Association of SNPs in CDKN2A (P14ARF) Tumour Suppressor Gene With Endometrial Cancer in Postmenopausal Women

Abstract

Background/Aim: This research was aimed to evaluate the association between three selected single nucleotide polymorphisms (SNPs) within the CDKN2A (P14ARF) tumour suppressor gene and the incidence of endometrial cancer (EC) in postmenopausal women. Patients and Methods: The study included 194 postmenopausal women; 144 with EC and 50 noncancer controls. Genotypes in P14ARF rs3088440, rs3731217 and rs3731245 polymorphisms were assayed using PCR-RFLP and confirmed by sequencing. Results: Regarding the rs3088440 polymorphism, CT, and CT-TT genotypes, were more prevalent among EC patients than in controls (OR=5.55, p=0.023, OR=5.29, p=0.027; and OR=2.92, p=0.023, respectively). The T allele within rs3088440 was more prevalent in EC females than in controls (χ 2 =4.7, p=0.030). Considering rs3731217, TG and TG-GG genotypes were less prevalent among EC (OR=0.34, p=0.024 or p=0.023; and OR=0.38, p=0.035, respectively). Conclusion: Polymorphisms in the CDKN2A gene are associated with EC in postmenopausal women. Endometrial cancer (EC) is the fourth most common cancer among Polish women (after breast, colon, and lung cancer) responsible for 3% of cancer deaths in this population. Moreover, the incidence rate of this cancer has almost doubled in the last three decades, due to several factors, especially the increased average life expectancy of women. Hence, EC is predominantly observed in postmenopausal women in their sixth/seventh decade of life, with the highest incidence rate of 80/100,000 at the end of the seventh decade (1). P14ARF belongs to three tumour suppressor proteins, including p16INK4a and p15INK4b encoded by the CDKN2A gene, genetic changes of which may cause cellular proliferation and tumour growth (2, 3). It has been shown that p14ARF influenced the course of cell cycle by activating p53 and inhibiting MDM2 expression thus leading to cell cycle arrest in G 1 and G 2 /M phases (4, 5). Altered expression of p14ARF, either decreased or increased, has been found in various human tumours (5-8). Considering EC, tumor heterogeneity in CDKN2A protein expression between four different cores of primary tumours, has been reported as significantly more prevalent among samples with a higher stage of the disease (9). In another study, CDKN2A tumour suppressor gene was included in a panel of seven immunohistochemical markers [ER, CDKN2A (p16), TP53, VIM, PTEN, PGR, and IGF2BP3] to differentiate endometrioid carcinoma in FIGO grade 3 from serous carcinoma, based on immunohistochemical qualitative assays performed by tissue microarrays (10). Moreover, moderate immunohistochemical expression of p14 has been observed in endometrioid endometrial carcinoma, while total lack has been found in endometrial hyperplasias without atypia, at the 943 This article is freely accessible online.

3’UTR-CDKN2A and CDK4 Germline Variants Are Associated With Susceptibility to Cutaneous Melanoma

“…However, prior studies reported that CDK4 variants frequencies are approximately between 2-15% in Greek (19), Latvian (20), and other populations (5). Germline variants (500C>G and 540C>T) in the CDKN2A 3'UTR gene have been found in approximately 12-31% of cutaneous melanomas and healthy controls, respectively (21)(22)(23), as well as associated with a risk of developing other types of cancer (24). However, it was shown in previous reports, that 14% of patients of 30 Israel melanoma families presented 500C>G germline variants, and other germline variants (25).…”

A bioinformatics study of autophagy biomarkers associated with the prognosis of endometrial carcinoma

“…The CDKN2A is a gene type of cyclin-dependent kinase inhibitor, its mutations have been related to breast cancer, melanoma and squamous cell carcinoma [31][32][33]. Recent findings show that polymorphisms in the CDKN2A gene are associated with EC in postmenopausal women [34]. As for PTK6, an intracellular tyrosine kinase, in tumors overexpressing PTK6, this unusual soluble tyrosine kinase is emerging as a mediator of cancer cell phenotypes, including increased proliferation, survival, and migration [35].…”

Bioinformational and clinical aspects of identificationof differentially expressed genes by tumor cells in endometrialcarcinoma and rare forms of uterine body cancer

“…Ген CDKN2A регулирует синтез белков р16 и p14ARF, а также (по механизму отрицательной обратной связи) протеина Rb и р53. При гиперэкспрессии гена CDKN2A нарушаются сигнальные пути p16-CDK4/циклин D1-pRb и p14ARF-MDM2-p53, что ведет к нарушениям клеточного цикла и потере онкосупрессорных свойств протеинов [11]. Ген L1CAM кодирует нейрональную белковую молекулу клеточной адгезии L1, которая принимает участие в процессах клеточной миграции, адгезии, миелинизации и нейрональной дифференцировки.…”