Recent studies have revealed that several genetic polymorphisms may play important roles in the pathogenesis of ovarian cancer[14, 15], and women who carried the gene mutation (BRCA1 mutation) had an increased risk (by up to 50%) of developing ovarian cancer in a lifetime. In one of the most recent genome-wide association study (GWAS) conducted in ovarian cancer, a strong association with 12 single-nucleotide polymorphisms (SNPs) in the Basonuclin 2 (BNC2) gene was found, where the minor allele of the associated SNPs were protective against disease[17, 18]. Moreover, a meta-analysis showed that patients with one of single nuclear polymorphisms vitamin D receptor (VDR), the FokI rs2228570 TT genotype, had a significantly higher risk for developing ovarian cancer as well as prostate, breast, skin, non-Hodgkin lymphoma, and colorectal cancer compared with its CC genotype[19, 20]. By seeking susceptibility genes and establishing high-risk populations, early diagnosis may be beneficial to improve ovarian cancer survival.
As tumor candidate genes, p63 and p73 are involved in the regulation of the cell cycle, apoptosis, differentiation and other critical cellular processes. The abnormal expression of the two genes can play catalytic roles in the development of ovarian tumors and achieve synergy in terms of early malignant transformation and enhanced tumor invasion. In recent years, there has been an increased interest in research into the connection between p63 and p73 variants generated by genetic polymorphisms and cancer progression. Meanwhile, several genetic polymorphisms have been implicated in the pathogenesis of ovarian cancer[14–20]. However, little is known about how the p63 and p73 polymorphisms are involved in ovarian cancer susceptibility and clinical pathology. Therefore, we conducted this study to genotype three SNPs in the p63 and p73 genes to determine whether this polymorphism functioned as a modifier of ovarian cancer development.
Prior studies have demonstrated that p63 and p73 were highly expressed in female germ cells during meiotic arrest and play an important role in DNA damage-induced apoptosis in female germ cells[21, 22]. Recently, three SNPs (rs873330 T > C, rs4648551 G > A, rs6695978 G > A) located in p63 and p73 were identified, and they appear to be under evolutionary selection pressures using the criteria of Atwal[23, 24] and information theory. That study showed a clear enrichment of the SNPs in infertility and IVF patients and revealed that polymorphisms in the human p63 and p73 genes could be involved in reproductive deficits[11, 25]. In theory, the factors including non-pregnancy, infertility and application of ovulation induction drugs that lead to continued ovulation can increase the incidence of ovarian cancer. Infertility therapies utilize products, such as IVF, that alter the hormonal balance and may also increase the risk of ovarian tumors. Based on the close relationship between infertility and ovarian cancer susceptibility, we genotyped these SNPs in ovarian cancer patients and normal individuals using a case–control study. Our results indicated that the A allele frequency in p73 rs6695978 G > A was statistically higher in the case group compared with the control group. Women with the A allele were at increased risk of ovarian cancer compared to carriers of the G allele, which also confirmed that this polymorphism may serve as a predictor of ovarian cancer susceptibility.
Ovarian cancers comprise a broad spectrum of malignancies, ranging from serous to mucinous, endometrioid, clear cell and other histologic subtypes. These histotypes have been recently associated with distinct molecular profiles and polymorphisms, supporting the idea that the distinct molecular pathways and genotype may strongly affect germinal histotypes in ovarian cancer[27–30]. As demonstrated in our research, the frequencies of A allele and combined GA + AA genotypes in p73 rs6695978 G > A were statistically elevated in mucinous ovarian cancer compared with other subtypes. In all histologic types, the prognosis of mucinous ovarian cancer is unsatisfactory and prone to metastasis and drug resistance, which introduces difficulties and challenges into clinical treatment. The median survival (MS) of mucinous adenocarcinomas did not differ significantly between the groups interpreted as primary or metastatic, but the overall survival (OS) of mucinous adenocarcinomas is significantly less than that for women with serous carcinoma. Mucinous carcinomas are independent predictors of poor prognosis in stage III/IV ovarian cancer. Consequently, our study indicates that the rs6695978 A allele may be more closely related to the occurrence of mucinous ovarian cancer and individuals carrying the AA and GA genotypes may suffer from poorer prognoses.
