Phenotype/Genotype Associations in TET2-Driven Myeloid Neoplasms

Autor: Hetty E. Carraway, Aziz Nazha, Cassandra M. Hirsch, Torsten Haferlach, Jaroslaw P. Maciejewski, Kassy E Kneen, Tomas Radivoyevitch, Mikkael A. Sekeres, Niroshan Nadarajah, Bartlomiej P Przychodzen, Manja Meggendorfer
Rok vydání: 2016
Předmět:
Zdroj: Blood. 128:4313-4313
ISSN: 1528-0020
0006-4971
DOI: 10.1182/blood.v128.22.4313.4313
Popis: TET2 is one of the most commonly mutated genes in myeloid neoplasia. The frequency of TET2 mutations (TET2MUT) increases with age and they have been found in aging healthy controls, in whom their presence was associated with a subsequent risk of developing a myeloid neoplasm. The TET2 gene product is an enzyme that uses alpha-ketoglutarate (αKG) and vitamin C to hydroxylate 5-methylcytosine (5MC), leading to both passive demethylation during cell replication and active demethylation via base excision DNA repair enzymes. Despite large studies, there is no consensus opinion as to the clinical impact of TET2 mutations and their mechanistic role in the pathogenesis of MDS. It is likely that the heterogeneity of TET2MUT, their configuration, sub-clonal context and co-associated variables result in biological heterogeneity that precludes proper assessment of clinical impact. To address these issues we analyzed a cohort of 4974 patients with myeloid neoplasms using targeted deep sequencing of a panel of 60 genes found to be most frequently affected by somatic mutations in myeloid neoplasms. A total of 1861 TET2 alterations were identified as somatic in 1238 cases using various bioanalytic algorithms and sequencing of germline DNA where possible. Of these mutations, 80% were frame shift/stop codons (fs/sc) likely leading to various truncations, while 20% were missense (ms) mutations. While no hotspots for mutations were found, 53% were located in the proximity of the catalytic domain. The most recurrent ms alteration was p.Ile1873Thr, found in 2% of all TET2MUT cases. Biallelic TE2MUT were present in 45% of mutant cases; of which fs/sc alteration combinations were the most common (333/557; 60%), and an additional 9% were homozygous fs/sc variants. Biallelic ms mutations were present in 5% of biallelic cases (3% of homozygous ms configurations). Clinically, TET2MUT were found in 17% of MDS patients, 65% of MDS/MPN, 12% of MPN, 21% of non-core binding factor pAML, and 26% of sAML, and were most frequently associated with normal cytogenetics (p TET2MUT tend to display a higher number of additional mutations than TETWT (p Analysis of clonal architecture including co-associated events revealed that 40% of TET2MUT were dominant/possibly ancestral within the clonal hierarchy. In cases with a dominant TET2MUT, the most commonly associated somatic events involved TET2 (18%), followed by SRSF2 (8%), ASXL1 (7%) and DNMT3A (6%). In those cases (26%) in which TET2 was not the dominant clone, SRSF2 (11%), ASXL1 (10%), DNMT3A (9%), and EZH2 (9%) were the most common early events. In 33% of TET2MUTcases, the TET2MUTclones were co-dominant with another TET2 (29%), SRSF2 (15%), DNMT3A (11%), or ASXL1 (9%). TET2MUT confers worse survival than WT cases (p Our analyses demonstrate that TET2 lesions are strongly selected for in myeloid neoplasia and a gene dose effect may dictate biological and molecular features. While ancestral TET2 ancestral events do not determine the subsequent phenotype, subtypes of myeloid neoplasms appear to be associated with specific sets of secondary or tertiary sub-clonal events. Disclosures Nadarajah: MLL Munich Leukemia Laboratory: Employment. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees. Meggendorfer:MLL Munich Leukemia Laboratory: Employment.
Databáze: OpenAIRE
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