N-myc downstream-regulated gene 1 as a downregulated target gene of PTEN in the controlling of tumourigenesis in endometrioid carcinoma.

BACKGROUND & OBJECTIVE: Mutation/deletion of PTEN has been known to be involved in the development of many cancers including endometrial carcinoma. NDRG1 (N-myc downstream-regulated gene 1) is reported to be associated with tumourigenesis. PTEN expression has been shown to be correlated with NDRG1 in both prostate and breast cancer. In this study, we explored the possibility that PTEN alteration may cause carcinogenesis of endometrioid carcinoma by regulating the expression of the NDRG1 gene. METHODS: Tissue blocks of 103 patients with pathologically confirmed endometrioid carcinoma were included. All the carcinoma tissues were accompanied with varied degree of necrosis. Using two-step method and avidin-biotin peroxidase complex immunohistochemistry method, the correlation of the two genes expression in ischaemic area and the relationship of NDRG1 expression between ischaemic and non-ischaemic area in endometrioid carcinomas was evaluated. RESULTS: PTEN alteration and NDRG1 expressions were significantly increased in the ischaemic area of endometrioid carcinoma compared with their expressions in the normal endometrium respectively (P<0.001, P<0.001). A positive correlation was found between PTEN alteration and NDRG1 expression in the ischaemic area of endometrioid carcinoma. INTERPRETATION & CONCLUSION: We suggest that NDRG1 may be an important candidate gene in facilitating endometrium carcinogenesis in the adaptation of hypoxia for survival. Alteration of PTEN may upregulate NDRG1 expression, which plays an important role in the process leading to endometrial carcinogenesis.

Rol patogénico del gen supresor de tumores PTEN en cáncer ovárico asociado a endometriosis / Pathogenic role of PTEN tumor suppressor gene in ovarian cancer associated to endometriosis

Background: Endometrioid carcinoma and clear cell carcinoma of the ovary are associated to endometriosis. Somatic mutations of PTEN (10q23.3) are present in endometrial endometrioid carcinoma. Therefore, these mutations could be also present in ovarian tumors. Molecular studies show that solitary endometriotic cysts are monoclonal, have aneuploid DNA, have a loss of 9p,11q and 22q heterozygosity (LOH) and a higher cellular proliferation index of the epithelial component. Aim: To determine the cellular proliferation index using Ki 67, the immunohistochemical expression of PTEN and LOH in patients with ovarian endometriosis without atypia (EN), ovarian endometriosis with atypia (EA) and endometriosis with adjacent ovarian carcinoma (ET). Material and methods: Paraffin embedded samples of 37 endometrioid and clear cell carcinomas of the ovary (CC/CE), 15 solitary ovarian EN and 15 ovarian EA, were studied. Expression of Ki 67 and PTEN was measured by immunohistochemistry. LOH of 10q23.3 locus was measured by polymerase chain reaction. Results: Ki 67 was 5.5 and 2.3% in EA and EN, respectively (p <0.005). There was a histological correlation between EA and a higher cellular proliferation index. PTEN was negative in 5 of 15 EN, 9 of 15 EA and 30 of 37 CE/CC. There was a correlation between LOH and loss of PTEN protein in EN, EA and ET (60%). Conclusions: Negative expression on PTEN in EN; EA; ET and CE/CC is a manifestation of the inactivation of this gene. The mechanisms that cause this inactivation, must be elucidated.

p53 tumor suppressor gene mutation in ovarian cancer in Thai patients.

OBJECTIVES: To characterize molecular mutations of p53 gene in Thai ovarian cancer and compare the mutations with their pathological and clinical findings. MATERIAL AND METHOD: Direct DNA sequencing of hot spot region of p53 gene (exons 5 to 8) from 28 primary ovarian cancer tissues, 2 metastatic tumors and their paired blood samples was performed. The detected mutations were compared to the pathological and clinical findings and responsiveness to treatments after 36 months of follow-up. RESULTS: One insertion and 4 point mutations in exon 5 of p53 gene were found in 5 out of 28 (18%) ovarian cancer patients. There was no mutation in the paired blood samples. The histological types of the detected tumors were 3 endometrioids and 2 serous cystadenocarcinomas. All 5 patients were in stage I to IV disease and showed overall 4 out of 5 (80%) complete response until 36 months after surgery followed by chemotherapy, compared to 14 out of 28 (50%) of complete response in all cases of ovarian cancer. CONCLUSION: The authors found 5 cases of ovarian cancer patients with p53 gene mutations giving the same response to complete standard treatment as all cases. Significant factors affecting responsiveness of these patients depended more on stages, grades and histological cell types of the cancer.