一项前瞻性巢式病例对照研究中全基因组外周血DNA甲基化与前列腺癌风险的测量

Genome-Wide Measures of Peripheral Blood Dna Methylation and Prostate Cancer Risk in a Prospective Nested Case-Control Study.

作者信息

FitzGerald Liesel M, Naeem Haroon, Makalic Enes, Schmidt Daniel F, Dowty James G, Joo Jihoon E, Jung Chol-Hee, Bassett Julie K, Dugue Pierre-Antoine, Chung Jessica, Lonie Andrew, Milne Roger L, Wong Ee Ming, Hopper John L, English Dallas R, Severi Gianluca, Baglietto Laura, Pedersen John, Giles Graham G, Southey Melissa C

机构信息

Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC, Australia.

Cancer, Genetics, and Immunology, Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.

出版信息

Prostate. 2017 Apr;77(5):471-478. doi: 10.1002/pros.23289. Epub 2017 Jan 24.

DOI:10.1002/pros.23289

PMID:28116812

Abstract

BACKGROUND

Global measures of peripheral blood DNA methylation have been associated with risk of some malignancies, including breast, bladder, and gastric cancer. Here, we examined genome-wide measures of peripheral blood DNA methylation in prostate cancer and its non-aggressive and aggressive disease forms.

METHODS

We used a matched, case-control study of 687 incident prostate cancer samples, nested within a larger prospective cohort study. DNA methylation was measured in pre-diagnostic, peripheral blood samples using the Illumina Infinium HM450K BeadChip. Genome-wide measures of DNA methylation were computed as the median M-value of all CpG sites and according to CpG site location and regulatory function. We used conditional logistic regression to test for associations between genome-wide measures of DNA methylation and risk of prostate cancer and its subtypes, and by time between blood draw and diagnosis.

RESULTS

We observed no associations between the genome-wide measure of DNA methylation based on all CpG sites and risk of prostate cancer or aggressive disease. Risk of non-aggressive disease was associated with higher methylation of CpG islands (OR = 0.80; 95%CI = 0.68-0.94), promoter regions (OR = 0.79; 95%CI = 0.66-0.93), and high density CpG regions (OR = 0.80; 95%CI = 0.68-0.94). Additionally, higher methylation of all CpGs (OR = 0.66; 95%CI = 0.48-0.89), CpG shores (OR = 0.62; 95%CI = 0.45-0.84), and regulatory regions (OR = 0.68; 95% CI = 0.51-0.91) was associated with a reduced risk of overall prostate cancer within 5 years of blood draw but not thereafter.

CONCLUSIONS

A reduced risk of overall prostate cancer within 5 years of blood draw and non-aggressive prostate cancer was associated with higher genome-wide methylation of peripheral blood DNA. While these data have no immediate clinical utility, with further work they may provide insight into the early events of prostate carcinogenesis. Prostate 77:471-478, 2017. © 2017 Wiley Periodicals, Inc.

摘要

背景

外周血DNA甲基化的整体测量已与某些恶性肿瘤的风险相关，包括乳腺癌、膀胱癌和胃癌。在此，我们研究了前列腺癌及其非侵袭性和侵袭性疾病形式中外周血DNA甲基化的全基因组测量。

方法

我们在一项更大的前瞻性队列研究中进行了一项匹配的病例对照研究，纳入了687例新发前列腺癌样本。使用Illumina Infinium HM450K BeadChip在诊断前的外周血样本中测量DNA甲基化。DNA甲基化的全基因组测量值计算为所有CpG位点的中位M值，并根据CpG位点位置和调控功能进行计算。我们使用条件逻辑回归来测试DNA甲基化的全基因组测量值与前列腺癌及其亚型风险之间的关联，以及采血与诊断之间的时间关联。

结果

我们观察到基于所有CpG位点的DNA甲基化全基因组测量值与前列腺癌或侵袭性疾病风险之间无关联。非侵袭性疾病风险与CpG岛甲基化水平较高相关（OR = 0.80；95%CI = 0.68 - 0.94），启动子区域（OR = 0.79；95%CI = 0.66 - 0.93）和高密度CpG区域（OR = 0.80；95%CI = 0.68 - 0.94）。此外，所有CpG（OR = 0.66；95%CI = 0.48 - 0.89）、CpG岸（OR = 0.62；95%CI = 0.45 - 0.84）和调控区域（OR = 0.68；95%CI = 0.51 - 0.91）甲基化水平较高与采血后5年内总体前列腺癌风险降低相关，但之后则不然。