Next-generation sequencing with a myeloid gene panel in core-binding factor AML showed KIT activation loop and TET2 mutations predictive of outcome

Cher, Chae-Yin; Leung, Gph; Au, Chun Hang; Chan, TM; S.K., Edmond; Sim, Joycelyn; Gill, Harinder; Lie, Albert K. W.; Liang, Raymond; Wong, K.F.; Siu, Lisa L. P.; Tsui, Cary; So, C.C; Wong, Hiu Yung; Yip, Sze‐Fai; Lee, H K K; Liu, H S Y; Lau, Justin Kai-Chi; Luk, Tsan-Hei; Lau, Chi Kuen; Lin, Sophia; Kwong, Yok–Lam; Leung, Anskar Y. H.

doi:10.1038/bcj.2016.51

Cited by 28 publications

(27 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These recurrent mutations likely represent other pathways that are relevant for RUNX1/RUNX1T1-initiated leukemogenesis. Of note, most of these mutations have been associated with unfavorable prognosis in AML in recent studies [14,16,17,[35][36][37][38]. In our RUNX1/RUNX1T1 cohort, aberrations in DHX15 and SMC1A were found to be strong and independent adverse prognostic factors for OS and RFS.…”

Section: Discussionmentioning

confidence: 52%

The clinical mutatome of core binding factor leukemia

et al. 2020

View full text Add to dashboard Cite

The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia. Supplementary informationThe online version of this article (https://

show abstract

Section: Discussionmentioning

confidence: 52%

The clinical mutatome of core binding factor leukemia

et al. 2020

View full text Add to dashboard Cite

show abstract

“…As a discovery cohort, INDELseek was applied to an additional MN panel dataset of 10 core-binding factor leukemia samples that were clinically predicted to be enriched for somatic mutations of KIT exon 8 [17]. A total of 10 KIT in-frame complex indels were detected from six of the samples (1 – 4 complex indels per sample; Table 2) and verified by orthogonal validation experiments (Additional file 2: Figure S9-S14).…”

Section: Resultsmentioning

confidence: 99%

“…Ten core-binding factor leukemia DNA samples were retrieved from Queen Mary Hospital, Hong Kong from January 2003 to December 2014 as a discovery cohort of KIT exon 8 mutations. A total of 32 DNA samples were screened by MiSeq sequencing of a 54-gene myeloid NGS gene panel as described [16, 17]. Complex indel detection by INDELseek was performed on BWA-MEM (version 0.7.7) alignments of MiSeq NGS data of CALR, JAK2 and KIT (exon 8 only).…”

Section: Methodsmentioning

confidence: 99%

INDELseek: detection of complex insertions and deletions from next-generation sequencing data

Leung

Kwong

et al. 2017

BMC Genomics

View full text Add to dashboard Cite

BackgroundComplex insertions and deletions (indels) from next-generation sequencing (NGS) data were prone to escape detection by currently available variant callers as shown by large-scale human genomics studies. Somatic and germline complex indels in key disease driver genes could be missed in NGS-based genomics studies.ResultsINDELseek is an open-source complex indel caller designed for NGS data of random fragments and PCR amplicons. The key differentiating factor of INDELseek is that each NGS read alignment was examined as a whole instead of “pileup” of each reference position across multiple alignments. In benchmarking against the reference material NA12878 genome (n = 160 derived from high-confidence variant calls), GATK, SAMtools and INDELseek showed complex indel detection sensitivities of 0%, 0% and 100%, respectively. INDELseek also detected all known germline (BRCA1 and BRCA2) and somatic (CALR and JAK2) complex indels in human clinical samples (n = 8). Further experiments validated all 10 detected KIT complex indels in a discovery cohort of clinical samples. In silico semi-simulation showed sensitivities of 93.7–96.2% based on 8671 unique complex indels in >5000 genes from dbSNP and COSMIC. We also demonstrated the importance of complex indel detection in accurately annotating BRCA1, BRCA2 and TP53 mutations with gained or rescued protein-truncating effects.ConclusionsINDELseek is an accurate and versatile tool for complex indel detection in NGS data. It complements other variant callers in NGS-based genomics studies targeting a wide spectrum of genetic variations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3449-9) contains supplementary material, which is available to authorized users.

show abstract

“…1 However, several prognostic factors, including genetic alterations, have been demonstrated. [2][3][4][5][6][7][8] In particular, KIT mutation has been suggested to be associated with a poor prognosis in AML patients with RUNX1-RUNX1T1 or CBFB-MYH11. 3,5,[9][10][11][12] Many types of KIT mutations have been identified in cancer cells, but there are 3 mutation hot-spots (exon 8, exon 10-11, and exon 17) in AML.…”

Section: Introductionmentioning

confidence: 99%