PO.CL06.03 · 临床研究

儿童急性髓系白血病（AML）风险的多祖源全基因组关联研究（GWAS）识别出四个风险位点

Multi-ancestry genome-wide association study (GWAS) of pediatric acute myeloid leukemia (AML) risk identifies four risk loci

编号 7892 展板 23 时间 4/22 09:00–12:00 区域 Section 47 主讲 Lauren Mills, PhD

分会场 Targeted Therapies, Predispositions, and Survivorship in Pediatric Cancers

该海报暂无可下载的资料 AACR 官方页面

作者与单位 Authors & Affiliations

Cindy Im¹, Lauren J. Mills¹, Peggy Meng², Marijana Vujkovic³, Jenny N. Poynter¹, Melissa Maria Hudson², Kirsten K. Ness², Joseph L. Wiemels⁴, Logan G. Spector¹, Saonli Basu⁵, Zhaoming Wang⁶, Richard Aplenc⁷

¹University of Minnesota, Minneapolis, MN,²St. Jude Children's Research Hospital, Memphis, TN,³University of Pennsylvania, Philadelphia, PA,⁴University of Southern California, Los Angeles, CA,⁵Masonic Cancer Center, Minneapolis, MN,⁶University of South Florida, Tampa, FL,⁷Children’s Hospital of Philadelphia, Philadelphia, PA

摘要 Abstract

中文摘要

引言：AML是一种相对罕见的儿童血液系统恶性肿瘤，但其治疗结局落后于其他急性白血病，5年生存率约为70%。虽然已开展了成人AML风险的全基因组尺度易感性研究，但类似的儿童AML研究尚未发表。方法：从儿童肿瘤协作组（临床试验AAML-03P1/0531/1031）、病童医院（加拿大）、国际柏林-法兰克福-明斯特研究组（德国）和皇家亚历山德拉儿童医院（澳大利亚）汇集了1854例儿童AML病例（诊断年龄<25岁）。使用Illumina HumanOmni 2.5 BeadChip对病例进行基因分型。利用ADMIXTURE推断的全局遗传祖源，将1355例病例分为非洲（AFR，N=95）、混合美洲（AMR，N=118）、东亚（EAS，N=74）和欧洲（EUR，N=1068）祖源组。以约4:1的比例识别出使用相同平台进行基因分型的性别/祖源匹配的公开可用成人对照，来自3个外部队列（年龄相关性眼病研究、健康与退休研究、长寿家族研究）。基于TOPMed的填补（版本r3）支持祖源特异性GWAS，包含550-1070万个常见变异（次要等位基因频率，MAF≥1%）。校正人群亚结构的Logistic回归模型检验变异风险关联。使用逆方差加权固定效应模型进行多祖源荟萃分析。结果：在EUR GWAS（N=5340）中识别出四个新的全基因组显著（P<5x10-8）儿童AML风险位点（PRIM2、HERC2、AGRN、DEFB131A），具有中等的每等位基因比值比（OR范围：1.9-2.9）。计算机模拟分析表明，HERC2、AGRN和DEFB131A位点的先导变异位于血液或骨髓组织的活性染色质区域，并与转录因子结合位点重叠，包括在白血病细胞系中。HERC2索引变异（OR=1.9，95% CI：1.5-2.3）与静脉血中HERC2表达相关（GTEx）。已知EUR成人AML风险位点KMT5B的多个变异也得到名义上的重复验证（P=8.7x10-3）。在AFR（N=475）和AMR（N=518）GWAS中观察到额外的提示性关联（P<1x10-6）；其中，推定的儿童AML风险位点KANK1的特征是低频率（MAF=1-5%）AFR特异性效应等位基因，即在其他祖源中几乎不存在，因其较大的风险效应而值得关注（OR=5.6，95% CI：3.0-10.7）。多祖源荟萃分析未揭示跨祖源组共享的额外遗传信号。结论：我们报告了首个使用国际数据的儿童AML GWAS结果（N=6507，1355例病例）。我们识别出4个新的EUR特异性风险位点、一个可能的新AFR特异性风险位点，并重复验证了KMT5B——一个在EUR成人AML荟萃分析中报告的风险位点。未来工作包括重复验证和功能验证研究。

查看英文原文 English abstract

Introduction: AML is a relatively rare pediatric hematological malignancy, but its treatment outcomes trail other acute leukemias with a 5-year survival rate at ~70%. While genome-scale susceptibility studies of adult AML risk have been conducted, similar pediatric AML studies have not been published. Methods: 1854 pediatric AML cases (diagnosis age <25y) were assembled from the Children's Oncology Group (clinical trials AAML-03P1/0531/1031), Hospital for Sick Children (CA), International Berlin-Frankfurt-Münster Study Group (DE), and Royal Alexandra Hospital for Children (AUS). Cases were genotyped with the Illumina HumanOmni 2.5 BeadChip. Using ADMIXTURE-inferred global genetic ancestry, 1355 cases were grouped in African (AFR, N=95), Admixed American (AMR, N=118), East Asian (EAS, N=74) and European (EUR, N=1068) ancestry groups. Sex-/ancestry-matched publicly available adult controls from 3 external cohorts (Age-Related Eye Disease Study, Health and Retirement Study, Long Life Family Study) genotyped with the same platform were identified at a ~4:1 ratio. TOPMed-based imputation (version r3) supported ancestry-specific GWAS with 5.5-10.7 million common variants (minor allele frequency, MAF≥1%). Logistic regression models adjusted for population substructure tested variant risk associations. Multi-ancestry meta-analysis was performed using an inverse variance-weighted fixed effects model. Results: Four novel genome-wide significant (P<5x10 -8 ) pediatric AML risk loci ( PRIM2 , HERC2 , AGRN , DEFB131A ) were identified in the EUR GWAS (N=5340), with moderate per-allele odd ratios (OR range: 1.9-2.9). In silico analyses indicated lead variants at HERC2 , AGRN , and DEFB131A loci are in active chromatin regions in blood or bone marrow tissues and overlap transcription factor binding sites, including in leukemia cell lines. The HERC2 index variant (OR=1.9, 95% CI: 1.5-2.3) is associated with HERC2 expression in venous blood (GTEx). Multiple variants at known EUR adult AML risk locus KMT5B were also nominally replicated (P=8.7x10 -3 ). Additional suggestive associations (P<1x10 -6 ) in the AFR (N=475) and AMR (N=518) GWAS were seen; among these, putative pediatric AML risk locus KANK1 , which was characterized by low frequency (MAF=1-5%) AFR-specific effect alleles, i.e., nearly absent in other ancestries, is notable for its large risk effects (OR=5.6, 95% CI: 3.0-10.7). The multi-ancestry meta-analysis did not reveal additional genetic signals shared across ancestry groups. Conclusion: We report results from the first pediatric AML GWAS (N=6507, 1355 cases) using international data. We identified 4 novel EUR-specific risk loci, a plausible novel AFR-specific risk locus, and replicated KMT5B , a risk locus reported in a EUR adult AML meta-analysis. Future work includes replication and functional validation studies.

利益披露 Disclosure

C. Im, None.. L. J. Mills, None.. P. Meng, None.. M. Vujkovic, None.. J. N. Poynter, None.. J. L. Wiemels, None.. L. G. Spector, None.. Z. Wang, None.. R. Aplenc, None.

← 返回 AACR 2026 检索