In Analogy to AML, MDS Can be Sub-Classified By Ancestral Mutations

• Published in: Blood 2014-12, Vol.124 (21), p.823-823
• Main Authors: Makishima, Hideki, Yoshida, Kenichi, LaFramboise, Thomas, Przychodzen, Bartlomiej P, Ruffalo, Matthew, Gómez-Seguí, Inés, Shiraishi, Yuichi, Sanada, Masashi, Nagata, Yasunobu, Sato, Yusuke, Sato-Otsubo, Aiko, Chiba, Kenichi, Tanaka, Hiroko, Nakamaki, Tsuyoshi, Hofmann, Wolf-Karsten, Miyawaki, Shuichi, Chiba, Shigeru, Miyano, Satoru, Husseinzadeh, Holleh, Hosono, Naoko, Polprasert, Chantana, Patel, Bhumika J, Thota, Swapna, Dienes, Brittney, Guinta, Kathryn M, Shih, Lee-Yung, Saunthararajah, Yogen, Okuno, Yusuke, Sekeres, Mikkael A., Ogawa, Seishi, Maciejewski, Jaroslaw P.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V124.21.823.823

Somatic mutations constitute key pathogenetic elements in MDS. Unbiased whole exome sequencing (WES) and deep NGS led to discovery of new somatic mutations and also to the recognition of i) tremendous diversity of mutations and their combinations; ii) individual intra-tumor heterogeneity and clonal hierarchy. Chromosomal lesions further increase the complexity of molecular defects. While in MDS molecular defects are acquired in order, observations made in AML highlight the importance of ancestral events; e.g., t(8;21), inv16 or t(15;17) and other lesions that are used as the basis for nosological sub-classification. Thus, it is the identity of individual ancestral events or their classes rather than the spectrum of secondary events or the distribution of mutations, that will allow for molecular, functionally-relevant and diagnostically useful classification within MDS. This would explain why only a few somatic mutations have been found to be prognostically important, as their position in the clonal hierarchy has not been accounted for. With this in mind, we applied WES (N=206) and targeted deep NGS (N=836) and studied 100 samples serially with analyses focused on ancestral events. Globally, through WES we identified and validated 2386 mutational events in 1458 genes. Of these, 112 genes were mutated at significant frequencies (q