Genomic Characterisation of Cervical Cancer

Keerthi Ranganathan

Scientific Content Developer
4baseCare

Cervical cancer is still one of the leading causes of cancer-related deaths worldwide. Cervical cancer is a heterogeneous disease caused by a variety of genetic abnormalities. Evidence has suggested specific genetic alterations linked to the onset and development of cervical cancer.

The genomic analysis of a significant number of cervical patients revealed a wide range of molecular genomic alterations, such as somatic gene mutation, copy number alterations, DNA methylation, Gene fusion, and dysfunctional micro-RNA. 

Chen et al. (2013) conducted the first genome-wide association analysis (GWAS) of cervical cancer and discovered three independently acting loci (DAP, NR5A2, and MIR365-2 gene regions) inside the major histocompatibility complex (MHC) region, which suggest its function in high-risk Human papillomavirus (HPV) infection and persistence.

Recent studies have focused on the molecular characteristics and mechanism of HPV+ cervical cancers, owing to the rapid advancement of genomic sequencing technology. For example, PIK3CA, PTEN, TP53, STK11, KRAS, SHKBP1, ERBB3, HLA-A, CASP8, and TGFBR2 have been shown to be substantially mutated genes in cervical cancer. New evidence for the role of PAX8, CLPTM1L, and HLA genes in cervical carcinogenesis was reported in research by Sarah Bowden and colleagues (PMID: 23442549), highlighting the impact of apoptotic and immune function disruption.

Molecular analysis reveals new possible therapeutic targets and sheds light on how to develop a precision cervical cancer treatment. One of the greatest comprehensive genomic studies of cervical cancer to date documented the detailed genetic characterization of 228 primary cervical cancers. They discovered SHKBP1, ERBB3, CASP8, HLA-A, and TGFBR2 as novel highly altered genes in cervical cancer after observing remarkable APOBEC mutagenesis patterns. Amplifications were also detected in immunological targets CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2), as well as the BCAR4 long non-coding RNA, which has been linked to lapatinib response. Human papillomavirus DNA/genome integration was found in all HPV18-related samples and 76% of HPV16-related samples and was linked to structural abnormalities and enhanced target-gene expression. A distinct group of endometrial-like cervical malignancies has been found, consisting primarily of HPV-negative tumors with high KRAS, ARID1A, and PTEN mutation rates.

A comprehensive analysis described the genetic characteristic and identified novel driver genes in cervical cancer. Based on 284 clinical cases, an integrated multi-platform study of a cervical cancer cohort from The Cancer Genome Atlas (TCGA) identified driver genes and possible molecular classification of cervical cancer.

Multi-platform integration showed that cervical cancer exhibited a wide range of mutations. TTN, PIK3CA, MUC4, KMT2C, MUC16, KMT2D, SYNE1, FLG, DST, and EP300 were the top ten mutated genes, with a mutation rate ranging from 12 to 33 percent. In addition, ten potential driver genes were identified, including GPR107, CHRNA5, ZBTB20, Rb1, NCAPH2, SCA1, SLC25A5, RBPMS, DDX3X, and H2BFM.

Another research looked at the genetic differences between HPV+ and HPV-cervical malignancies. ANKRD7, SERPINB3, EMX2, MEI1, RNF212, RP11-13 K12.5, RP11-325F22.2, and ZFR2 gene expression patterns differed considerably between HPV+ and HPV- tumors and were shown to be strongly related to cervical cancer prognosis.

Between HPV+ and HPV- cancers, mutations in TP53, ARID5B, ARID1A, CTNNB1, and PTEN were shown to be substantially different. These prospective indicators might provide insight into how to better personalize treatment decision-making in HPV-positive cervical cancer patients, thereby improving survival.