Cancer develops by the accumulation of irreversible alterations. Although epigenetic alterations as well as mutations are widely known to be important in carcinogenesis, epigenetic alterations differ from mutations in many respects. First, epigenetic alterations are present in many cells far in advance of the onset of carcinogenesis. Measurement of their accumulation levels enables us to diagnose the cancer risk. Secondly, chronic inflammation is an important inducer of epigenetic abnormalities while mutagens, ultraviolet, and radiation are important inducers of mutations. Third, aberrant DNA methylation is known to be induced in specific genes, unlike mutations, which are induced in mostly random genes. The most important difference is that epigenetic alterations can be reversed by the use of DNA-demethylating agents and histone deacetylase inhibitors. To avoid long-term adverse effects, it is necessary to ensure that these agents have minimal effects in the genomic regions where physiological epigenetic modifications exist, and act only in the regions where abnormal epigenetic modifications exist. Recent epigenomic analyses have begun to provide clues to the generation of specificity in these agents.

Vorinostat (suberoylanilide hydroxamic acid) is a small molecule inhibitor of class I and II histone deacetylase (HDAC) enzymes that promotes cell cycle arrest and the apoptosis of cancer cells by regulating gene expression. Vorinostat shows activity against various types of hematological malignancies as a monotherapy or in combination regimens. It has been already approved for cutaneous T cell lymphoma in Japan.
In several subtypes of B-NHL including follicular lymphoma (FL), frequent somatic mutations in the CREBBP and EP300 genes, which encode histone acetyltransferases (HATs), are present in primary tumors and are acquired at the time of relapse. The mutation-induced loss of the acetylation of histones and other transcription factors causes an imbalance between HDACs and HATs. According to these reports, 41% of FL patients exhibited somatic mutations and/or genomic deletions in the CREBBP and EP300 genes as well as decreased levels of acetyltransferase activity. HDAC inhibitors, such as vorinostat, offer a very promising anti-tumor effect by normalizing acetylation activity.
Here I will review the results of clinical trials of vorinostat for malignant lymphoma.

Prof. Ushijima, Prof. Ando and the Chairman, Prof. Saya held a panel discussion in which the participants of the meeting also took part. At this discussion, increasing expectations for epigenetic therapeutic agents, which have begun to be practically used, could be perceived.