Introduction: The development of molecular targeted therapies as anti-cancer strategies raises important questions regarding the biological and molecular behavior of the metastatic sites as compared to their corresponding primary tumors. We analysed telomere related markers (telomere length and telomeric proteins) and DNA damage repair (DDR) markers in a cohort of patients with surgically resected primary lung NSCLC and adrenal metastasis. These markers were selected for two reasons: (i) small molecule inhibitors of 'druggable' DDR components as well as telomere-interacting agents are already being developed for clinical use; and (ii) limited data is available comparing the expression of these biomarkers between primary tumors and their metastases.
Material and methods: We studied a single series of 21 patients who had undergone surgery of both their primary lung tumor and its related adrenal gland metastasis in a single Institution. DDR and telomeric proteins were analysed by immunohistochemistry and telomere length was assessed by fluorescent in situ hybridization in 17 paired samples.
Results: DDR activation was observed in primary tumors and their corresponding metastasis. However, higher levels of p-Chk2 were observed in metastasis than in primary tumors (p=0.0113). This was not observed for p-ATM and gamma-H2AX. Telomere length was independent from primary or metastatic status (p=0.29). There was no correlation between primary and metastatic sites, although approximately 65% of metastases had shorter telomeres than their corresponding primary tumors. In the same way, telomeric protein expression was independent from primary/metastatic localization. Cluster analysis of each specimen according to its protein's expression levels and telomere length showed that matched primary tumors/adrenal metastasis were mostly separated into different clusters. Overall, our findings suggest that the levels of biomarkers analysed differ substantially between primary lung tumors and corresponding metastases.
Conclusion: There are clear molecular discrepancies at the telomeric and DDR level between primary tumors and their corresponding metastases. Our results may have important implications for the development of molecular targeted therapies aiming at DNA damage repair and telomeric components. Our findings suggest that primary tumors and their relevant metastases may respond differently to such approaches.