Abstract 2019: Whole exome analysis reveals spectrum of gene mutations in adult T-cell leukemia/lymphoma.
Authors: Nagata Yasunobu , Okuno Yusuke , Sato Aiko , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Yoshida Kenichi , Sanada Masashi , Ishiyama Ken , Miyawaki Shuichi , Kitanaka Akira , Shimoda Kazuya , Miyano Satoru , Ogawa Seishi 
Published: August 2014

Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell neoplasm, which is etiologically associated with human T-lymphotropic virus type I (HTLV-1) infection during early infancy. Although HTLV-1 can effectively immortalize T-cells, there is a long latency period of ∼50 years prior to the onset of ATL, suggesting that HTLV-1 infection alone is not sufficient for the development of ATL, but additional acquired genetic hits that occur in immortalized T-cells during the later life are essential for its pathogenesis. However, little has been known about the gene mutations commonly involved in ATL pathogenesis.

So, in order to understand the genetic basis of ATL, we performed whole exome sequencing of paired-normal DNA from 24 patients with different ATL subtypes, including acute (N=13), chronic (N=3), lymphoma (N=8) types. With a mean coverage of 96, 83% of the target sequences were analyzed at more than 20 depth on average. The mutation rate of 108 (44-207) per sample was significantly higher than that in acute myeloid leukemia (7.3-13), myelodysplastic syndromes (9.2) and chronic lymphocytic leukemia (11.5).

What immediately drew our attention were the recurrent mutations involving TET2 mutations. They are found in a wide variety of myeloid malignancies in high frequency and implicated in their pathogenesis. The TET families of proteins are thought to be involved in the epigenetic regulation of gene expression through catalyzing conversion of 5’-methyl cytosine to 5’-hydroxymethyl cytosine, which are supposed to be further converted to unmethylated cytosine. One of the recent interests in TET2 mutations was the recent report of frequent TET2 mutations in peripheral T cell neoplasms, including angioimmunoblastic T-cell lymphomas(AITL), peripheral T-cell lymphomas not otherwise specified(PTCL-NOS), as well as other B cell neoplasms.

In addition, 145 samples of ATL were screened for mutations in TET2 and other epigenetic regulators commonly mutated in myeloid malignancies, including DNMT3A, IDH1/2 using target deep sequencing. In total, 17 TET2 mutations were identified in 14 (9.6%) out of the 145 ATL samples. Less frequent mutations of IDH2 and DNMT3A were also identified. Different subtypes of ATL were almost evenly affected with 6 out of 47 acute, 3 out of 36 chronic and 5 out of 46 lymphoma types having TET2 mutations. In most evaluable cases, the TET2 mutations harbored a major tumor population, while the mutations in two cases only involved a minor population and was suggested to represent a relatively late event during clonal evolution. Combined with the recent studies reporting similar AITL and PTCL-NOS, our finding suggested a common role of deregulated epigenetic machinery in the development of mature T-cell neoplasms including ATL.

Citation Format: Yasunobu Nagata, Yusuke Okuno, Aiko Sato, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Kenichi Yoshida, Masashi Sanada, Ken Ishiyama, Shuichi Miyawaki, Akira Kitanaka, Kazuya Shimoda, Satoru Miyano, Seishi Ogawa. Whole exome analysis reveals spectrum of gene mutations in adult T-cell leukemia/lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2019. doi:10.1158/1538-7445.AM2013-2019