Allelic loss at TP53 in metastatic human endometrial carcinomas

Abstract

Loss of heterozygosity (LOH) is implicated in the initiation and progression of various human neoplasia, and is observed in both early or in advanced-stage human cancers. The current study was aimed at investigating the frequency of LOH TP53 in human endometrial carcinoma (EC) metastases. LOH was analyzed using 3 intragenic polymorphisms in 38 primary ECs and corresponding metastatic lesions. Allelic loss at intron 1 was detected in 14 out of 38 (37%) primary carcinomas and in 11 out of 38 (29%) metastatic lesions. LOH at intron 1 in primary and metastatic tumors was concomitantly noted in 8 out of 38 (21%) cases. LOH at intron 4 was seen in 46% (17 out of 37) primary ECs and in 35% (13 out of 37) metastatic lesions. LOH at intron 4 in primary tumor/metastasis was concomitantly demonstrated in 27% (10 out of 33) cases. Allelic loss at exon 4 was detected in 5 out of 33 (15%) primary ECs and in one out of 33 (3%) corresponding metastases. Coexistence of LOH TP53 in primary ECs with metastases at intron 1 and intron 4 was observed in three out of 33 (9%) cases. Correlation between allelic loss at intron 1 in primary ECs and corresponding metastases was found (R = 0.475, p = 0.003). Moreover, there was correlation between LOH at intron 1 in metastastic ECs and allelic imbalance at intron 4 in primary uterine tumors (R = 0.416, p = 0.01). There was a relationship between LOH at intron 4 in primary ECs and corresponding metastatic lesions (R = 0.457, p = 0.004). LOH TP53 at intron 4 correlated with the presence of the neoplasm in the uterine cervix (R = 0.319, p = 0.049), and with the non-endometrioid type of primary tumor (R = 0.371, p = 0.024). There was a significant correlation between exon 4 LOH and patient age (less or equal to 50 years and above this age; R = -0.375, p = 0.032). p53 overexpression was present in thirteen out of 38 (34%) cases, both in primary ECs and in metastatic lesions. Overexpression of p53 was higher in non-endometrioid ECs (three out of 5; 60%) than in endometrioid-type uterine tumors (ten out of 33; 30.3%; p = 0.315). p53 overexpression correlated with the presence of cancer in the lumen of fallopian tube(s) (R = 0.032, p = 0.046), and with allelic loss at intron 1 in primary ECs (R = 0.599, p = 0.0001). In conclusion, LOH occurs not only in primary uterine tumors but also in corresponding metastases, with the higher incidence being reported at intron 4 of the TP53. A significant link existed between LOH TP53 at intron 1 and p53 overexpression in primary ECs, but not in the corresponding metastatic lesions.

The dynamics of nuclear receptors and nuclear receptor coregulators in the pathogenesis of endometriosis

“…TP53 has been described as a tumor suppressor gene because it has anticancer functions and plays a role in apoptosis, genomic stability and inhibition of angiogenesis (Matlashewski et al, 1984;Isobe et al, 1986). The level and/or activity of TP53 is significantly downregulated in most types of cancer cells compared with normal tissues (Semczuk et al, 2010). As in cancer, TP53 levels also are down-regulated in endometriotic tissues compared with the normal endometrium (Arimoto et al, 2003) (Table II).…”

Induced mitotic homologous recombination by the babesicide imidocarb dipropionate in Aspergillus nidulans diploid cells

“…Alterations in tumor suppressor genes, which have the normal physiological role of delaying the cell division process, have been described as relevant in the development of neoplasia (Velasco et al, 2008;Szewczuk et al, 2009). According to Knudson's hypothesis (1993), the heterozygous state of a mutationbearing cell ("first hit") could be lost when it is exposed to cancer-promoting events ("second hit").…”

Mitotic recombination: a genotoxic effect of the antidepressant citalopram in Aspergillus nidulans

“…LOH of the TP53 locus is implicated in the initiation and progression of various human malignancies and has been observed in both early or in advanced-stage neoplasms. 34–37…”