Comprehensive whole-genome sequencing of an early-stage primary myelofibrosis patient defines low mutational burden and non-recurrent candidate genes
| Autor: | Rhonda Hewitt, Dana Ng, Carol D. Jones, Michael Snyder, Jason D. Merker, Krishna M. Roskin, James L. Zehnder, Jasmine J. King, Scott D. Boyd, Linda Gojenola, Lawrence M. Okumoto, Athena M. Cherry, Parveen Abidi, Michael Stadler, Tracy I. George, Dianna G. Fisk, Andrew Fire, Bing Zhang, Cuiping Pan, Ramona A. Hoh, Jason Gotlib, Michael J. Clark |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Genetics
Male Mutation Essential thrombocythemia Point mutation Nonsense mutation Genetic Variation Hematology Articles Biology Middle Aged medicine.disease_cause medicine.disease Genome Germline mutation Primary Myelofibrosis medicine Humans Myelofibrosis Gene Cells Cultured Genetic Association Studies Genome-Wide Association Study |
| Zdroj: | Haematologica. 98(11) |
| ISSN: | 1592-8721 |
| Popis: | In order to identify novel somatic mutations associated with classic BCR/ABL1-negative myeloproliferative neoplasms, we performed high-coverage genome sequencing of DNA from peripheral blood granulocytes and cultured skin fibroblasts from a patient with MPL W515K-positive primary myelofibrosis. The primary myelofibrosis genome had a low somatic mutation rate, consistent with that observed in similar hematopoietic tumor genomes. Interfacing of whole-genome DNA sequence data with RNA expression data identified three somatic mutations of potential functional significance: i) a nonsense mutation in CARD6, implicated in modulation of NF-kappaB activation; ii) a 19-base pair deletion involving a potential regulatory region in the 5'-untranslated region of BRD2, implicated in transcriptional regulation and cell cycle control; and iii) a non-synonymous point mutation in KIAA0355, an uncharacterized protein. Additional mutations in three genes (CAP2, SOX30, and MFRP) were also evident, albeit with no support for expression at the RNA level. Re-sequencing of these six genes in 178 patients with polycythemia vera, essential thrombocythemia, and myelofibrosis did not identify recurrent somatic mutations in these genes. Finally, we describe methods for reducing false-positive variant calls in the analysis of hematologic malignancies with a low somatic mutation rate. This trial is registered with ClinicalTrials.gov (NCT01108159). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|