How the epigenetic clock of lung tumors is ticking

Gene activities are determined by a transciptome analysis.

ARCN scientists are the first to find that the epigenetic age of lung tumors differs from healthy tissue of the same patient. Surprisingly, particular lung cancer entities showed differences in this property. The results of this study were recently published in the International Journal of Cancer.

Lung cancer has been treated as one uniform entity until the nineties of the last century. In the meantime, it has become possible to discern a number of distinct lung cancer types: Basic categories are small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC).  The latter is the more prominent (85% of all cases) and can further be subclassified in adeno carcinomas, squamous cell carcinomas and rare forms. The entities differ in their original tissue, their prognosis and the way they are therapeutically treated.

In a recent study, an ARCN team headed by Prof. Dr. Ole Ammerpohl and Prof. Dr. Torsten Goldmann compared the so-called epigenetic age of NSCLC tumors with the chronological age of healthy tissues of the same patient. The chronological age is usually identical with his/her lifetime. Epigenetics deal with mechanisms that influence gene regulation which activate or silence genes. For example many genes that are important for embryonic development are not necessary in later life and are therefore epigenetically ‘switched off’. Thus, epigenetic mechanisms are important modulators in order to switch genes on and off due to development or even environmental influences during lifetime. The epigenetic age is determined by measuring DNA methylation of several genes. Most times it correlates well with the factual (chronological) age of a person. A deviation might point to a disease or an adverse influence of environmental factors.  

An ARCN research team wanted to find out, if there’s a difference in epigenetic age between adeno carcinomas and squamous cell carcinomas. This was actually the case: While adeno carcinomas have a higher epigenetic age when compared to healthy tissue of the same patient, it is about 30 years lower in squamous cell carcinomas. Strikingly, some genes responsible for embryonic development are switched on in the younger tumors. Gene regulation seems to work completely different in the two tumor entities as seen in the gene expression of many genes: deregulated developmental processes are dominating in epigenetically young squamous cell carcinomas, while many metabolic genes are deregulated in adeno carcinomas. “This underlines the epigenetic regulation once more and suggests that completely different mechanisms contribute to tumor development in both cases”, says Ole Ammerpohl. “Tumors are not only employing genetic mechanisms, but also epigenetic mechanism to promote growth.”

What can we learn from this for cancer therapy? The results are well in line with earlier findings that squamous cell carcinomas contain a higher number of tumor stem cells. Stem cells are capable of indefinite replication and bear properties of embryonic stem cells – similar to what is found for squamous cell carcinomas in this study. This also explains why these carcinomas often respond less to chemotherapy and have a worse prognosis. Other research groups started to develop drugs target epigenetic modifications. Unfortunately, these drugs are not working in a specific manner until now. The findings from this study might help finding deregulated target genes for therapy of non-small-cell lung cancer.

The study was realized in cooperation of the ARCN members University Medical Center Schleswig-Holstein (Campus Kiel), Research Center Borstel and LungenClinic Grosshansdorf together with the University Medical Center Ulm and has been published in the International Journal of Cancer.


Further information:

Marwitz S, Heinbockel L, Scheufele S, Kugler C, Reck M, Rabe KF, Perner S, Goldmann T, Ammerpohl O (2018) Fountain of youth for squamous cell carcinomas? On the epigenetic age of NSCLC and corresponding tumor-free lung tissues. Int J Cancer [Electronic publication July 6, 2018]



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