Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse.

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المؤلفون: Farrar JE;Farrar JE; Schuback HL; Schuback HL; Ries RE; Ries RE; Wai D; Wai D; Hampton OA; Hampton OA; Trevino LR; Trevino LR; Alonzo TA; Alonzo TA; Guidry Auvil JM; Guidry Auvil JM; Davidsen TM; Davidsen TM; Gesuwan P; Gesuwan P; Hermida L; Hermida L; Muzny DM; Muzny DM; Dewal N; Dewal N; Rustagi N; Rustagi N; Lewis LR; Lewis LR; Gamis AS; Gamis AS; Wheeler DA; Wheeler DA; Smith MA; Smith MA; Gerhard DS; Gerhard DS; Meshinchi S; Meshinchi S
المصدر:
Cancer research [Cancer Res] 2016 Apr 15; Vol. 76 (8), pp. 2197-205. Date of Electronic Publication: 2016 Mar 03.
نوع النشر :
Journal Article; Research Support, N.I.H., Extramural; Validation Study
اللغة:
English

معلومة اضافية
- المصدر:
  Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
- بيانات النشر:
  Publication: Baltimore, Md. : American Association for Cancer Research
  Original Publication: Chicago [etc.]
- الموضوع:
  Gene Expression Profiling* ; Mutation*; Leukemia, Myeloid, Acute/*genetics; Adolescent ; Child ; Child, Preschool ; DNA Copy Number Variations ; Female ; Humans ; Infant ; Leukemia, Myeloid, Acute/diagnosis ; Leukemia, Myeloid, Acute/pathology ; Male ; Recurrence
- نبذة مختصرة :
  The genomic and clinical information used to develop and implement therapeutic approaches for acute myelogenous leukemia (AML) originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative used whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations/patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants [in (greater than or equal to) 2 patients] were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared with those that resolved at relapse (median VAF 0.43 vs. 0.24, P < 0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared with 28% with VAF <0.2 (P < 0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting. Cancer Res; 76(8); 2197-205. ©2016 AACR.
  (©2016 American Association for Cancer Research.)
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- Grant Information:
  T32 CA009351 United States CA NCI NIH HHS; HHSN261200800001C United States CA NCI NIH HHS; R01 CA114563 United States CA NCI NIH HHS; U10 CA098543 United States CA NCI NIH HHS; U10 CA180899 United States CA NCI NIH HHS; U10 CA180886 United States CA NCI NIH HHS; HHSN261200800001E United States CA NCI NIH HHS
- الموضوع:
  Date Created: 20160305 Date Completed: 20170227 Latest Revision: 20240615
- الموضوع:
  20240615
- الرقم المعرف:
  PMC4873364
- الرقم المعرف:
  10.1158/0008-5472.CAN-15-1015
- الرقم المعرف:
  26941285

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