LBPO.PS01 · 人群科学 · Late-Breaking

前列腺癌的遗传风险：来自前列腺癌测序联盟的见解

Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium

编号 LB390 展板 20 时间 4/21 02:00–05:00 区域 Section 55 主讲 Yifan Zhang, BS;MS

分会场 Late-Breaking Research: Population Sciences

查看 PDF 下载 PDF 🔒 查看 / 下载完整 PDF 需登录并开通下载套餐 · 查看套餐 / 开通 AACR 官方页面

作者与单位 Authors & Affiliations

Yifan Zhang¹, Shuyan Cheng², Nicholas Boddicker³, Matthew Lebo⁴, Alexander S. F. Berry⁵, Roni Haas⁶, Ryan Hausler⁷, Tokhir Dadaev⁸, Heena Desai⁷, Alex A. Rodriguez⁹, Ravi K. Madduri⁹, Andrew Hill¹⁰, Xin Sheng¹, Susan M. Gundell¹, Mine Cicek³, Penn Medicine Biobank, Regeneron Genetic Center, Hans Lilja¹¹, Olle Melander¹², Chris R. Gignoux¹⁰, Isla P. Garraway⁶, Bogdan Pasaniuc⁷, Paul C. Boutros¹³, Matt Oetjens⁵, Adam S. Kibel¹⁴, Robert J. Klein¹⁵, Zsofia Kote-Jarai⁸, Fergus J. Couch³, Kara N. Maxwell⁷, Burcu F. Darst¹⁶, David V. Conti¹⁰, Christopher A. Haiman¹, Fei Chen¹

¹University of Southern California, Los Angeles, CA,²University of Washington, Seattle, WA,³Mayo Clinic, Rochester, MN,⁴Mass General Brigham, Brigham and Women's Hospital, Harvard Medical School, Broad Institute of MIT and Harvard, Cambridge, MA,⁵Geisinger College of Health Sciences, Lewisburg, PA,⁶University of California, Los Angeles, Los Angeles, CA,⁷University of Pennsylvania, Philadelphia, PA,⁸The Institute of Cancer Research, London, United Kingdom,⁹Argonne National Laboratory, Lemont, IL,¹⁰University of Colorado Anschutz, Aurora, CO,¹¹Memorial Sloan Kettering Cancer Center, New York, NY,¹²Lund University, Malmö, Sweden,¹³Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA,¹⁴Brigham and Women's Hospital, Boston, MA,¹⁵Icahn School of Medicine at Mount Sinai, New York, NY,¹⁶Fred Hutchinson Cancer Research Center, Seattle, WA

