TDP1 and TOP1 as targets in anticancer treatment of NSCLC: Activity and protein level in normal and tumor tissue from 150 NSCLC patients correlated to clinical data.

OBJECTIVES: Topoisomerase 1 (TOP1) is a drug target used in anticancer treatment of various cancer types. The effect of the TOP1 drugs can be counteracted by the enzymatic activity of tyrosyl-DNA phosphodiesterase 1 (TDP1). Thus, to elucidate the relevance of combining TDP1 and TOP1 as drug targets for anticancer treatment in NSCLC, TDP1 and TOP1 was for the first time quantified in a large cohort of paired normal and tumor tissue from NSCLC patients, and data were correlated between the two enzymes and to clinical data. MATERIALS AND METHODS: TDP1 and TOP1 activity and protein concentration were measured in paired normal and tumor tissue from 150 NSCLC patients using TDP1 and TOP1 specific biosensors and ELISA. TDP1 and TOP1 activity and protein concentration were correlated to clinical data. RESULTS: TDP1 and TOP1 activity and protein concentration were significantly upregulated from normal to tumor tissue for the individual patients, but did not correlate to any of the clinical data. TDP1 and TOP1 activity were upregulated in 89.3% and 82.7% of the patients, respectively, and correlated in both normal and tumor tissue. The same tendency was observed for protein concentration with an upregulation of TDP1 and TOP1 in 73.0% and 84.4% of the patients, respectively. The activity and protein concentration correlated in normal and tumor tissue for both TDP1 and TOP1. CONCLUSION: The upregulations of TDP1 and TOP1 from normal to tumor tissue combined with the observation that TDP1 and TOP1 did not correlate to any of the clinical data indicate that both proteins are important for development or maintenance of the tumor cells in NSCLC. Correlations between TDP1 and TOP1 indicate a biological dependency and potential co-regulation of the enzymes. These observations is encouraging in relation to using TOP1 and TDP1 as targets in anticancer treatment of NSCLC.

Telomerase reverse transcriptase promoter mutations and solar elastosis in cutaneous melanoma.

The aims of this study were to assess the prognostic potential of solar elastosis grading and telomerase reverse transcriptase (TERT) promoter mutations (TERTp) in melanoma and to evaluate whether an association between solar elastosis and TERTp exists. Solar elastosis in the dermis was evaluated in hematoxylin and eosin-stained whole slides from 486 malignant melanomas. Pyrosequencing was used to detect TERTp in 189 samples. There was no association between solar elastosis and TERTp (P=0.3). Severe elastosis was associated with older age (P<0.0001), ulceration (P=0.03), and location in the head/neck region (P<0.0001). The absence of elastosis was associated with younger age (P<0.0001), benign nevus remnants (P=0.001), and a positive BRAF V600E expression (P<0.0001). Severe elastosis predicted a worse relapse-free survival (hazard ratio: 2.18; 95% confidence interval: 1.30-3.64; P=0.003). However, it was not independent of age. TERTp was not associated with any adverse prognostic or clinicopathological outcome, nor any mitogen-activated protein kinase-related protein expressions. However, at a cutoff corresponding to the sensitivity of Sanger sequencing, TERTp predicted melanoma-specific death independently of age, and was associated with Breslow thickness, ulceration, tumor stage at diagnosis, BRAF V600E oncoprotein, and absence of p16 expression. In conclusion, TERTp were not related to severe elastosis and may thus be triggered by both chronic and acute intermittent sun exposure, the latter not visible on ordinary hematoxylin and eosin-stained slides. Neither TERTp nor severe elastosis predicted an adverse outcome in melanoma. An absence of elastosis was seen in younger melanoma patients and may be used to select those melanomas originating in a nevus, which often harbors a BRAF mutation.