OR = 2.14，95％CI 1.18-3.36，Ptrend = 0.002）与生存没有显着关联。在WCHS数据集中，使用Illumina GoldenGate分析方法测量了上述12个基因中的154个变异体。 Logistic回归，Haploview和PLINK用于研究变体与乳腺癌风险之间的单SNP和单倍型关联性，按雌激素受体（ER）状态和LN状态以及ER阴性和LN阳性肿瘤的可能性进行分层。使用适应性等级截断乘积（ARTP）方法进行路径分析，以评估SNP与这些结果的综合作用。对于重要的基因和/或途径（p = 0.10），使用重要基因中的SNP创建多等位基因风险评分。为了探索每个SNP在通过ARTP鉴定的重要基因中的贡献，使用了惩罚逻辑回归的弹性网形式。使用错误发现率方法校正单SNP，单倍型和风险评分分析的P值。 p值校正后，没有任何单个SNP或单倍型关联保持显着性。然而，在ARTP分析中有几个基因很重要[AA-CDH1（淋巴结阳性疾病的风险，p = 0.10）和SIPA1（ER阴性肿瘤的可能性，p = 0.09）； EA-MTA2（ER阳性，ER阴性和淋巴结阴性乳腺癌的风险），SNAI1 / CD82 / NME1 / CTNNB1（淋巴结阳性乳腺癌的风险），SATB1（ER阴性肿瘤的风险，p = 0.03）]。从这些重要基因的SNPs计算得到的多等位基因风险评分也与它们各自的结局密切相关。第二，参与转移相关过程的蛋白质，例如上皮-间质转化（EMT），可能是复发的有用的生物标志物乳腺癌患者。为了研究这一假设，在151名接受RPCI手术的妇女中，在原发性乳腺肿瘤和匹配的淋巴结（LN）转移中测量了三种与EMT相关的蛋白E-钙粘着蛋白，N-钙粘着蛋白和SATB1的表达。使用免疫组织化学在组织微阵列中测量蛋白质表达。使用4类强度/范围得分和Aperio的正像素计数算法（Aperio，v9）进行了半定量和定量评估。无条件和多项式逻辑回归用于检查原发性肿瘤表达与肿瘤等级和亚型之间的关联。使用配对t检验和McNemar检验比较了原发肿瘤和转移灶中的表达。使用Kaplan-Meier和Cox比例风险回归技术进行了复​​发时间和无病生存分析。 N-钙黏着蛋白阳性表达与罹患高级别肿瘤以及富含HER2和三阴性肿瘤亚型的可能性增加相关。 E-钙黏着蛋白表达降低还与富含HER2和三阴性肿瘤亚型的可能性增加有关。平均SATB1像素强度越高，表示表达越弱，与降低富含HER2的可能性（OR = 0.91，95％CI 0.84-0.98）和三阴性（OR = 0.91）的可能性有关。，95％CI 0.84-0.99）亚型。对于E-钙粘蛋白和SATB1，原发性肿瘤和LN转移之间表达变量的平均差异通常很显着，但对N-钙粘蛋白没有显着差异。与表达阳性的患者相比，原发性肿瘤中E-钙粘蛋白表达阴性的患者的无病生存期较差（对数秩检验，p = 0.04； HR = 2.30，95％CI 1.01-5.23）。与该指标阴性的患者相比，LN转移中N-钙粘蛋白表达阳性的患者复发风险更高（HR = 2.93，95％CI 1.01-8.49）。 LN转移中SATB1的表达还与复发风险增加（HR = 2.69，95％CI 1.14-6.36）和较差的无病生存期（HR = 2.27，95％CI 1.10-4.70）相关。提示与转移有关的基因的遗传变异和表达可能与与更具侵略性的行为以及预后相关的肿瘤特征有关，尽管需要更大的研究来证实这些发现。进一步研究与转移相关的基因对于更好地了解转移的生物学以及鉴定可以通过复发风险准确地对患者进行分层的其他生物标志物是必要的。

著录项

  • 作者

    Roberts, Michelle R.;

  • 作者单位

    State University of New York at Buffalo.;

  • 授予单位 State University of New York at Buffalo.;
  • 学科 Epidemiology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 334 p.
  • 总页数 334
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号