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Integrated Genomic Analysis Identifies UBTF Tandem Duplications as a Recurrent Lesion in Pediatric Acute Myeloid Leukemia

Umeda, Masayuki 京都大学 DOI:10.14989/doctor.r13538

2023.03.23

概要

RESULTS
Comprehensive Genetic Background of Relapsed
Pediatric AML
We investigated the genomic profile of relapsed pediatric AML from 136 patients (median age of 9.2) utilizing
whole-genome sequencing (WGS), whole-exome sequencing
(WES), target capture sequencing (TCS), and RNA sequencing (RNA-seq; Fig. 1A; Supplementary Fig. S1A and S1B;
Supplementary Tables S1–S7, see Methods for details).
These analyses identified gene fusions in 106 patients
(77.9%; Supplementary Figs. S2A–S2C and S3; Supplementary Tables S8–S10). The most common in-frame fusions
involved KMT2A (n = 36, 26.5%) or NUP98 (n = 18, 13.2%).
We also found rare fusions associated with poor prognosis,
including PICALM-MLLT10 (ref. 11; n = 5, 3.7%), FUS-ERG
(ref. 12; n = 4, 2.9%), DEK-NUP214 (ref. 6; n = 4, 2.9%), and
GLIS family fusions (ref. 5; n = 3, 2.2%). Structural variants
leading to outlier high expression and allele-specific expression (ASE) of oncogenic genes were detected by cis-X (13),
most notably involving MECOM (refs. 14, 15; n = 3, 2.2%),
BCL11B (ref. 16; n = 2, 1.5%), or MNX1 (ref. 17; n = 1, 0.7%;
Supplementary Figs. S2A and S4A–S4C; Supplementary
Table S11). In comparison to a patient cohort at diagnosis
in the TARGET AML study (7, 18), this relapse cohort was
enriched for NUP98 rearrangements (P = 0.02) along with
fewer CBFB-MYH11 fusions (P < 0.001). We also identified
recurrent somatic mutations, including single-nucleotide
variant (SNV), insertion and deletion (Indel), tandem
duplications, copy-number alterations (CNA), and copy
neutral loss of heterozygosity (CN-LOH; Fig. 1B; Supplementary Fig. S5A; Supplementary Tables S12–S14). Overall,
14.1 ± 13.3 (mean ± SD) somatic coding mutations and
CNA/CN-LOH were identified per patient with WGS data,
many of which are in cell signaling genes and transcription
factors (Supplementary Fig. S5B–S5D). Using the genomic
random interval (GRIN) model (19), we identified 39 significantly mutated genes, including genes associated with
poor prognosis, such as WT1 (n = 33, 24.3%), FLT3 (n = 30,
22.1%), and TP53 (n = 9, 6.6%; Fig. 1B; Supplementary
Tables S12 and S15). Recurrent somatic and heterozygous
tandem duplications in UBTF (herein referred to as UBTFTD) were identified in nearly 9% of the relapse AML cohort.
The genome-wide mutation pattern of relapsed AML is
significantly different (P < 0.001) from the TARGET cohort
(7, 18), with more FLT3, WT1, and UBTF mutations. We also
identified 9 pathogenic or likely pathogenic germline alterations from 8 patients (8/91, 8.8%), including one germline
RUNX1 mutation (Supplementary Table S16). ...

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We thank all the patients and their families at St. Jude Children’s

Research Hospital (SJCRH) for their contribution of the biological

specimens used in this study. We also thank the Biorepository, the

Flow Cytometry and Cell Sorting Core, and the Hartwell Center

for Bioinformatics and Biotechnology at SJCRH for their essential

services. Julie Justice in the Anatomic Pathology lab established the

IHC for UBTF. This work was funded by the American Lebanese and

Syrian Associated Charities of St. Jude Children’s Research Hospital

and grants from the NIH (P30 CA021765, Cancer Center Support

Grant and a Developmental Fund Award, to J.M. Klco and X. Ma).

This work was also supported in part by the Fund for Innovation in

Cancer Informatics (www.the-ici-fund.org, to X. Ma and J.M. Klco),

St. Baldrick’s Consortium Grant (to S. Meshinchi), Target Pediatric

AML (to S. Meshinchi), Leukemia and Lymphoma Society (6558-18,

to S. Meshinchi), National Institutes of Health (R01-CA114563-10

and HHSN-261200800001E, to S. Meshinchi), COG Chair’s Grant

U10-CA098543 (to S. Meshinchi), Andrew McDonough B+ Foundation (to S. Meshinchi), Hyundai Hope on Wheels (to S. Meshinchi),

NCTN Statistics & Data Center U10-CA180899 (to S. Meshinchi and

T.A. Alonzo), NCTN Operations Center Grant U10CA180886 (to

S. Meshinchi), and Project Stella (to S. Meshinchi). J.M. Klco holds

a Career Award for Medical Scientists from the Burroughs Wellcome Fund and is a previous recipient of the V Foundation Scholar

Award (Pediatric).

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