| 1. |
- Castro, Felipe A, et al.
(författare)
-
Contribution of TMC6 and TMC8 (EVER1 and EVER2) variants to cervical cancer susceptibility
- 2012
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 130:2, s. 349-355
-
Tidskriftsartikel (refereegranskat)abstract
- Cervical cancer (CxCa) is caused by persistent human papillomavirus (HPV) infection; genetic predisposition is also suspected to play a role. Our study is a targeted candidate gene follow-up based on: (i) strong clinical evidence demonstrating that mutations in the TMC6 and TMC8 (EVER1 and EVER2) genes associate with the HPV-associated disease epidermodysplasia verruciformis (EV) and (ii) recent epidemiological data suggesting a genetic susceptibility conferred by polymorphisms in such genes for skin and CxCa. Clarifying the association of the TMC6/8 genes with risk of CxCa will help in understanding why some HPV-infected women develop persistent infection, cervical lesions and eventually cancer while others do not. Twenty-two single nucleotide polymorphisms (SNPs) harboring the TMC6/8 genes were genotyped in 2,989 cases with cervical intraepithelial neoplasia grade III or invasive CxCa and 2,281 controls from the Swedish population. Association was evaluated in logistic regression models. Two SNPs displayed association with cervical disease: rs2290907 [odds ratio (OR)(GGvsAA) = 0.6, 95% confidence interval (95% CI): 0.3-0.9, p = 0.02)] and rs16970849 (OR(AGvsGG) = 0.8, 95% CI: 0.66-0.98, p = 0.03). The present data support the involvement of the TMC6/8 region in CxCa susceptibility but further analyses are needed to replicate our findings, fully characterize the region and understand the function of the genetic variants involved.
|
|
| 2. |
- Chen, Dan, et al.
(författare)
-
Genome-wide Association Study of Susceptibility Loci for Cervical Cancer
- 2013
-
Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 105:9, s. 624-633
-
Tidskriftsartikel (refereegranskat)abstract
- Background Cervical carcinoma has a heritable genetic component, but the genetic basis of cervical cancer is still not well understood. Methods We performed a genome-wide association study of 731 422 single nucleotide polymorphisms (SNPs) in 1075 cervical cancer case subjects and 4014 control subjects and replicated it in 1140 case subjects and 1058 control subjects. The association between top SNPs and cervical cancer was estimated by odds ratios (ORs) and 95% confidence intervals (CIs) with unconditional logistic regression. All statistical tests were two-sided. Results Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were associated with cervical cancer: the first is adjacent to the MHC class I polypeptide-related sequence A gene (MICA) (rs2516448; OR = 1.42, 95% CI = 1.31 to 1.54; P = 1.6 x 10(-18)); the second is between HLA-DRB1 and HLA-DQA1 (rs9272143; OR = 0.67, 95% CI = 0.62 to 0.72; P = 9.3 x 10(-24)); and the third is at HLA-DPB2 (rs3117027; OR=1.25, 95% CI = 1.15 to 1.35; P = 4.9 x 10(-8)). We also confirmed previously reported associations of B*0702 and DRB1*1501-DQB1*0602 with susceptibility to and DRB1*1301-DQA1*0103-DQB1*0603 with protection against cervical cancer. The three new loci are statistically independent of these specific human leukocyte antigen alleles/haplotypes. MICA encodes a membrane-bound protein that acts as a ligand for NKG2D to activate antitumor effects. The risk allele of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) of MICA, which results in a truncated protein. Functional analysis shows that women carrying this mutation have lower levels of membrane-bound MICA. Conclusions Three novel loci in the MHC may affect susceptibility to cervical cancer in situ, including the MICA-A5.1 allele that may cause impaired immune activation and increased risk of tumor development.
|
|
| 3. |
- Gustavsson, Inger, et al.
