A minority of women infected with human papilloma virus (HPV) will develop cervical intraepithelial neoplasia (CIN) or cervical cancer, suggesting the presence of innate factors predisposing to chronic infection or tumor development. Untreated CIN has been associated with spontaneous preterm delivery (PTB), but the causal pathway remains unclear. We conducted a genome-wide association study to identify underlying genetic risk variants which might predispose to CIN/cervical cancer only or to both outcomes.
Using Finland’s nationwide Registers we identified 353 women with CIN or cervical cancer and 1868 controls without a history of any cytological abnormalites from Northern Finland Birth Cohort 1966 (NFBC66). Women were genotyped using Illumina arrays and SNP imputation was done across genome using 1000 genomes phase 1 data. In the first stage we ran genome wide analyses for the dichotomous outcome CIN or cervical cancer. In the second stage we re-ran the analyses for PTB (122 cases with spontaneous PTB of <37 pregnancy weeks and 1813 controls with no history preterm birth) only for the single nucleotide polymorphisms (SNPs) considered at least suggestive for CIN or cervical cancer (p <1x10e-5).
We identified ten novel SNPs (p<5x10E-8) associated with increased risk of CIN or cervical cancer (Figure 1). Two of the top variants were intronic or upstream variants for three protein-coding genes at the same locus 13q22: PIBF1, BORA and MZT1 — all with roles in pregnancy, mitotic cell division and/or cancer development. Among the 234 SNPs analysed in the second stage, two remained significant for PTB and were associated with protein coding sites: at SEPT8 (regulator of cytoskeletal organization, associated with cellular polarity and carcinogenesis) and one at CAPN1 (associated with both human carcinogenesis and low birth weight in animal models).
We observed variants significantly associated with CIN or cervical cancer as well as loci suggesting a presence of shared genetic susceptibility to both outcomes in this cohort. The protein-coding genes in the loci identified are suggested to have roles both in aetiology of carcinogenesis and regulation of pregnancy. These results are promising but require external replication for confirmation.