Lee Min Joon, Jayalath Viranda H, Xu Wei, Lu Lin, Freedland Stephen J, Fleshner Neil E, Kulkarni Girish S, Finelli Antonio, van der Kwast Theodorus H, Hamilton Robert J
Division of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.
Department of Biostatistics, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Prostate Cancer Prostatic Dis. 2021 Mar;24(1):96-105. doi: 10.1038/s41391-020-0238-y. Epub 2020 May 18.
The relationship between metformin use and prostate cancer risk remains controversial. Genetic variation in metformin metabolism pathways appears to modify metformin glycemic control and the protective association with some cancers. However, no studies to date have examined this pharmacogenetic interaction and prostate cancer chemoprevention.
Clinical data and germline DNA were collected from our prostate biopsy database between 1996 and 2014. In addition to a genome-wide association study (GWAS), 27 single nucleotide polymorphisms (SNPs) implicated in metformin metabolism were included on a custom SNP array. Associations between metformin use and risk of high-grade (Grade Group ≥ 2) and overall prostate cancer were explored using a case-control design. Interaction between the candidate/GWAS SNPs and the metformin-cancer association was explored using a case-only design.
Among 3481 men, 132 (4%) were taking metformin at diagnosis. Metformin users were older, more likely non-Caucasian, and had higher body mass index, Gleason score, and number of positive cores. Overall, 2061 (59%) were diagnosed with prostate cancer, of which 922 (45%) were high-grade. After adjusting for baseline characteristics, metformin use was associated with higher risk of high-grade prostate cancer (OR = 1.76, 95% CI 1.1-2.9, p = 0.02) and overall prostate cancer (OR = 1.77, 95% CI 1.1-2.9, p = 0.03). None of the 27 candidate SNPs in metformin metabolic pathways had significant interaction with the metformin-cancer association. Among the GWAS SNPs, one SNP (rs149137006) had genome-wide significant interaction with metformin for high-grade prostate cancer, and another, rs115071742, for overall prostate cancer. They were intronic and intergenic SNPs, respectively, with largely uncharacterized roles in prostate cancer chemoprevention.
In our cohort, metformin use was associated with increased risk of being diagnosed with prostate cancer. While SNPs involved in metformin metabolism did not have modifying effects on the association with disease risk, one intronic and one intergenic SNP from the GWAS study did, and these require further study.
二甲双胍的使用与前列腺癌风险之间的关系仍存在争议。二甲双胍代谢途径中的基因变异似乎会改变二甲双胍的血糖控制以及与某些癌症的保护关联。然而，迄今为止尚无研究探讨这种药物遗传学相互作用与前列腺癌化学预防之间的关系。
从我们1996年至2014年的前列腺活检数据库中收集临床数据和生殖系DNA。除全基因组关联研究（GWAS）外，定制SNP芯片上还纳入了27个与二甲双胍代谢相关的单核苷酸多态性（SNP）。采用病例对照设计探讨二甲双胍使用与高级别（分级组≥2）及总体前列腺癌风险之间的关联。采用病例单组设计探讨候选/SNP芯片SNP与二甲双胍-癌症关联之间的相互作用。
在3481名男性中，132名（4%）在诊断时正在服用二甲双胍。二甲双胍使用者年龄较大，更可能是非白种人，且体重指数、Gleason评分和阳性核心数较高。总体而言，2061名（59%）被诊断为前列腺癌，其中922名（45%）为高级别前列腺癌。在调整基线特征后，二甲双胍的使用与高级别前列腺癌（OR = 1.76，95%CI 1.1 - 2.9，p = 0.02）和总体前列腺癌（OR = 1.77，95%CI 1.1 - 2.9，p = 0.03）的较高风险相关。二甲双胍代谢途径中的27个候选SNP均未与二甲双胍-癌症关联产生显著相互作用。在GWAS的SNP中，一个SNP（rs149137006）与二甲双胍在高级别前列腺癌方面存在全基因组显著相互作用，另一个SNP（rs115071742）在总体前列腺癌方面存在这种相互作用。它们分别是内含子SNP和基因间SNP，在前列腺癌化学预防中的作用基本未明。
在我们的队列中，二甲双胍的使用与被诊断为前列腺癌的风险增加相关。虽然参与二甲双胍代谢的SNP对与疾病风险的关联没有修饰作用，但GWAS研究中的一个内含子SNP和一个基因间SNP有这种作用，这些需要进一步研究。