With respect to the clinical stage, differentiation degree and lymph node status in ovarian cancer, which can guide clinical treatment and outcomes, there is also mounting evidence that p73 protein expression may play a vital role in malignant transformation, clinical stage, differentiation degree and metastasis of ovarian cancer. The lower the differentiation degree, the higher the level of p73 expression. Increasing the expression of the p73 protein in tumor cells may strengthen the suppression of cellular apoptosis; the survivability and malignancy of the tumor are enhanced accordingly. Thus, tumor cells may have an easier time to invade the surrounding tissues and metastasize to the lymph nodes, which shorten the survival of ovarian cancer patients. In this study, we clarified the association of the A allele frequency in the p73 rs6695978 G > A with a low degree of differentiation and lymph node metastasis, which is similar to what was seen in previous studies on the status of p73 expression in ovarian cancer. However, the biological relevance for an association between rs6695978 A allele and ovarian cancer remains unclear. Therefore, we will sought to assess whether there was a necessary link between p73 expression status and the p73 rs6695978 G > A polymorphism in the next step. Further investigation in a larger sample size involved molecular mechanisms are indispensable.
Ovarian cancer is a hormone-dependent malignancy, and estrogen/ progesterone and its receptors may play important roles in the pathogenesis of ovarian cancer. For a long time, progesterone has been considered to be a protective factor for ovarian cancer. Approximately 26% to 49% of ovarian cancers have PR expression, and patients with a high expression of PR often have a good prognosis. In contrast, estrogen has been considered as a risk factor for epithelial ovarian cancer. The proliferation of ovarian tissue with estrogenic stimulation and estrogen/hormone replacement therapy (HRT) may possibly increase the risk of ovarian cancer[37, 38]. Approximately 61% to 79% of ovarian cancers express the ER. From the pathological standpoint, estrogen and ER expression can accelerate the mitosis of ovarian cancer cells, which rely on inhibiting apoptosis and promoting cell proliferation to participate in the development of tumors. Hence, ER-positive ovarian cancer patients often suffer from a poor prognosis. The data in our research illustrated that ER-positive patients tend to carry the AA and GA genotypes in p73 rs6695978 compared with the GG genotypes. In contrast with ER-negative, the A allele frequency in rs6695978 were also statistically increased in ER-positive patients. There appears to be a potential connection between rs6695978 A allele and bad clinical outcomes.
In conclusion, this is the first study to indicate the p73 rs6695978 G > A A allele as the at-risk allele may enhance susceptibility to ovarian cancer in Chinese women. The individuals with the A allele were at increased risk of ovarian cancer compared to carriers of the G allele, and positively associated with the occurrence of mucinous ovarian cancer, poor differentiation, lymph node metastasis and estrogen receptor status, which all indicate a poor prognosis for ovarian cancer. However, detailed ovarian tumor histology data were not available, and the biological and mechanistic relevances between rs6695978 A allele and ovarian cancer remain unclear. Meanwhile, the process of ovarian cancer development in women is probably mediated by other candidate genotypes and different pathways; this analysis leads to future work in the following directions (a) with large samples and detailed surveys focusing on the functional pattern of this polymorphism (b) examination of p73 expression levels by genotype among the current population. (c) analysis of genotypic interactions with closely-related genes. Further research of this critical gene and those which are biologically related may lead to a better informed biological understanding of ovarian cancers. Substantiating its independent prognostic value for clinical diagnosis and outcome is of great significance. In addition, findings such as these will lead to the development of genetic risk prediction panels for eventual classification of women who may most benefit from targeted surveillance or prevention strategies.