Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
Ann Oncol. 2020 May;31(5):641-649. doi: 10.1016/j.annonc.2020.01.066. Epub 2020 Mar 10.
Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference.
We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls.
In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01-1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER) tumours, but no effect found for estrogen-negative (ER) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97-1.04; P = 0.98).
Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.
流行病学证据支持循环胰岛素样生长因子-1（IGF-1）浓度与乳腺癌风险之间存在正相关关系，但这种关系的程度和因果关系尚不确定。我们进行了观察性分析，并调整了回归稀释偏差，孟德尔随机分析允许进行因果推断。
我们在英国生物库中对 206263 名女性进行了循环 IGF-1 浓度与乳腺癌发病风险的相关性研究。使用 Cox 比例风险模型估计多变量风险比（HR）和 95%置信区间（CI）。在 6711 名女性的亚组中，使用重复 IGF-1 测量值校正 HR 以纠正回归稀释。对于 MR 分析，鉴定与循环 IGF-1 和 IGF 结合蛋白-3（IGFBP-3）水平相关的遗传变异，并使用来自 122977 例病例和 105974 例对照的全基因组数据，使用两样本 MR 方法研究它们与乳腺癌的关联。
在英国生物库中，中位随访 7.1 年后，发生了 4360 例乳腺癌病例。在调整了回归稀释的多变量调整模型中，较高的 IGF-1 浓度与乳腺癌风险增加相关（每增加 5nmol/l IGF-1 的 HR = 1.11，95%CI = 1.07-1.16）。通过随访时间、绝经状态、体重指数和其他危险因素也发现了类似的正相关关系。在 MR 分析中，遗传预测的 IGF-1 浓度增加 5nmol/l 与乳腺癌风险增加相关（比值比 = 1.05，95%CI = 1.01-1.10；P = 0.02），与雌激素阳性（ER）肿瘤的效应估计值相似，但对雌激素阴性（ER）肿瘤没有影响。遗传预测的 IGFBP-3 浓度与乳腺癌风险无关（每增加 1 个标准差的比值比 = 1.00，95%CI = 0.97-1.04；P = 0.98）。
我们的结果支持循环 IGF-1 浓度与乳腺癌之间可能存在因果关系，这表明靶向 IGF 途径的干预措施可能有益于预防乳腺癌的发生。
