Assessment of HER-2/neu, с-MYC and CCNE1 gene copy number variations and protein expression in endometrial carcinomas

Abstract

Summary. Aim: To analyze copy number variations of HER-2/neu, c-MYC and CCNE1 oncogenes and their protein expression in endometrioid endometrial carcinomas in relation to the degree of tumor progression and presence of a family history of cancer in cancer patients. Materials and Methods: The study was conducted on endometrial cancer (EC) samples from 68 patients with I–II FIGO stages of disease. Copy number analysis of HER-2/neu, c-MYC and CCNE1 genes was performed by quantitative PCR. Protein expression was analyzed using immunohistochemistry. Results: Assessment of copy number variations of HER-2/neu, c-MYC and CCNE1 genes revealed their amplification in the tumors of 18.8, 25.0 and 14.3% of EC patients, respectively. High expression of corresponding proteins was detected in 14.6, 23.5 and 65.6% of patients, respectively. It was established that HER-2/neu gene amplification is more common in the group of tumors of low differentiation grade than in moderate grade EC (35.7 and 5.5% of cases, respectively, p < 0.05). Also, high expression of c-Myc protein was more frequently observed in low differentiated tumors compared to the moderately differentiated EC (36.6 and 13.2% of cases, respectively, p < 0.05). Expression of HER-2/neu and cyclin E proteins was found to be dependent on the depth of tumor invasion into the myometrium. High expression of HER-2/neu protein was observed in 25.0 and 4.1% of EC patients with tumor invasion > ½ and < ½ of the myometrium, respectively, and cyclin E — in 86.7 and 46.6% of cases, respectively, p < 0.05. It was shown that among patients with a family history of cancer, a larger proportion of cases with high expression of c-Myc protein was observed compared to the group of patients with sporadic tumors (43.8 and 17.3%, respectively; p < 0.05). Conclusions: Amplification of HER-2/neu gene, along with high expression of c-Myc, HER-2/neu and cyclin E proteins, are associated with such indices of tumor progression as a low differentiation grade and deep myometrial invasion, suggesting the potential possibility of including these markers in the panel for determining the molecular EC subtype associated with an aggressive course of the disease. In a certain category of EC patients, there is a relationship between a family history of cancer and high expression of c-Myc protein.

KAT6A amplifications are associated with shorter progression-free survival and overall survival in patients with endometrial serous carcinoma

“…MYC amplification in EC has been reported in other studies [30,31]. In agreement with our results, MYC amplification along with HER-2/neu and cyclin E high protein expression have been associated with tumor progression, higher tumor grade and deep myometrial invasion in the literature [32]. Although MYC copy number and mRNA expression levels were not highly correlated, PVT1 was co-amplified with MYC (p<0.001) ( Fig 5) in 25% of the cases, and had a strong correlation with gene expression (r = 0.60).…”

“…DNA hypermethylation of the upstream CEBPA promoter region is responsible for very low CEBPA expression in lung and endometrial cancers [36]. Decreased expression of CEBPA by posttranscriptional regulation was also shown in myeloid leukemia [32]. Therefore, CEBPA does not appear to be a likely candidate driver gene in ESC.…”

Immunohistochemical expression of insulin‑like growth factor‑1Ec in primary endometrial carcinoma: Association with PTEN, p53 and survivin expression

“…Endometrial carcinoma type I is frequently associated with alterations in phosphatase and tensing homologue deleted on chromosome 10 (PTEN), K-ras, β-catenin, phosphatidyl-inositol-3-kinase catalytic subunit (PIK3CA), MutL homolog (MLH)-1 and MLH-6, and alterations in DNA-mismatch repair genes and microsatellite instability (79,80). Endometrial carcinoma type II is frequently associated with alterations in p53, p16, human epidermal growth factor receptor type 2 (also known as proto-oncogene neu or receptor tyrosine-protein kinase, c-erbB-2), E-type Cyclin E1, c-MYC, fibroblast growth factor receptor 3, SOX17, STK15 and E-cadherin, including loss of heterozygosity (79)(80)(81)(82)(83)(84). Metabolic syndrome is accompanying by chronic proinflammatory status and is associated with the development of cardiovascular disease and diabetic morbidity and mortality (85,86).…”

Endometrial Cancer Stem Cells: Where Do We Stand and Where Should We Go?

“…The Myc family of transcription factors are one of the few master regulators of oncogenesis, as deregulation has been detected in over 70% of human cancers and associated with poor prognosis [ 71 ]. A study conducting immune histochemical stainings found a 78.3% positive rate of c-Myc in endometrial cancer tissues and an amplified c-Myc in 25% of the cases [ 72 , 73 ]. Additionally, high expression of c-Myc was more often observed in low differentiated endometrial cancers than moderately differentiated ones [ 73 ].…”

“…A study conducting immune histochemical stainings found a 78.3% positive rate of c-Myc in endometrial cancer tissues and an amplified c-Myc in 25% of the cases [ 72 , 73 ]. Additionally, high expression of c-Myc was more often observed in low differentiated endometrial cancers than moderately differentiated ones [ 73 ]. Regarding endometrial carcinogenesis, upregulation of c-Myc in endometrial cancer cells was shown to induce EMT, drug resistance and invasion [ 74 , 75 ].…”