Dataset Information

Consequences of mutant TET2 on clonality and subclonal hierarchy.

ABSTRACT: Somatic mutations in TET2 are common in myelodysplastic syndromes (MDS), myeloproliferative, and overlap syndromes. TET2 mutant (TET2^MT) clones are also found in asymptomatic elderly individuals, a condition referred to as clonal hematopoiesis of indeterminate potential (CHIP). In various entities of TET2^MT neoplasia, we examined the phenotype in relation to the strata of TET2 hits within the clonal hierarchy. Using deep sequencing, 1781 mutations were found in 1205 of 4930 patients; 40% of mutant cases were biallelic. Hierarchical analysis revealed that of TET2^MT cases >40% were ancestral, e.g., representing 8% of MDS. Higher (earlier) TET2 lesion rank within the clonal hierarchy (greater clonal burden) was associated with impaired survival. Moreover, MDS driven by ancestral TET2^MT is likely derived from TET2^MT CHIP with a penetrance of ~1%. Following ancestral TET2 mutations, individual disease course is determined by secondary hits. Using multidimensional analyses, we demonstrate how hits following the TET2 founder defect induces phenotypic shifts toward dysplasia, myeloproliferation, or progression to AML. In summary, TET2^MT CHIP-derived MDS is a subclass of MDS that is distinct from de novo disease.

SUBMITTER: Hirsch CM

PROVIDER: S-EPMC8673139 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Consequences of mutant TET2 on clonality and subclonal hierarchy.

Hirsch Cassandra M CM Nazha Aziz A Kneen Kassy K Abazeed Mohamed E ME Meggendorfer Manja M Przychodzen Bartlomiej P BP Nadarajah Niroshan N Adema Vera V Nagata Yasunobu Y Goyal Abhinav A Awada Hassan H Asad Mohammad Fahad MF Visconte Valeria V Guan Yihong Y Sekeres Mikkael A MA Olinski Ryszard R Jha Babal Kant BK LaFramboise Thomas T Radivoyevitch Tomas T Haferlach Torsten T Maciejewski Jaroslaw P JP

Leukemia 20180524 8

Somatic mutations in TET2 are common in myelodysplastic syndromes (MDS), myeloproliferative, and overlap syndromes. TET2 mutant (TET2<sup>MT</sup>) clones are also found in asymptomatic elderly individuals, a condition referred to as clonal hematopoiesis of indeterminate potential (CHIP). In various entities of TET2<sup>MT</sup> neoplasia, we examined the phenotype in relation to the strata of TET2 hits within the clonal hierarchy. Using deep sequencing, 1781 mutations were found in 1205 of 4930 ...[more]

PMID: 29795413

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Project description:Recent improvements in next-generation sequencing of tumor samples and the ability to identify somatic mutations at low allelic fractions have opened the way for new approaches to model the evolution of individual cancers. The power and utility of these models is increased when tumor samples from multiple sites are sequenced. Temporal ordering of the samples may provide insight into the etiology of both primary and metastatic lesions and rationalizations for tumor recurrence and therapeutic failures. Additional insights may be provided by temporal ordering of evolving subclones--cellular subpopulations with unique mutational profiles. Current methods for subclone hierarchy inference tightly couple the problem of temporal ordering with that of estimating the fraction of cancer cells harboring each mutation. We present a new framework that includes a rigorous statistical hypothesis test and a collection of tools that make it possible to decouple these problems, which we believe will enable substantial progress in the field of subclone hierarchy inference. The methods presented here can be flexibly combined with methods developed by others addressing either of these problems. We provide tools to interpret hypothesis test results, which inform phylogenetic tree construction, and we introduce the first genetic algorithm designed for this purpose. The utility of our framework is systematically demonstrated in simulations. For most tested combinations of tumor purity, sequencing coverage, and tree complexity, good power (≥ 0.8) can be achieved and Type 1 error is well controlled when at least three tumor samples are available from a patient. Using data from three published multi-region tumor sequencing studies of (murine) small cell lung cancer, acute myeloid leukemia, and chronic lymphocytic leukemia, in which the authors reconstructed subclonal phylogenetic trees by manual expert curation, we show how different configurations of our tools can identify either a single tree in agreement with the authors, or a small set of trees, which include the authors' preferred tree. Our results have implications for improved modeling of tumor evolution and the importance of multi-region tumor sequencing.

Dataset Information

Consequences of mutant TET2 on clonality and subclonal hierarchy.

Publications

Consequences of mutant TET2 on clonality and subclonal hierarchy.

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