(författare)
-
Comparison between the Hybrid Capture 2 and the hpVIR real-time PCR for detection of human papillomavirus in women with ASCUS or low grade dysplasia
- 2009
-
Ingår i: Journal of Clinical Virology. - : Elsevier BV. - 1386-6532 .- 1873-5967. ; 45:2, s. 85-89
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Human papillomavirus (HPV) testing is an important part of cervical carcinoma screening, and the most widely used assay for detection of HPV is Hybrid Capture 2 (HC2). OBJECTIVES: We compare the HC2 with the real-time PCR hpVIR assay for detection of HPV in follow-up smears of 398 women diagnosed with atypical squamous cells of unknown significance (ASCUS) or low grade cervical intraepithelial neoplasia (CIN 1) in their initial smear. STUDY DESIGN: The two assays target the same set of high-risk (HR) HPVs with exception of HPV68. hpVIR identify individual or groups of HPV types as well as their viral load, while HC2 identify HR HPVs without specification of type. RESULTS: 34% (131/391) of the women were positive with HC2 and 45% (175/391) with hpVIR. 16% (63/391) were positive only with hpVIR and among those with cytology available 6% (3/52) had a CIN 2. The 3% (13/391) of women positive only with HC2 either contained low-risk HPVs or copy numbers below the cut-off for the hpVIR assay. CONCLUSION: The hpVIR assay has a similar sensitivity and specificity as HC2, but hpVIR detect a higher frequency of high-risk HPV infections.
|
|
| 4. |
- Ivansson, Emma L., et al.
(författare)
-
Interaction of immunological genes on chromosome 2q33 and IFNG in susceptibility to cervical cancer
- 2010
-
Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 116:3, s. 544-548
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Cervical cancer is caused by persistent infection with human papillomavirus and genetic susceptibility factors may augment disease risk. The immune response consists of complex interactions and it was recently proposed that the association of combinations of genotypes at several genes should be examined. In support of this the combination CD28+17(TT)/IFNG+874(AA) was shown to increase cervical cancer risk in a Brazilian population (VB Guzman et al. New approach reveals CD28 and IFNG gene interaction in the susceptibility to cervical cancer. Hum Mol Genet 2008;17:1838-44) and our aim was to replicate this finding. METHODS: We re-examined the proposed associations by analysis of polymorphisms at CD28, IFNG, TNF, PDCD1, ICOS and CTLA4 in 1306 Swedish cases and 811 controls. RESULTS: Logistic regression analysis detected association at single SNP level for CD28+17 (p=0.01), IFNG+874 (p=0.02), and PDCD1+7785 (p=0.04). The two locus combination CD28+17(TT)/IFNG+874(AA) (OR=0.76 (0.60-0.96, empirical p=0.03) and the three-locus combination CD28+17(TT)/IFNG+874(AA)/ICOS+1564(TT) (OR=0.65(0.49-0.87), empirical p=0.006) were associated with decreased risk. The strongest association was detected for the combination CTLA4-319 (CC)/IFNG (AA) (OR=0.67(0.53-0.84), empirical p=0.0007). CONCLUSION: The observation that these combinations of loci are associated in different populations supports their importance in cervical cancer development although the opposite directions of the effect call for clarification. The polymorphisms studied might not be the functional variants per se, but linked to those exerting a functional effect. The opposite associations in the two populations could then be explained by differences in linkage disequilibrium and population structure.
|
|
| 5. |
- Ivansson, Emma L., et al.
(författare)
-
Pathway-based analysis of genetic susceptibility to cervical cancer in situ : HLA-DPB1 affects risk in Swedish women
- 2011
-
Ingår i: Genes and Immunity. - : Springer Science and Business Media LLC. - 1466-4879 .- 1476-5470. ; 12:8, s. 605-614
-
Tidskriftsartikel (refereegranskat)abstract
- We have conducted a pathway-based analysis of genome-wide single-nucleotide polymorphism (SNP) data in order to identify genetic susceptibility factors for cervical cancer in situ. Genotypes derived from Affymetrix 500k or 5.0 arrays for 1076 cases and 1426 controls were analyzed for association, and pathways with enriched signals were identified using the SNP ratio test. The most strongly associated KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways were Asthma (empirical P=0.03), Folate biosynthesis (empirical P=0.04) and Graft-versus-host disease (empirical P=0.05). Among the 11 top-ranking pathways were 6 related to the immune response with the common denominator being genes in the major histocompatibility complex (MHC) region on chromosome 6. Further investigation of the MHC revealed a clear effect of HLA-DPB1 polymorphism on disease susceptibility. At a functional level, DPB1 alleles associated with risk and protection differ in key amino-acid residues affecting peptide-binding motifs in the extracellular domains. The results illustrate the value of pathway-based analysis to mine genome-wide data, and point to the importance of the MHC region and specifically the HLA-DPB1 locus for susceptibility to cervical cancer.
