Cervical Cancer
A number sign (#) is used with this entry because of evidence that various genes are involved in the causation of cervical cancer.
PathogenesisIn the vast majority of cases, invasive carcinoma of the uterine cervix is thought to arise from preinvasive cervical intraepithelial neoplasias, designated CIN I-CIN III, which represent a pathologic continuum from mild to severe epithelial dysplasia. Only some cases of the more dysplastic lesions progress further to invasive carcinoma. Whereas most of the precursor lesions are readily curable, the prognosis for invasive carcinoma is generally poor, making the dissection of the molecular events that cause invasion considerably important. The observations are consistent with models describing a multistep genetic pathway for human tumorigenesis as proposed by Fearon and Vogelstein (1990) for colorectal cancer. Cervical cancer is strongly associated with infection by oncogenic types of human papillomavirus (HPV; see 167959 and 167960), but only a small fraction of those infected develop cancer, indicating that other factors contribute to the progression to cervical cancer.
InheritanceMagnusson et al. (1999) compared the incidence of cervical cancer in relatives of cases of cervical cancer and controls, and found a significant familial clustering among biologic, but not adoptive, relatives. They used the Swedish national registers to identify relatives of cases with cervical cancer (126,893 relatives of 71,533 cases) and randomly selected age-matched controls. The relative risk for biologic mothers to cases was 1.83, whereas for adopted mothers the relative risk was not significantly different from 1. The relative risk for biologic full sisters to cases was 1.93, whereas that for nonbiologic sisters to cases was 1. Examining second-degree relatives, Magnusson et al. (1999) found that half sisters to cases had a relative risk of 1.45, which is close to that expected if the familial aggregation seen for first-degree relatives is caused mainly by genetic factors. Vertical transmission of HPV does not explain the difference in risk for half sisters since the relative risk for half sisters to cases having a father in common or a mother in common was not different. Magnusson et al. (1999) concluded that the familial risk for cervical tumors is of the same magnitude as that seen for other forms of cancer, such as prostate cancer (176807), for which genetic contribution has long been recognized.
MappingPursuing the functional studies showing that human chromosome 11 contains a gene or genes capable of suppressing tumorigenicity in cell lines derived from different histopathologic types of cervical carcinoma, Hampton et al. (1994) carried out a systematic analysis of chromosome 11 in primary tumors of 32 patients with cervical carcinoma. To identify the likely chromosomal position of the relevant gene or genes, they used 16 highly polymorphic markers to compare matched DNA samples from noninvolved tissue and portions of tumor tissue highly enriched for neoplastic cells. Of the 32 patients examined, 14 (44%) demonstrated clonal genetic alterations resulting in loss of heterozygosity for 1 or more markers. From the fact that 7 of the clonal genetic alterations on chromosome 11 were specific to the long arm and by the overlap between these and other allelic deletions, Hampton et al. (1994) concluded that at least 1 suppressor gene relevant to cervical carcinoma maps to 11q22-q24 (see ST3; 191181).
Molecular GeneticsSomatic Mutation
Cappellen et al. (1999) found constitutively activated FGFR3 (134934) in a large proportion of 2 common epithelial cancers, cervical cancer and bladder cancer (109800). The most frequent FGFR3 mutation identified in epithelial tumors was ser249 to cys (134934.0013), affecting 5 of 9 bladder cancers and 3 of 3 cervical cancers.
Ojesina et al. (2014) reported whole-exome sequencing analysis of 115 cervical carcinoma and normal tissue paired samples, transcriptome sequencing of 79 cases, and whole-genome sequencing of 14 tumor-normal pairs. Previously unknown somatic mutations in 79 primary squamous cell carcinomas included recurrent E322K substitutions in the MAPK1 gene (176948; 8%), inactivating mutations in the HLA-B gene (142830; 9%), and mutations in EP300 (602700; 16%), FBXW7 (606278; 15%), NFE2L2 (600492; 4%), TP53 (191170; 5%); and ERBB2 (164870; 6%). Ojesina et al. (2014) also observed somatic ELF3 (602191; 13%) and CBFB (121360; 8%) mutations in 24 adenocarcinomas. Squamous cell carcinomas have higher frequencies of somatic nucleotide substitutions occurring at cytosines preceded by thymines than adenocarcinomas. Gene expression levels at HPV integration sites were statistically significantly higher in tumors with HPV integration compared with expression of the same genes in tumors without viral integration at the same site. Ojesina et al. (2014) noted that somatic mutations in PIK3CA (171834), PTEN (601728), TP53, STK11 (602216) and KRAS (190070) had been implicated in several studies (Crook et al., 1992; McIntyre et al., 2013; Kang et al., 2007; Wingo et al., 2009).
The Cancer Genome Atlas Research Network (2017) reported the extensive molecular characterization of 228 primary cervical cancers and observed notable APOBEC (see 600130) mutagenesis patterns and identified SHKBP1 (617322), ERBB3 (190151), CASP8 (601763), HLA-A (142800), and TGFBR2 (190182) as novel significantly mutated genes in cervical cancer. The Cancer Genome Atlas Research Network (2017) also discovered amplifications in immune targets CD274 (also known as PDL1; 605402) and PDCD1LG2 (also known as PDL2; 605723), and the BCAR4 (613746) long noncoding RNA, which has been associated with response to lapatinib. Integration of human papilloma virus (HPV) was observed in all HPV18-related samples and 76% of HPV16-related samples, and was associated with structural aberrations and increased target gene expression. The Cancer Genome Atlas Research Network (2017) identified a unique set of endometrial-like cervical cancers, comprised predominantly of HPV-negative tumors with relatively high frequencies of KRAS, ARID1A (603024), and PTEN mutations. Integrative clustering of 178 samples identified keratin-low squamous, keratin-high squamous, and adenocarcinoma-rich subgroups. The Cancer Genome Atlas Research Network (2017) concluded that these molecular analyses revealed potential therapeutic targets for cervical cancers.