CD83 gene polymorphisms increase susceptibility to human invasive cervical cancer
CD83 gene polymorphisms increase susceptibility to human invasive cervical cancer
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DOI：
10.1158/0008-5472.can-07-2677
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发表时间：
2007-12-01
期刊：
影响因子：
11.2
通讯作者：
Rader, Janet S.
中科院分区：
文献类型：
--
作者：
Zhang, Zhengyan;Borecki, Ingrid;Rader, Janet S.
我们之前将宫颈癌中的非随机频繁杂合性丢失 (LOH) 区域映射到 6p23 的 1 Mb。在这里，我们描述了一种新型宫颈癌易感基因 CD83 的鉴定。该基因是通过几种互补的方法鉴定的，包括基于家族的关联研究、正常组织和癌组织中转录表达的比较以及候选基因的基因组测序。 CD83 编码免疫球蛋白超家族中的诱导型糖蛋白，是成熟树突状细胞的标记。包括 377 个家族三人组的关联研究表明，其 3' 端 8 kb 内的 5 个单核苷酸多态性 (SNP) 显示出显着的等位基因关联，这种关联在感染 16 型和 18 型高危人乳头瘤病毒的侵袭性癌症女性亚组中得到加强（rs9296925，P = 0.0193；rs853360，P = 0.0035； rs9230，P = 0.0011；rs9370729，P = 0.0012；rs750749，P = 0.0133）。对 CD83 的研究发现了宫颈组织和细胞系中的三种替代转录物，其中变体 3（缺乏外显子 3 和 4）在宫颈癌中比在正常宫颈上皮中更常见（P = 0.0181）。对 36 对正常和宫颈肿瘤的基因组测序揭示了 CD83 启动子、外显子和内含子中的一些体细胞突变和新的 SNP。 LOH 在> 90% 的宫颈癌标本中得到证实。免疫荧光将 CD83 蛋白共定位于宫颈癌细胞系的高尔基体和细胞膜。七个邻近基因在宫颈癌中均没有差异表达。需要确定 CD83 在上皮细胞与树突状细胞中的重要性，以及它在促进宫颈癌中的作用。
We previously mapped a nonrandom frequent loss of heterozygosity (LOH) region in cervical cancers to 1 Mb of 6p23. Here, we describe the identification of a novel cervical cancer susceptibility gene, CD83. The gene was identified by several complementary approaches, including a family-based association study, comparison of transcript expression in normal and cancerous tissue, and genomic sequencing of candidate. CD83 encodes an inducible glycoprotein in the immunoglobulin superfamily and is a marker for mature dendritic cells. The association study that includes 377 family trios showed that five single nucleotide polymorphisms (SNP) within 8 kb of its 3'-end showed significant allelic association that was strengthened in a subgroup of women with invasive cancers infected by high-risk human papillomavirus type 16 and 18 (rs9296925, P = 0.0193; rs853360, P = 0.0035; rs9230, P = 0.0011; rs9370729, P = 0.0012; rs750749, P = 0.0133). Investigation of CD83 uncovered three alternative transcripts in cervical tissue and cell lines, with variant 3 (lacking exons 3 and 4) being more frequent in cervical cancer than in normal cervical epithelium (P = 0.0181). Genomic sequencing on 36 paired normal and cervical tumors revealed several somatic mutations and novel SNPs in the promoter, exons, and introns of CD83. LOH was confirmed in > 90% of cervical cancer specimens. Immunofluorescence colocalized CD83 protein to the Golgi apparatus and cell membrane of cervical cancer cell lines. None of seven nearby genes was differentially expressed in cervical cancer. The importance of CD83 in epithelial versus dendritic cells needs to be determined, as does its role in promoting cervical cancer.