PO.PS01.01 · 人群科学

白细胞中Y染色体的嵌合性丢失与278,998例无癌男性中非侵袭性前列腺癌发病率升高相关

Mosaic loss of the Y chromosome in leukocytes is associated with increased incidence of non-aggressive prostate cancer in 278,998 cancer-free males

编号 2330 展板 29 时间 4/20 09:00–12:00 区域 Section 35 主讲 Rebecca Kelly, MPH;PhD

分会场 Biomarkers of Endogenous or Exogenous Exposures, Early Detection, Biological Effects, and Prognosis

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作者与单位 Authors & Affiliations

Rebecca L. Kelly¹, Anqi Wang², Yifan Zhang³, Weyin Zhou⁴, Kara M. Barnao⁴, Corey D. Young⁴, Aubrey K. Hubbard⁴, Wen-Yi Huang⁴, Steven C. Moore⁴, Christopher A. Haiman³, Stephen J. Chanock⁴, Ying Wang⁵, Konrad H. Stopsack⁶, Lorelei A. Mucci⁷, Fei Chen³, Mitchell J. Machiela⁴

¹Division of Cancer Epidemiology and Genetics, Division of Cancer Prevention, National Cancer Institute, Rockville, MD,²USC School of Pharmacy, Los Angeles, CA,³Department of Population and Public Health Sciences, University of Southern California Keck School of Medicine, Los Angeles, CA,⁴Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD,⁵American Cancer Society, Atlanta, GA,⁶Leibniz Institute for Prevention Research and Epidemiology, Bremen, Germany,⁷Harvard T.H. Chan School of Public Health, Boston, MA

摘要 Abstract

中文摘要

背景：Y染色体嵌合性丢失（mLOY）是一种克隆性造血，是老龄男性白细胞中最常检测到的染色体改变。前列腺癌（PCa）在老龄男性中呈指数级增长，既往研究显示mLOY遗传风险与PCa诊断之间存在正相关。需要在基于人群的研究中确证这一关联，以确定mLOY是否可作为PCa风险的信息性生物标志物。方法：为评估mLOY与前列腺癌风险之间的潜在关联，我们使用MoChA算法，对六个前瞻性队列中278,998例无癌男性血源性DNA的现有高密度基因分型芯片数据检测mLOY：UK Biobank（UKBB，N=210,103）；前列腺癌、肺癌、结直肠癌和卵巢癌筛查试验（PLCO，N=26,275）；卫生专业人员随访研究（HPFS，N=4,933）；医师健康研究（PHS，N=1,148）；多族裔队列（MEC，N=24,370）；以及癌症预防研究II（CPSII，N=12,169）。采用以年龄为时间尺度的Cox比例风险模型，估计mLOY与前列腺癌发病率关联的风险比（HR）和95%置信区间（CI），并校正体质指数、吸烟状态、基因分型芯片和前10个遗传主成分。在各队列中进行关联检验，然后进行meta分析。结果：各队列mLOY检出率和PCa诊断率的平均值分别为23.4%和17.9%。对校正后HR的固定效应meta分析发现，mLOY与总体PCa风险呈正相关（HR=1.09，CI 1.05, 1.13；P值（P）=2.25 x 10-6）。mLOY与诊断时Gleason评分≤6相关（HR=1.13，95% CI 1.04, 1.23；P=0.0029）、与非侵袭性PCa诊断的更高风险相关（HR=1.15，95% CI 1.05, 1.26；P=0.0022），以及与诊断时PSA<10ng/mL相关（HR=1.11，95% CI 1.02, 1.22；P=0.015）。我们未观察到mLOY与Gleason评分≥8、侵袭性PCa或诊断时转移相关的证据。我们确证，在与欧洲参照人群遗传相似的参与者中，mLOY的种系遗传风险与PCa发病率呈正相关（每1个SD的mLOY PRS，HR=1.02，95% CI 1.00, 1.03；P=0.0083），而在与非洲参照人群相似的参与者中证据较弱（每1个SD的mLOY PRS，HR=1.01，95% CI 0.94, 1.08；P=0.769）。结论：我们对mLOY与PCa诊断关系的研究，为血液中检测到的mLOY与非侵袭性PCa风险升高之间的关联提供了证据，提示mLOY在PCa风险分层中可能具有应用价值。

查看英文原文 English abstract

Background: Mosaic loss of the Y chromosome (mLOY), a type of clonal hematopoiesis, is the most frequently detected chromosomal alteration in the leukocytes of aging males. Prostate cancer (PCa) increases exponentially in aging males and previous studies have shown a positive association between genetic risk of mLOY and PCa diagnosis. Confirmation of this association in population-based studies is needed to determine if mLOY could be an informative biomarker for PCa risk. Methods: To evaluate the potential association between mLOY and prostate cancer risk, we detected mLOY using the MoChA algorithm on existing high-density genotyping array data from blood-derived DNA of 278,998 cancer-free males across six prospective cohorts: UK Biobank (UKBB, N=210,103); Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, N=26,275); Health Professionals' Follow-Up Study (HPFS, N=4,933); Physicians' Health Study (PHS, N=1,148); Multiethnic Cohort (MEC, N=24,370); and Cancer Prevention Study II (CPSII, N=12,169). Cox proportional hazards models with age as a timescale estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association of mLOY on prostate cancer incidence adjusted for body mass index, smoking status, genotyping array, and the top 10 genetic principal components. Association tests were performed in each cohort and then meta-analyzed. Results: The average mLOY detection and PCa diagnosis across cohorts were 23.4% and 17.9%, respectively. Fixed effects meta-analysis of the adjusted HRs identified a positive association of mLOY with overall PCa risk (HR=1.09, CI 1.05, 1.13; P-Value ( P )=2.25 x 10 -6 ). mLOY was associated with a Gleason score ≤6 at diagnosis (HR=1.13, 95% CI 1.04, 1.23; P =0.0029), a greater hazard of non-aggressive PCa diagnosis (HR=1.15, 95% CI 1.05, 1.26; P =0.0022), and PSA <10ng/mL at diagnosis (HR=1.11, 95% CI 1.02, 1.22; P =0.015). We did not observe evidence for mLOY associations with Gleason score ≥8, aggressive PCa or metastasis at diagnosis. We confirmed germline genetic risk of mLOY was positively associated with PCa incidence in participants with genetic similarity to European reference populations (HR=1.02 per 1 SD mLOY PRS, 95% CI 1.00, 1.03; P =0.0083), there was less evidence in participants similar to African reference populations (HR=1.01 per 1 SD mLOY PRS, 95% CI 0.94, 1.08; P =0.769). Conclusion: Our investigation of the relationship between mLOY and PCa diagnosis provides evidence for an association between mLOY detected in the blood and increased risk of non-aggressive PCa, suggesting mLOY could have utility in PCa risk stratification.

利益披露 Disclosure

R. L. Kelly, None.. A. Wang, None.. Y. Zhang, None.. W. Zhou, None.. K. M. Barnao, None.. C. D. Young, None.. A. K. Hubbard, None.. W. Huang, None.. S. C. Moore, None.. C. A. Haiman, None.. S. J. Chanock, None.. Y. Wang, None.. K. H. Stopsack, None.. L. A. Mucci, None.. F. Chen, None.. M. J. Machiela, None.

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