Cancer is a multi-factorial disease that remains a serious global concern. Cervical carcinoma is the fourth most frequent cancer in women with a global incidence rate of 570,000 reported in 2018, and representing 6.6% of all cancers in females [1]. Approximately 90% of cancer-related deaths occur in low- and middle-income countries [2], with about 85% of the 250,000 deaths recorded annually from cervical cancer are reported in developing countries where most cases are presented in the late stages of the disease. The incidence of cervical cancer in Nigeria is about 250/100,000 with about 8000 deaths annually [3].
Three major factors have been identified in cervical cancer pathogenesis out of which two are related to human papillomavirus (HPV) infection. These include the consequences of HPV DNA integration in the host genome, the effects of viral oncoproteins and the accumulation of cellular genetic damage not associated with HPV infection [4]. High risk of HPV infection, late diagnosis due to poor screening uptake and prognosis and low uptake of HPV vaccination have been attributed as the major factors culpable in the cervical cancer burden in women [4].
HPV is the primary causative biological agent involved in cervical cancer pathogenesis [4, 5]. The high-risk HPV’s DNA encodes the oncoproteins E6 and E7 which bind to p53 and retinoblastoma proteins, respectively. The binding of the E6 protein, through its interaction with the E6-associated protein (E6AP), to p53 induces the degradation of p53, the tumour suppressor protein [6] (as schematically shown in Fig. 1). This proteasomal degradation pathway could play a crucial role in cervical carcinogenesis through the promotion of cell cycle entry that leads to unregulated proliferation of invasive cells [7, 8].
On the other hand, the protooncogenes and tumour suppressor genes play vital roles in carcinogenesis [9]. The p53 protein (commonly referred to as the guardian of the genome), which contains 11 exons, is a nuclear phosphoprotein whose gene is located on the short arm of chromosome 17 at the 17p13.1 locus [10,11,12]. It plays an important role in the regulation of cell proliferation, the cell cycle, as well as apoptosis and senescence in response to DNA damage [13, 14], and is frequently mutated in most human cancers [15]. Most mutations observed in the p53 gene are single base-pair substitutions and occur predominantly between codons 130 and 290 [5]. The p53 gene has been rarely observed to be mutated in early cervical tumours [6]. In addition, some p53 mutant proteins are unsusceptible to E6-mediated degradation, thereby suggesting that p53 polymorphisms might be culpable in the variation of cell responses to the HPV infection [6].
Mutations in p53 are also associated with genomic instability [16] and delay in cell cycle progression [17, 18]. The proline-rich region of the p53 protein is essential for induction of apoptotic response to cellular stressors [19] and inhibition of tumourigenesis [20]. However, the E6 oncoprotein causes more efficient degradation of the arginine polymorph at codon 72 than the proline polymorph, thereby, reducing cellular levels of p53 protein and increasing the risk of HPV-associated cervical cancers in individuals with the arginine polymorph [21]. The first p53 gene mutation in human cancer was described by Bakers and his team [22]. Codon 72 is located within the proline-rich region of the gene and may have a significant effect on the putative (sarcoma homology) SH3-binding domain [14]. Studies have linked genetic polymorphism of the codon 72 of p53 to cervical cancer progression [8], and the variation in this codon can either be arginine (GCG) or proline (GGG).
The divergence in the polymorphic variations that exist in p53 with respect to the pathogenesis of cervical cancer has been attributed to varying geographic locations, and the different environmental exposures [23]. It has also been reported that greater than 85% of known cancer-related p53 mutations are missense mutations [2, 4]. Some of the missense mutations resulting from single nucleotide substitutions can affect p53 conformation and result in inactive protein.
The exon 4 in the p53 gene is one of the largest, spanning 311 nucleotide base pairs (bp). It contains the proline-rich region and is essential for DNA specific binding, apoptosis, and transcription [10, 16].
To understand further the role of this tumour-suppressor gene mutation-pattern in cervical cancer, we performed a mutational analysis for the polymorphicvariations in the exons 3 and 4 of p53 gene in patients diagnosed with cervical cancer in Ibadan, Nigeria.