Polymorphisms in 9q32 and TSCOT are linked to cervical cancer in affected sib-pairs with high mean age at diagnosis.

Cervical cancer is a multifactorial disease influenced by both environmental and genetic factors. We have previously found linkage to 9q32 in a genomewide scan of affected sib-pairs (ASPs) with cervical cancer and to the thymic stromal co-transporter (TSCOT), a candidate gene in this region. Here we examined the contribution of 9q32 and TSCOT to cervical cancer susceptibility using at larger material of 641 ASPs, 278 of which were included in the earlier genome-scan. Since heritable forms of cancer frequently show stronger genetic effects in families with early onset of disease, we stratified the ASPs into two groups based on mean age at diagnosis (MAAD) within sib-pairs. Surprisingly, ASPs with high MAAD (30.5-47.5 years) showed increased sharing at all microsatellite markers at 9q31.1-33.1 and linkage signals of up to MLS = 2.74 for TSCOT SNPs, while ASPs with low MAAD (19-30 years) showed no deviation from random genetic sharing (MLS = 0.00). The difference in allelic sharing between the two MAAD strata was significant (P < 0.005) and is not likely to be explained by the HLA haplotype, a previously known genetic susceptibility factor for cervical cancer. Our results indicate locus heterogeneity in the susceptibility to cervical cancer between the two strata, with polymorphisms in the 9q32 region mainly showing an effect in women with high MAAD.

Variants of chemokine receptor 2 and interleukin 4 receptor, but not interleukin 10 or Fas ligand, increase risk of cervical cancer.

Cervical cancer is caused by persistent infection of oncogenic human papillomavirus (HPV). Most infected women clear the virus without developing cervical lesions and it is likely that immunological host factors affect susceptibility to cervical cancer. The impact of the human leukocyte antigen (HLA) locus on the risk of cervical cancer is established and several other genes involved in immunological pathways have been suggested as biologically plausible candidates. The aim of this study was to examine the potential role of polymorphisms in 4 candidate genes by analysis of 1,306 familial cervical cancer cases and 288 controls. The following genes and polymorphisms were studied: Chemokine receptor 2 (CCR-2) V64I; Interleukin 4 receptor alpha (IL-4R) I75V, S503P and Q576R; Interleukin 10 (IL-10) -592; and Fas ligand (FasL) -844. The CCR-2 64I variant was associated with decreased risk of cervical cancer; homozygote carriers of the 64I variant had an odds ratio of 0.31 (0.12-0.77). This association was detected in both carriers and noncarriers of the HLA DQB1*0602 cervical cancer risk allele. The IL-4R 75V variant was associated with increased risk of cervical tumors, cases homozygote for 75V had an odds ratio of 1.91 (1.27-2.86) with a tendency that the association was stronger in noncarriers of the DQB1*0602 allele. We did not find any association for IL-10 -592, or FasL -844, previously reported to be associated with cervical cancer in the Dutch and Chinese populations, respectively.

Identification of susceptibility loci for cervical carcinoma by genome scan of affected sib-pairs.

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.

Interaction of host and viral risk factors for development of cervical carcinoma in situ.

Infection by oncogenic human papillomavirus (HPV) is a necessary but not sufficient cause of cervical carcinoma. Several host genetic and viral factors have been reported to increase the risk of carcinoma development given an HPV infection. In our study, we have analysed the contribution of HPV 16 E6 sequence subtype and allelic variation at human leukocyte antigen (HLA) class II loci to the risk of developing cervical carcinoma in situ. Non-European-like HPV 16 E6 sequence subtypes were not found to be associated with an increased risk of cervical carcinoma, as compared to European-like variants. However, an association was found between the HPV 16 E6 L83V variant and the DR*04-DQ*03 haplotype. This association has been observed in several independent studies and shows that both the host HLA class II genotype and viral subtype will affect the risk of an infection progressing into cervical carcinoma.