ID

45175

Beskrivning

Principal Investigator: Charles Mullighan, MD, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA MeSH: Leukemia, T-cell https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000340 *CREST* The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, 80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution. *T-ALL* Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; *NRAS*, *KRAS*, *FLT3*, *IL7R*, *JAK3*, *JAK1*, *SH2B3* and *BRAF*), inactivating lesions disrupting haematopoietic development (58%; *GATA3*, *ETV6*, *RUNX1*, *IKZF1* and *EP300*) and histone-modifying genes (48%; *EZH2*, *EED*, *SUZ12*, iSETD2/i and iEP300/i). We also identified new targets of recurrent mutation including iDNM2/i, iECT2L/i and iRELN/i. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.

Länk

dbGaP study = phs000340

Nyckelord

Versioner (2)

1. 2022-08-22 2022-08-22 - Simon Heim
2. 2022-10-12 2022-10-12 - Adrian Schulz

Rättsinnehavare

Charles Mullighan, MD, Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA

Uppladdad den

12 oktober 2022

DOI

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