Abstract
Simple SummaryCervical cancer is the fourth leading cause of cancer-related deaths in females worldwide. Despite an active immunisation strategy in many countries, high-risk human papillomavirus infection and environmental factors may result in cervical cancer progression. Genetic factors contributing to host–pathogen interactions are incompletely understood and remain largely unknown, apart from the variants at the human leukocyte antigen (HLA) locus on 6p21.3, which replicates across populations. Novel cervical cancer susceptibility loci from recent large biobank-based genome-wide association studies and meta-analyses are likely to be more robust as compared to previous candidate gene based studies. In this review, we summarize findings from recent genome-wide association studies on cervical cancer and propose variants that may be universal susceptibility loci.Cervical cancer is the fourth common cancer amongst women worldwide. Infection by high-risk human papilloma virus is necessary in most cases, but not sufficient to develop invasive cervical cancer. Despite a predicted genetic heritability in the range of other gynaecological cancers, only few genomic susceptibility loci have been identified thus far. Various case-control association studies have found corroborative evidence for several independent risk variants at the 6p21.3 locus (HLA), while many reports of associations with variants outside the HLA region remain to be validated in other cohorts. Here, we review cervical cancer susceptibility variants arising from recent genome-wide association studies and meta-analysis in large cohorts and propose 2q14 (PAX8), 17q12 (GSDMB), and 5p15.33 (CLPTM1L) as consistently replicated non-HLA cervical cancer susceptibility loci. We further discuss the available evidence for these loci, knowledge gaps, future perspectives, and the potential impact of these findings on precision medicine strategies to combat cervical cancer.
Highlights
Cervical cancer is the fourth common cancer amongst women worldwide
There is clear evidence for a high familial relative risk (FRR), which has been deduced from the Swedish cancer registry and indicated towards disease clustering in families [54,55,56]
The power of GWAS for the detection of cervical cancer susceptibility has been increasingly exploited over the past decade [115]
Summary
Genetic factors contributing to the development of HSIL and invasive cervical cancer are largely unknown. There is clear evidence for a high familial relative risk (FRR), which has been deduced from the Swedish cancer registry and indicated towards disease clustering in families [54,55,56] These studies reported that female offspring and siblings have a relative risk (RR) of 1.5–2.3 for developing cervical cancer. Further studies towards the hypothesis of germline predisposition suggested that heritability via genetic factors might contribute some 27–36% of cervical cancer risk variation [56,66], and a large proportion of this heritability was attributed to unidentified autosomal common SNPs with low penetrance [67]. The contribution of these variants is small, and the major fraction of the estimated heritability still remains to be defined
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