Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women

Ivansson, Emma; Juko-Pecirep, Ivana; Erlich, Henry A.; Gyllensten, Ulf

doi:10.1038/gene.2011.40

Cited by 22 publications

(21 citation statements)

References 53 publications

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“…Another cervical cancer GWAS performed in China also found associations with the HLA-DPB1 and HLA-DPB2 genes (42). Further support for a role for HLA molecules as modulators of susceptibility to cervical cancer comes from a pathway analysis performed on the cervical cancer GWAS, in which a subset was used as replication cohort in this study and identified several pathways, including HLA genes, that influence risk of cervical cancer (26). However, in the oropharyngeal cancer GWAS, the pathways and SNPs associated with HLA molecules were not highly ranked, with the most significant SNP P value equal to 1 × 10 −2 .…”

Section: Discussionmentioning

confidence: 98%

“…The details of population and QC have been described by Ivansson and colleagues (26). The data we received included for each SNP, the SNP identifier, the genomic location, and the P value from the association analysis that was estimated by ORs and 95% CI using multivariable unconditional logistic regression assuming a log-additive genetic model.…”

Section: Methodsmentioning

confidence: 99%

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TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

et al. 2014

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Only a minority of those exposed to human papillomavirus (HPV) develop HPV-related cervical and oropharyngeal cancer. Because host immunity affects infection and progression to cancer, we tested the hypothesis that genetic variation in immune-related genes is a determinant of susceptibility to oropharyngeal cancer and other HPV-associated cancers by performing a multitier integrative computational analysis with oropharyngeal cancer data from a head and neck cancer genome-wide association study (GWAS). Independent analyses, including single-gene, gene-interconnectivity, protein–protein interaction, gene expression, and pathway analysis, identified immune genes and pathways significantly associated with oropharyngeal cancer. TGFβR1, which intersected all tiers of analysis and thus selected for validation, replicated significantly in the head and neck cancer GWAS limited to HPV-seropositive cases and an independent cervical cancer GWAS. The TGFβR1 containing p38–MAPK pathway was significantly associated with oropharyngeal cancer and cervical cancer, and TGFβR1 was overexpressed in oropharyngeal cancer, cervical cancer, and HPV+ head and neck cancer tumors. These concordant analyses implicate TGFβR1 signaling as a process dysregulated across HPV-related cancers. This study demonstrates that genetic variation in immune-related genes is associated with susceptibility to oropharyngeal cancer and implicates TGFβR1/TGFβ signaling in the development of both oropharyngeal cancer and cervical cancer. Better understanding of the immunogenetic basis of susceptibility to HPV-associated cancers may provide insight into host/virus interactions and immune processes dysregulated in the minority of HPV-exposed individuals who progress to cancer.

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Section: Discussionmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

et al. 2014

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“…However, 50%–90% of early cervical intraepithelial neoplasia (CIN) cases regress spontaneously [2, 3], suggesting a genetic influence. Previous evidence for host genetic factors contributing to susceptibility to cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) has come from family-based and case-control studies [4–8]. …”

Section: Introductionmentioning

confidence: 99%

Polymorphisms in immune mediators associate with risk of cervical cancer

Zhang¹,

Fye²,

Borecki³

et al. 2014

Gynecologic Oncology

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Objective The immune system is critical for controlling the progression of HPV cervical disease and the development of cancer. This study aimed to identify cervical cancer susceptibility alleles in candidate immune-modulating genes. Methods Our family-based study involved a cohort of 641 probands (women with ICC / CIN III) and their biologic parents or siblings (641 trios). In the discovery phase (stage 1), involving 288 of the trios, 81 tag single nucleotide polymorphisms (SNPs) in 11 immune-modulating genes (IFNG, IFNGR1, IFNGR2, JAK1, JAK2, STAT1, STAT6, IL12A, TNF, LTA and LTB) were evaluated on the GoldenGate platform. We used the combined dataset for a total of 641 trios (stage 2) and the Taqman platform to validate the SNPs that had proved significant in the discovery dataset. The transmission disequilibrium test was used to detect significant shifts in allelic transmissions in the datasets. Results Two SNPs in JAK2 and one SNP in STAT6 showed significant allelic association with cervical cancer in the stage 1 discovery dataset and were replicated in the larger joint analysis stage 2 dataset (JAK2 rs10815144, P = 0.0029 and rs12349785, P = 0.0058; and STAT6 rs3024971, P = 0.0127). An additional SNP in exon 19 of JAK2 (rs2230724) was also examined in the combined dataset due to its strong linkage disequilibrium (LD) with rs10815144. It was also significant (P=0.0335). Conclusions Our results suggest an association of SNPs in JAK2 and STAT6 with cervical cancer. This association should be investigated in additional cervical cancer populations.

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“…7–11 A growing body of literature also highlights the important role of immunogenetics in HPV-related carcinogenesis. 12–15 …”

Section: Introductionmentioning

confidence: 99%

Nucleotide variation in IL‐10 and IL‐12 and their receptors and cervical and vulvar cancer risk: A hybrid case–parent triad and case–control study

Hussain

Madeleine

Johnson

et al. 2013

Intl Journal of Cancer

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Given the important role of cell mediated immunity in viral clearance and control of premalignant lesions, we hypothesize that variation in the IL12/IL10 cytokine and cytokine receptor genes may influence cervical and vulvar cancer risk. We evaluated 76 tagSNPs from 7 candidate genes (IL10, IL12A, IL12B, IL10RA, IL10RB, IL12RB1, and IL12RB2) in case-parent sets (n=43 cervical squamous cell carcinoma (SCC), n=96 cervical adenocarcinoma, n=53 vulvar SCC), additional cases (n=356 cervical SCC, n=406 cervical adenocarcinoma, and n=473 vulvar SCC) and population based controls (1,111). We calculated log-additive odds ratios (ORs) and 95% confidence intervals (CIs) for the association between tagSNP and cancer risk using a pseudo-likelihood based method which combined genotype information on cases, parents, and population controls. After correction for multiple comparisons, we identified several statistically significant SNP associations. Cervical SCC risk was associated with the minor alleles of the IL10RA rs9610 3′ UTR SNP (OR=1.76, 95% CI= 1.15–2.68) and two synonymous IL12RB2 SNPs (rs4297265, OR=0.46, 95% CI=0.26–0.82; rs2229546, OR=0.43, 95% CI=0.21–0.87). Cervical adenocarcinoma risk was associated with the minor alleles of the IL10RA rs4252314 intronic SNP (OR=2.23, 95% CI = 1.26–3.96) and IL12RB1 rs11575934 non-synonymous SNP (OR=1.51, 95% CI=1.12–2.05). Finally, the minor allele of the IL12B rs3181224 3′ UTR SNP was associated with a reduced risk of vulvar SCC (OR=0.30, 95% CI=0.12–0.74). These results raise the possibility that a shift in the balance of the immune response due to genetic variants in key cytokine genes could influence the development of cervical and vulvar cancer.

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Pathway-based analysis of genetic susceptibility to cervical cancer in situ: HLA-DPB1 affects risk in Swedish women

Cited by 22 publications

References 53 publications

TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

TGFβ Receptor 1: An Immune Susceptibility Gene in HPV-Associated Cancer

Polymorphisms in immune mediators associate with risk of cervical cancer

Nucleotide variation in IL‐10 and IL‐12 and their receptors and cervical and vulvar cancer risk: A hybrid case–parent triad and case–control study

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