Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case-Control and Family-Based Studies in Multiethnic Populations.
Novel Gene and Network Associations Found for Acute Lymphoblastic Leukemia Using Case-Control and Family-Based Studies in Multiethnic Populations.
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通过在多种族人群中进行病例对照和基于家庭的研究，发现了急性淋巴细胞白血病的新基因和网络关联。
DOI：
10.1158/1055-9965.epi-17-0360
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Ramachandran,Sohini
中科院分区：
文献类型：
--
作者：
Nakka,Priyanka;Archer,NatalieP;Xu,Heng;Lupo,PhilipJ;Raphael,BenjaminJ;Yang,JunJ;Ramachandran,Sohini
Background:Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, suggesting that germline variants influence ALL risk. Although multiple genome-wide association (GWA) studies have identified variants predisposing children to ALL, it remains unclear whether genetic heterogeneity affects ALL susceptibility and how interactions within and among genes containing ALL-associated variants influence ALL risk.Methods:Here, we jointly analyzed two published datasets of case–control GWA summary statistics along with germline data from ALL case–parent trios. We used the gene-level association method PEGASUS to identify genes with multiple variants associated with ALL. We then used PEGASUS gene scores as input to the network analysis algorithm HotNet2 to characterize the genomic architecture of ALL.Results:Using PEGASUS, we confirmed associations previously observed at genes such asARID5B, IKZF1, CDKN2A/2B, andPIP4K2A, and we identified novel candidate gene associations. Using HotNet2, we uncovered significant gene subnetworks that may underlie inherited ALL risk: a subnetwork involved in B-cell differentiation containing the ALL-associated geneCEBPE, and a subnetwork of homeobox genes, includingMEIS1.Conclusions:Gene and network analysis uncovered loci associated with ALL that are missed by GWA studies, such asMEIS1. Furthermore, ALL-associated loci do not appear to interact directly with each other to influence ALL risk, and instead appear to influence leukemogenesis through multiple, complex pathways.Impact:We present a new pipeline forpost hocanalysis of association studies that yields new insight into the etiology of ALL and can be applied in future studies to shed light on the genomic underpinnings of cancer.Cancer Epidemiol Biomarkers Prev; 26(10); 1531–9. ©2017 AACR.
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