Topoisomerase 2α and thymidylate synthase expression in adrenocortical cancer

Abstract

Topoisomerase II alpha (TOP2A) and thymidylate synthase (TS) are known prognostic parameters in several tumors and also predictors of efficacy of anthracyclines, topoisomerase inhibitors and fluoropirimidines, respectively. Expression of and mRNA was assessed in 98 patients with adrenocortical carcinoma (ACC) and protein expression was assessed by immunohistochemistry in a subset of 39 tumors. Ninety-two patients were radically resected for stage II-III disease and 38 of them received adjuvant mitotane. Twenty-six patients with metastatic disease received the EDP-M (etoposide, doxorubicin, Adriamycin, cisplatin plus mitotane). and expression in ACC tissue was directly correlated with the clinical data. Both markers were not associated with either disease free survival (DFS) or overall survival (OS) in multivariate analyses and failed to be associated to mitotane efficacy. Disease response or stabilization to EDP-M treatment was observed in 12/17 (71%) and 1/9 (11%) patients with high and low TOP2A expressing tumors ( = 0.0039) and 9/13 (69%) and 4/13 (31%) patients with high and low TS expressing ACC, respectively ( = 0.049). High TOP2A expression was significantly associated with longer time to progression (TTP) after EDP-M. TOP2A and TS proteins assessed by immunohistochemistry significantly correlated with mRNA expression. Immunohistochemical TOP2A expression was associated with a non-significant better response and longer TTP after EDP-M. TOP2A and TS were neither prognostic nor predictive of mitotane efficacy in ACC patients. The predictive role of TOP2A expression of EDP-M activity suggests a significant contribution of Adriamycin and etoposide for the efficacy of the EDP scheme.

Molecular markers of prognosis in canine cortisol‐secreting adrenocortical tumours

“…The chemotherapy protocol that is most effective in human ACCs is the combination of etoposide, doxorubicin and cisplatin with mitotane (EDP‐M) . Of these, etoposide and doxorubicin are topoisomerase II inhibitors, and a recent study showed that the level of TOP2A expression in human ACCs is predictive of the response to the EDP‐M chemotherapy protocol . In view of the prognostic relevance of TOP2A in canine ACTs, topoisomerase II inhibitors could be an interesting treatment to improve the prognosis of dogs with high intra‐tumoural TOP2A expression.…”

“…TOP2A is predominantly associated with proliferating cells, which makes it an interesting therapeutic target in cancer. TOP2A is also a prognostic marker in human ACCs and other tumour types . Several TOP2A inhibitors are therefore successfully used in the clinic as anticancer drugs .…”

“…High expression of SF‐1 is also an important negative prognostic indicator in human ACTs . Other molecular markers that have prognostic value in human ACTs include pituitary tumour‐transforming gene‐1 (PTTG1), topoisomerase II alpha (TOP2A), Vav Guanine Nucleotide Exchange Factor 2 (VAV2) and (for childhood ACTs) B‐cell lymphoma 2 (BCL2) …”

The next step: mechanisms driving adrenocortical carcinoma metastasis

“…High RRM1 expression levels are associated with reduced DFS and OS (Volante et al 2012); • Topoisomerase II alpha (TOP2A) is an enzyme responsible for transcription, replication and chromosome condensation and segregation during cell division. High TOP2A expression is correlated with longer time for progression after etoposidedoxorubicin -cisplatin -mitotane (EDP-M) treatment (Roca et al 2017).…”

Biochemical mechanism of the o,p’-DDD effect on the adrenal cortex

“…Moreover, the level of immunoreactive CYP2W1 in tumors is associated with hormoneactivity,amoredifferentiatedphenotype,and in cancer, with a better response to mitotane treatment. These findings allow considering CYP2W1 as a possible marker to prognose tumor response to mitotane used as an adjuvant or palliative therapy aftersurgery.TheactivityoftopoisomeraseIIαand thymidylate synthase as prognostic criteria was analyzed in [14]. The activity of these enzymes in tumor tissuewasfoundnottobeassociatedwiththeeffect of mitotane.…”