BackgroundCervical cancer is one of the most important cancers in African women. Polymorphisms in the Fas (FasR) and Fas ligand (FasL) genes have been reported to be associated with cervical cancer in certain populations. This study investigated whether these polymorphisms are associated with cervical cancer or human papillomavirus (HPV) infection in South African women.FindingsParticipants were 447 women with invasive cervical cancer (106 black African and 341 women of mixed-ancestry) and 424 healthy women controls, matched by age, (101 black African and 323 women of mixed-ancestry) and domicile (rural or urban). Two polymorphisms in Fas gene (FasR-1377G/A, FasR-670A/G) and one in FasL gene (FasL844T/C) were genotyped by TaqMan. None of the polymorphisms, or the Fas haplotypes, showed a significant association with cervical cancer. There was also no association with HPV infection in the control group. However, on analysis of the control group, highly significant allele, genotype and haplotype differences were found between the two ethnic groups. There were generally low frequencies of FasR-1377A alleles, FasR-670A alleles and FasL-844C alleles in black women compared to the women of mixed-ancestry.ConclusionThis is the first study on the role of Fas and FasL polymorphisms in cervical cancer in African populations. Our results suggest that these SNPs are not associated with cervical cancer in these populations. The allele frequencies of the three SNPs differed markedly between the indigenous African black and mixed-ancestry populations.

No abstract

Cervical cancer is caused by a combination of environmental and genetic risk factors. Infection by oncogenic types of human papillomavirus is recognized as the major environmental risk factor and epidemiological studies indicate that host genetic factors predispose to disease development. A number of genetic susceptibility factors have been proposed, but with exception of the human leukocyte antigen CHLA, class II, have not shown consistent results among studies. We have performed the first genomewide linkage scan using 278 affected sib-pairs to identify loci involved in susceptibility to cervical cancer. A two-step qualitative non-parametric linkage analysis using 387 microsatellites with an average spacing of 10.5 cM revealed excess allelic sharing at nine regions on eight chromosomes. These regions were further analysed with 125 markers to increase the map density to 1.28 cM. Nominal significant linkage was found for three of the nine loci [9q32 (maximum lod-score, MLS) =1.95, P<0.002), 12q24 (MLS=1.25, P<0.015) and 16q24 (MLS=1.35, P<0.012)]. These three regions have previously been connected to human cancers that share characteristics with cervical carcinoma, such as esophageal cancer and Hodgkin's lymphoma. A number of candidate genes involved in defence against viral infections, immune response and tumour suppression are found in these regions. One such gene is the thymic stromal co-transporter (TSCOT). Analyses of TSCOT single nucleotide polymorphisms further strengthen the linkage to this region (MLS=2.40, P<0.001). We propose that the 9q32 region contains susceptibility locus for cervical cancer and that TSCOT is a candidate gene potentially involved in the genetic predisposition to this disease.

Cervical cancer is a multifactorial disease and infection by oncogenic human papilloma viruses represents the main environmental risk factor. Only a subset of infections becomes persistent and develops into cancer, implying that genetic susceptibility factors are needed for malignant progression. Here, we use a population-based cohort of affected sib-pairs (ASPs) to examine the role of the human leukocyte antigen (HLA) class I and class II loci in cervical cancer susceptibility. Analysis of 278 ASPs revealed significant excess genetic sharing for all three HLA class II loci studied, DPB1, DQB1 and DRB1, with the strongest evidence for DQB1 and DRB1. No evidence of excess sharing was observed for the HLA class I HLA-B and HLA-A loci. When the material was stratified on the basis of the DQB1*0602/DRB1*1501 susceptibility haplotype, carriers showed significant sharing for all loci, whereas non-carriers showed no evidence of excess genetic sharing at any of the loci. However, for the DPB1 locus there was no difference in allele frequency between carriers and non-carriers indicating that the effect seen in DPB1 is not simply due to linkage disequilibrium. Our results show that the HLA class II represents a major genetic susceptibility locus to cervical cancer in contrary to the class I that do not appear to have a significant impact on predisposition to the disease. The strongest class II effects are coming from the DQB1 and DRB1 loci, but the DPB1 locus also contributes to the susceptibility to cervical cancer.

Dear Sir,In a recent study in this journal of Chinese patients, Lai et al. 1 suggest that a single nucleotide polymorphism (SNP) at position Ϫ670 in the Fas receptor promoter is associated with development of cervical cancer, implying a possible effect of Fas-mediated apoptosis. We studied this candidate locus in 278 affected sib-pairs (ASPs) from Sweden with a diagnosis of cervical cancer by genotyping of the Fas SNP and calculation of maximum lod-score (MLS) values. The ASPs show no significant deviation from random genetic sharing for the Fas receptor SNP either using the entire set of sib-pairs or when the material is stratified on the basis of carrier status of the human leukocyte antigen (HLA) class II susceptibility DQB1*0602/ DRB1*1501 haplotype. We conclude that the SNP in the Fas promoter does not have a major impact on the susceptibility to cervical carcinoma in Swedish patients.Infection with oncogenic human papillomavirus (HPV) is a necessary cause of cervical cancer, but genetic susceptibility factors are likely to affect the risk of malignant progression. 2,3 Associations between the HLA class II DQB1*0602/DRB1*1501 haplotype and cervical cancer have been reported, 4 -9 and higher HPV16 titer has been found in carriers of this haplotype. 10 Members of the tumour necrosis factor receptor superfamily, such as the transmembrane receptor Fas (CD95/APO-1), have a key role in apoptosis. A SNP at position Ϫ670 in the Fas promoter 11 was recently found to be associated with development of cervical carcinogenesis in a cohort of Chinese cases. 1 The binding of the Fas ligand (FasL) to the cell surface death receptor Fas activates intracellular cascades that ultimately cause apoptotic death of the cell. 12 The Fas SNP may affect risk of development of squamous cell carcinoma (SCC) through the Fas-mediated activation induced cell death (AICD), which normally prevents uncontrolled activation of lymphocytes. 1,13 If the Fas Ϫ670 A allele increases the Fas-mediated AICD resulting in a reduction of the cytotoxic T-lymphocyte (CTL) response, this might contribute to a persistent HPV infection. Elimination of virus-specific CTLs through Fas-mediated apoptosis has been documented in rodent livers, and this might point to a similar mechanism for development of chronic infections in hepatocytes. 14 We used a material consisting of 278 ASPs derived from the Swedish population to reexamine the role of the Fas polymorphism in cervical cancer development. The ASPs were identified by cross-linking the Swedish Cancer Registry and the National Family Register (Statistics, Sweden). DNA was extracted from peripheral blood leukocytes using standard phenol chloroform procedures. Ethical approval for the study was obtained from the Research Ethics Committee of Uppsala University. For our present study, 576 individuals corresponding to 278 ASPs were used (Table I). In this material, 23 (4%) of the women were diagnosed with invasive cervical cancer and 553 (96%) were diagnosed with cervical cancer in situ.Restriction fragment lengt...