|
|
| 6. |
- Juko-Pecirep, Ivana, 1984-
(författare)
-
Analysis of genetic susceptibility to cervical cancer using candidate gene and GWAS approaches
- 2015
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cervical cancer is the forth most commonly diagnosed cancer among women worldwide. It is caused by persistent infection with an oncogenic type of Human Papillomavirus (HPV). The HPV is a necessary but not sufficient cause of cervical cancer. Environmental factors such as smoking, high parity and long-term use of oral contraceptives increases the risk of cervical cancer. Genetic factors also affect the risk of developing the disease. The aim of this thesis is to search for and evaluate genetic risk factors for cervical cancer using both a candidate gene approach and a genome-wide association study (GWAS).Paper I examined the association of genetic variation in three Fanconi Anemia (FA) genes (FANCA, FANCC and FANCL), involved in DNA repair, with cervical cancer susceptibility in the Swedish population. No association was observed. Paper II evaluated the association of genetic variation in the TMC6 and TMC8 genes with susceptibility to cervical cancer in the Swedish population and an association of two SNPs (rs2290907 and rs16970849) with cervical cancer was observed. In paper III the first GWAS performed in cervical cancer was reported. Three independent loci in the major histocompatibility complex (MHC) region at 6p21.3 were found to affect the susceptibility to cervical cancer. Paper IV examined the sequence variation in the TMC6 and TMC8 region and its association with cervical cancer. A highly polymorphic 21 bp sequence was identified and found to be repeated 5 to 42 times in both cases and controls. Lack of this repeat was associated with increased risk of cervical cancer. An intronic SNP (rs2926778) located in between the TNRC6C and TMC6 genes was also found to be associated with cervical cancer.The thesis provides evidence for the importance of genes in the immune system for cervical cancer susceptibility. The genetic risk factors identified explain only a part of the genetic susceptibility, implying that other risk factors remains to be identified
|
|
| 7. |
|
|
| 8. |
- Juko-Pecirep, Ivana, et al.
(författare)
-
Evaluation of Fanconi anaemia genes FANCA, FANCC and FANCL in cervical cancer susceptibility
- 2011
-
Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 122:2, s. 377-381
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. Disrupting the function of any of the 13 Fanconi anaemia (FA) genes causes a DNA repair deficiency disorder, with patients being susceptible to a number of cancer types. Variation in the family of FA genes has been suggested to affect risk of cervical cancer. The current study evaluates the influence of three genes in the FA pathway on cervical cancer risk in Swedish women. Methods. TagSNPs in FANCA, FANCC and FANCL were selected using the Tagger algorithm in Haploview. A total of 81 tagSNPs were genotyped in 782 cases (CIN3 or ICC) and 775 controls using the Illumina GoldenGate Assay and statistically analyzed for association with cervical cancer. Results. 72 SNPs were successfully genotyped in >98% of the samples. Nominal associations were detected for FANCA rs11649196 (p = 0.05) and rs4128763 in FANCC (p = 0.02). The associations did not withstand correction for multiple testing. Conclusions. The current study does not support that genetic variation in FANCA, FANCC or FANCL genes affects susceptibility to cervical cancer in the Swedish population.
|
|
| 9. |
- Nyström, Niklas, et al.
(författare)
-
Human Enterovirus Species B in Ileocecal Crohn's Disease
- 2013
-
Ingår i: Clinical and Translational Gastroenterology. - : Ovid Technologies (Wolters Kluwer Health). - 2155-384X. ; 4:6
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency ofNOD2mutations. Recent findings implicate a role ofNOD2and another CD susceptibility gene,ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.METHODS:We used immunohistochemistry andin situhybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis.RESULTS:All patients with ICD had disease-associated polymorphisms inNOD2orATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia.CONCLUSIONS:The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.
|
|
