Genetic determinants and clinical significance of circulating and tumor-specific levels of insulin-like growth factor binding protein 7 (IGFBP7) in a Swedish breast cancer cohort.

IF 3.3 3区 医学 Q2 ONCOLOGY
Christopher Godina, Ann H Rosendahl, Kelin Gonçalves de Oliveira, Somayeh Khazaei, Sofie Björner, Karin Jirström, Karolin Isaksson, Michael N Pollak, Helena Jernström
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Abstract

Previous research indicates that insulin-like growth factor binding protein 7 (IGFBP7) protein levels in breast cancer tissue and blood are prognostic. However, genetic determinants of IGFBP7 in breast cancer remain largely unexplored. We examined IGFBP7 in a cohort of 1701 patients with first breast cancer from Sweden, enrolled prior to surgery 2002-16 and followed for up to 15 years. Genotyping was performed on blood samples using OncoArray. Tumor-specific protein levels of IGFBP7, insulin receptor (InsR), and IGF-I receptor (IGFIR) were assessed on tumor tissue microarrays in 964 patients. Furthermore, 275 patients had plasma IGFBP7 levels measured. A genetic proxy marker for circulating IGFBP7 levels was constructed from five candidate single-nucleotide polymorphisms (SNPs) (rs6852762, rs1714014, rs9992658, rs10004910, and rs4865180) based on number of recessive genotypes. Age-adjusted linear regression was used to evaluate SNPs and tumor-specific IGFBP7 levels in relation to circulating IGFBP7 levels. Cox regression adjusted for age, tumor characteristics, and adjuvant treatments was used to assess associations with clinical outcomes. Circulating and tumor-specific IGFBP7 levels were significantly positively correlated. High circulating and genetically predicted IGFBP7 levels were associated with increased risk for distant metastasis and all-cause mortality. A significant interaction between high tumor-specific IGFBP7 levels and membrane-bound InsR resulted in a four-fold increased risk of breast cancer events and distant metastases. Both measured and genetically predicted IGFBP7 levels were independent prognostic biomarkers in breast cancer.

瑞典乳腺癌队列中胰岛素样生长因子结合蛋白7 (IGFBP7)循环和肿瘤特异性水平的遗传决定因素和临床意义
既往研究表明,乳腺癌组织和血液中胰岛素样生长因子结合蛋白7 (IGFBP7)蛋白水平与预后有关。然而,乳腺癌中IGFBP7的遗传决定因素在很大程度上仍未被探索。我们在1701名瑞典首发乳腺癌患者中检测了IGFBP7,这些患者在2002- 2016年手术前入组,随访长达15年。使用OncoArray对血样进行基因分型。在964例患者的肿瘤组织微阵列上评估了IGFBP7、胰岛素受体(InsR)和IGF-I受体(IGFIR)的肿瘤特异性蛋白水平。此外,275名患者检测了血浆IGFBP7水平。基于5个候选单核苷酸多态性(rs6852762、rs1714014、rs9992658、rs10004910和rs4865180)的隐性基因型数量,构建循环IGFBP7水平的遗传代理标记。使用年龄调整线性回归来评估snp和肿瘤特异性IGFBP7水平与循环IGFBP7水平的关系。采用Cox回归校正年龄、肿瘤特征和辅助治疗来评估与临床结果的关联。循环和肿瘤特异性IGFBP7水平显著正相关。高循环和基因预测的IGFBP7水平与远处转移和全因死亡风险增加相关。高肿瘤特异性IGFBP7水平和膜结合InsR之间的显著相互作用导致乳腺癌事件和远处转移的风险增加4倍。测量和基因预测的IGFBP7水平都是乳腺癌的独立预后生物标志物。
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来源期刊
Carcinogenesis
Carcinogenesis 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
95
审稿时长
1 months
期刊介绍: Carcinogenesis: Integrative Cancer Research is a multi-disciplinary journal that brings together all the varied aspects of research that will ultimately lead to the prevention of cancer in man. The journal publishes papers that warrant prompt publication in the areas of Biology, Genetics and Epigenetics (including the processes of promotion, progression, signal transduction, apoptosis, genomic instability, growth factors, cell and molecular biology, mutation, DNA repair, genetics, etc.), Cancer Biomarkers and Molecular Epidemiology (including genetic predisposition to cancer, and epidemiology), Inflammation, Microenvironment and Prevention (including molecular dosimetry, chemoprevention, nutrition and cancer, etc.), and Carcinogenesis (including oncogenes and tumor suppressor genes in carcinogenesis, therapy resistance of solid tumors, cancer mouse models, apoptosis and senescence, novel therapeutic targets and cancer drugs).
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