摘要 Abstract

中文摘要

遗传易感性在前列腺癌（PCa）风险中发挥关键作用。利用大型生物样本库和病例对照数据集，我们评估了常见变异和罕见种系致病变异（PV）对总体PCa风险的贡献。前列腺癌外显子组测序联盟目前包括427,388名男性参与者（51,452例PCa病例和375,936例对照），这些参与者拥有来自十个生物样本库和研究的全外显子组测序数据：UK Biobank（14,669例病例/195,600例对照）、All of Us研究项目（7,577/75,226）、非洲血统前列腺癌联盟（7,176/4,675）、Mayo Clinic Biobank（6,031/15,084）、Mass General Brigham Biobank（3,393/14,095）、Geisinger的MyCode社区健康计划（3,026/15,130）、UCLA ATLAS精准医学生物样本库（2,850/16,904）、Penn Medicine Biobank（2,598/16,255）、科罗拉多个性化医学中心（2,269/13,399）以及Malmo饮食与癌症研究（1,863/9,568）。根据自我报告的种族/族裔和估计的遗传血统，病例包括约79%欧洲血统、18%非洲血统和3%其他血统人群。单变异关联分析检验了1-22号及X染色体上次要等位基因计数≥ 5的所有变异。在基于基因的分析中，PV定义为罕见变异（对照中次要等位基因频率[MAF] < 1%），且具有Variant Effect Predictor（VEP）"高"影响评分或ClinVar致病或可能致病分类。采用Firth逻辑回归估计关联，对年龄和前十个遗传主成分进行校正。各单项研究的结果通过固定效应荟萃分析进行合并。在单变异关联分析中，496个变异达到全基因组显著性（p < 5×10-8；MAF > 0.02%）。其中，458个（92%）变异映射到既往已知的风险区域，包括HOXB13（rs138213197）、CHEK2（rs555607708）和FAM111A（rs533676902）中的三个罕见PV。对其余38个变异的特征分析正在进行中。基于基因的分析鉴定出8个基因的显著关联（p < 2.4×10-6）：HOXB13（OR = 3.7，95% CI = 3.3-4.2）、BRCA2（OR = 2.0，95% CI = 1.7-2.3）、CHEK2（OR = 1.6，95% CI = 1.5-1.8）、ATM（OR = 1.6，95% CI = 1.4-1.9）、FAM111A（OR = 1.4，95% CI = 1.3-1.5）、BIK（OR = 1.4，95% CI = 1.2-1.6）、SAMHD1（OR = 2.1，95% CI = 1.6-2.7）和SMOC2（OR = 3.2，95% CI = 2.0-5.1）。除SMOC2外，所有基因此前均已被认为与PCa易感相关。在癌症易感基因和DNA修复基因中，XRCC2（OR = 1.6，95% CI = 1.2-2.3）和BRCA1（OR = 1.2，95% CI = 1.0-1.4）也观察到名义关联，而PALB2（OR = 1.2，95% CI = 0.9-1.5）的关联不显著。这些发现强化了罕见种系PV（尤其是癌症易感基因和DNA修复基因中的PV）在PCa易感性中的作用。随着更多研究纳入该联盟，我们预期这项工作将为PCa的遗传结构提供更全面的表征。

查看英文原文 English abstract

Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427,388 male participants (51,452 PCa cases and 375,936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14,669 cases/195,600 controls), All of Us Research Program (7,577/75,226), African Ancestry Prostate Cancer Consortium (7,176/4,675), Mayo Clinic Biobank (6,031/15,084), Mass General Brigham Biobank (3,393/14,095), Geisinger's MyCode Community Health Initiative (3,026/15,130), UCLA ATLAS Precision Medicine Biobank (2,850/16,904), Penn Medicine Biobank (2,598/16,255), Colorado Center for Personalized Medicine (2,269/13,399), and Malmo Diet and Cancer (1,863/9,568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency [MAF] < 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p<5×10 -8 ; MAF>0.02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p<2.4×10 -6 ) for eight genes: HOXB13 (OR=3.7, 95% CI=3.3-4.2) , BRCA2 (OR=2.0, 95% CI=1.7-2.3) , CHEK2 (OR=1.6, 95% CI=1.5-1.8) , ATM (OR=1.6, 95% CI=1.4-1.9) , FAM111A (OR=1.4, 95% CI=1.3-1.5) , BIK (OR=1.4, 95% CI=1.2-1.6) , SAMHD1 (OR=2.1, 95% CI=1.6-2.7), and SMOC2 (OR=3.2, 95% CI=2.0-5.1) . All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1.6, 95% CIs=1.2-2.3) and BRCA1 (OR=1.2, 95% CI=1.0-1.4), whereas the association was not significant for PALB2 (OR=1.2, 95% CI=0.9-1.5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa.

利益披露 Disclosure

Y. Zhang, None.. S. Cheng, None.. N. Boddicker, None.. M. Lebo, None.. A. S. F. Berry, None.. R. Haas, None.. R. Hausler, None.. T. Dadaev, None.. H. Desai, None.. A. A. Rodriguez, None.. R. K. Madduri, None.. A. Hill, None.. X. Sheng, None.. S. M. Gundell, None.. M. Cicek, None.. H. Lilja, None.. O. Melander, None.. C. R. Gignoux, None.. I. P. Garraway, None.. B. Pasaniuc, None.. P. C. Boutros, None.. M. Oetjens, None.. A. S. Kibel, None.. R. J. Klein, None.. Z. Kote-Jarai, None.. F. J. Couch, None.. K. N. Maxwell, None.. B. F. Darst, None.. D. V. Conti, None.. C. A. Haiman, None.. F. Chen, None.

← 返回 AACR 2026 检索