Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk.
Shared genomic segment analysis in a large high-risk chronic lymphocytic leukemia pedigree implicates CXCR4 in inherited risk.
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DOI：
10.20517/jtgg.2021.05
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Camp NJ
中科院分区：
文献类型：
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作者：
Feusier JE;Madsen MJ;Avery BJ;Williams JA;Stephens DM;Hu B;Osman AEG;Glenn MJ;Camp NJ
慢性淋巴细胞性白血病(CLL)有家族聚集性。慢性淋巴细胞性白血病患者的一级亲属患恶性疾病的风险增加约8倍。很强的遗传力表明系谱研究将有很好的能力定位致病基因。然而，CLL相对罕见和异质性，使查明和分析变得复杂。我们的目标是利用犹他州独特的可用资源和处理家庭内异质性的方法来识别CLL风险基因。我们利用犹他州人口数据库确定了一个六代高危慢性淋巴细胞性白血病家系。该家系包括24例CLL病例，由一个共同的祖先相连。我们使用高密度SNP阵列确定了8例CLL病例并进行了基因分型，然后进行了共享基因组片段(SGS)分析-这是一种为解释异质性的扩展高危家系而设计的方法。我们在2q22.1发现了一个全基因组显著区域(P=1.90×10−7，相当于5.6个LOD值)。0.9Mb区在26个减数分裂中遗传，并被8个基因型例中的7个所共有。它位于先前对206个小型CLL家系进行的连锁研究中确定的~6.25Mb基因座内。我们的狭窄区域与包括CXCR4在内的两个基因相交，CXCR4在CLL细胞中高表达，并与维持和进展有关。对一个扩展的高危CLL家系的SGS分析确定了迄今为止最重要的证据，即位于2q22.1的0.9Mb CLL疾病基因座，含有CXCR4。这一发现促进了越来越多的文献表明CXCR4与CLL的遗传风险有关。家系中分离单倍型的研究将对阐明风险变异有价值(S)。
Chronic lymphocytic leukemia (CLL) has been shown to cluster in families. First-degree relatives of individuals with CLL have an ~8 fold increased risk of developing the malignancy. Strong heritability suggests pedigree studies will have good power to localize pathogenic genes. However, CLL is relatively rare and heterogeneous, complicating ascertainment and analyses. Our goal was to identify CLL risk loci using unique resources available in Utah and methods to address intra-familial heterogeneity. We identified a six-generation high-risk CLL pedigree using the Utah Population Database. This pedigree contains 24 CLL cases connected by a common ancestor. We ascertained and genotyped eight CLL cases using a high-density SNP array, and then performed shared genomic segment (SGS) analysis - a method designed for extended high-risk pedigrees that accounts for heterogeneity. We identified a genome-wide significant region (P = 1.9 × 10−7, LOD-equivalent 5.6) at 2q22.1. The 0.9 Mb region was inherited through 26 meioses and shared by seven of the eight genotyped cases. It sits within a ~6.25 Mb locus identified in a previous linkage study of 206 small CLL families. Our narrow region intersects two genes, including CXCR4 which is highly expressed in CLL cells and implicated in maintenance and progression. SGS analysis of an extended high-risk CLL pedigree identified the most significant evidence to-date for a 0.9 Mb CLL disease locus at 2q22.1, harboring CXCR4. This discovery contributes to a growing literature implicating CXCR4 in inherited risk to CLL. Investigation of the segregating haplotype in the pedigree will be valuable for elucidating risk variant(s).