Identification of a class of human cancer germline genes with transcriptional silencing refractory to the hypomethylating drug 5-aza-2ˈ-deoxycytidine

Ahmed Almatrafi1,2, Julia Feichtinger3,4, Ellen G. Vernon1, Natalia Gomez Escobar1, Jane A. Wakeman1, Lee D. Larcombe5 and Ramsay J. McFarlane1

1 North West Cancer Research Institute, School of Medical Sciences, Bangor University, Bangor, United Kingdom

2 Current address: Department of Biology, Faculty of Science, University of Taibah, Medinah, Saudi Arabia

3 Institute for Knowledge Discovery, Graz University of Technology, Graz, Austria

4 Core Facility Bioinformatics, Austrian Centre of Industrial Biotechnology, Graz, Austria

5 MRC Functional Genomics Unit, Department of Anatomy, Physiology and Genetics, University of Oxford, Oxford, United Kingdom


Ramsay J. McFarlane, email:

Keywords: cancer/testis antigen, germline gene, oncogenesis, hypomethylation, gene silencing

Received: October 24, 2014 Accepted: November 10, 2014 Published: November 10, 2014


Bona fide germline genes have expression restricted to the germ cells of the gonads. Testis-specific germline development-associated genes can become activated in cancer cells and can potentially drive the oncogenic process and serve as therapeutic/biomarker targets; such germline genes are referred to as cancer/testis genes. Many cancer/testis genes are silenced via hypermethylation of CpG islands in their associated transcriptional control regions and become activated upon treatment with DNA hypomethylating agents; such hypomethylation-induced activation of cancer/testis genes provides a potential combination approach to augment immunotherapeutics. Thus, understanding cancer/testis gene regulation is of increasing clinical importance. Previously studied cancer/testis gene activation has focused on X chromosome encoded cancer/testis genes. Here we find that a sub-set of non-X encoded cancer/testis genes are silenced in non-germline cells via a mechanism that is refractory to epigenetic dysregulation, including treatment with the hypomethylating agent 5-aza-2ˈ-deoxycytidine and the histone deacetylase inhibitor tricostatin A. These findings formally indicate that there is a sub-group of the clinically important cancer/testis genes that are unlikely to be activated in clinical therapeutic approaches using hypomethylating agents and it indicates a unique transcriptional silencing mechanism for germline genes in non-germline cells that might provide a target mechanism for new clinical therapies.

PII: 95