CD83 Gene Polymorphisms Increase Susceptibility to Human Invasive Cervical Cancer

Abstract

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.

Association of Signal Transducer and Activator of Transcription 3 Gene Polymorphisms with Cervical Cancer in Chinese Women

“…Therefore, genetic variation of immune system factors may influence susceptibility to cervical cancer (Zur Hausen, 2000;Konac et al, 2007;Jumnainsong, et al, 2007;Schlee et al, 2007;Han et al, 2008;Yu et al, 2009). Recent research has investigated SNPs in CD83, IL-1, IL-6, IL-12, VEGF, and nuclear factor-kappa B in cervical cancer patients (Konac et al, 2007;Zhang et al, 2007;Singh et al, 2008;Castro et al, 2009;Chen et al, 2009;Zhou et al, 2010); however, it remains to be elucidated how the genetic variation is involved in the regulation of the immune response and tumorigenesis (Zhang et al, 2007;Yu et al, 2009).…”

“…Also, genetic factors involved in immune recognition and antigen presentation may play a crucial role in the pathogenesis of cervical cancer (Zur Hausen, 2000;Han et al, 2008). Zhang et al (2007) reported an association between cervical cancer and five single-nucleotide polymorphisms (SNPs) of CD83. Yu et al (2009) replicated this study and confirmed the possible role of CD83 polymorphisms in cervical carcinogenesis.…”

Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6

“…Normal cervix and cervical cancer tissues were obtained from women with an age range from 40 to 50 yr old. HPV genotyping was done by sequencing-based techniques as previously described (Zhang et al 2007). Use of these tissues was approved both by the Washington University Medical Center Human Studies Committee and by the NIH Office of Human Subjects Research.…”

Human Papillomavirus Detection by PCR Assay in a Large Series of High-Grade Squamous Intraepithelial Lesions with Cytohistological Correlation and Follow-Up

“…HPV infection in the anogenital tract is a common sexually transmitted disease that usually produces transient cervical inflammation; neoplasia is in fact very uncommon [24]. Differences in the response to HPV infection may be linked to immune status, such as the presence of HIV infection, or to genetic factors,such as HLA type [25], CD83 polymorphisms, [26] or single-nucleotide polymorphisms (SNPs) at the IL-10 promoter or the Fas promoter [25,27]. Nevertheless, HPV is considered the single most important factor in the development of cervical carcinoma, and HPV DNA would undoubtedly be identified in almost all specimens of invasive cervical carcinoma if the appropriate molecular technology were used [23,28].…”