Gene Changes During Aging Predispose To Cancer Formation Interview with:

Hariharan Easwaran, PhD Assistant Professor of Oncology The Sidney Kimmel Comprehensive Cancer Center The Johns Hopkins University School of Medicine Bunting/Blaustein Cancer Research Building 1 Baltimore, MD 21287

Dr. Easwaran

Hariharan Easwaran, PhD
Assistant Professor of Oncology
The Sidney Kimmel Comprehensive Cancer Center
The Johns Hopkins University School of Medicine
Bunting/Blaustein Cancer Research Building 1
Baltimore, MD 21287 What is the background for this study? What are the main findings? 

Response: The interpretation of the information encoded in our DNA by the various cells in our body is mediated by a plethora of modifications of DNA and proteins that complex with DNA. DNA methylation is one such important modification, which is normally established in a very orchestrated fashion during development. All normal cells have a defined pattern of DNA methylation, which may vary by tissue type, but is consistent within tissues. This normal pattern is disrupted in all known cancers, and is considered a hallmark of cancers.

Over the years, we have learned that during cancer development, the human genome undergo global loss of DNA methylation and at the same time some local gains of DNA methylation. The latter process leads to silencing of very important tumor suppressor genes, therefore contributing to tumorigenesis. The origins of these DNA methylation changes in cancers are incompletely understood. Similar changes occur during cellular process called senescence, which occurs when cells are exposed to DNA damage or when cells undergo too many cell divisions. Senescence is an in-built mechanism for preventing cells from becoming cancerous by restraining growth of cells that have become exposed to mutation causing stress. Because of the shared methylation changes in senescence and cancer cells, one possibility is that DNA methylation alterations in human cancers may arise from senescence, and that the senescence process may itself promote tumorigenesis.

To address this paradox, we explored in detail the DNA methylation changes during development of cancer and senescence. We used a model where in we induced senescence, and the process of tumorigenesis (called transformation), and mapped the dynamic DNA methylation changes during senescence and transformation.

In our paper, we show that DNA methylation abnormalities in human cancer evolve independently of cellular senescence, but may arise from aging of cells.

We are excited by two key findings:

(a) the DNA methylation changes during senescence are different in a nuanced way from the cancer-associated epigenetic changes, and may actually prevent tumorigenesis;

(b) we identified genes that were most prone to get methylated during early tumor formation and during aging.” These findings will help us further stratify aging-associated cancer risks. What should readers take away from your report?

Response: Aging is the leading risk factor for human cancers, and it has been known in the field that epigenetic changes occur during aging. Our finding that the genes getting methylated during cancer formation, are very frequently methylated during aging emphasizes that the genes that get methylated during aging may gradually increase the potential of some of the aged cells to convert to cancer cells, potentially upon acquiring important cancer causing mutations. These observations support various other previous work that have explored the DNA methylation changes during aging. Thus, the work paves way to identifying methylation biomarkers that may help identifying individuals with an increased risk of cancer, stratified by age, which will help in early cancer interception or reducing cancer risk. What recommendations do you have for future research as a result of this work? 

Response: In future work, we will explore human tissue-specific patterns of DNA methylation gains for the senescence and transformation classes of genes, and hope to use that to devise strategies for determining age-associated risk of tumor development. 

No disclosures 


Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W. Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L.F. Carvalho, Subhojit Sen, Ray-Whay Chiu Yen, Cynthia A. Zahnow, Nita Ahuja, Stephen B. Baylin, Hariharan Easwaran. DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk. Cancer Cell, 2018; 33 (2): 309 DOI: 10.1016/j.ccell.2018.01.008 

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