Nature Commun Shen Shuhong/Liu Yu's team mapped the AML genomic variation in Chinese children and established a precise risk stratification scheme for Chinese children

The following article is from Frontiers of Children's Oncology, and the author specializes in Ignite Hope | Edited by Liu Ting | Zhou Yebin Acute leukemia is the most common childhood tumor, of which acute myeloid leukemia (AML) accounts for about 15-20%, and its overall prognosis is poor,5 The annual survival rate is about 65-70%
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Currently, there is no uniform reference standard for risk stratification of childhood AML
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In recent years, next-generation sequencing (NGS)-based genomic analysis has established a genomic variation profile of childhood AML and detected key molecular variants associated with prognosis
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At the same time, these studies revealed striking differences in the spectrum of genomic variation in cancer drivers in children and adults
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However, these studies were mainly based on Western children, and it is unclear whether the results are biased in Chinese children
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On March 28, 2022, the research team of Shen Shuhong and Liu Yu from the National Children's Medical Center/Shanghai Children's Medical Center published a research paper entitled Distinct genomic landscape of Chinese pediatric acute myeloid leukemia impacts clinical risk classification in Nature Communications.
Genomic analysis of the patients' primary tumor samples, detailed description of the genomic driver variation characteristics of Chinese children with acute myeloid leukemia, revealed the unique driver variants and combinations of Chinese children with AML that are different from Western populations, and further based on their prognosis, clinical classification.
A risk stratification model suitable for Chinese children's AML was established, which laid the foundation for the development of precision medicine for children's AML in China
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Based on the pediatric AML research cohort established by Shanghai Children's Medical Center in the past two decades from 2001 to 2018, this study performed RNA-seq analysis on tumor samples from a total of 292 patients with newly diagnosed AML (the AML-SCMC-2009 program was the mainstay).

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The research team first conducted a multi-dimensional analysis of RNA-seq data by optimizing and developing computational analysis methods, covering various types of mutations such as gene mutations and fusions
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By comparing with the results of whole-genome sequencing and deep target capture sequencing, the research team demonstrated the high sensitivity and specificity of the analysis method, and based on this, the driver genome variation map of Chinese childhood acute myeloid leukemia was mapped
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Through analysis, the authors firstly delineated the driver variants and their co-mutation relationships in AML in Chinese children, and discovered XPO1-related fusion genes XPO1-TNRC18 and XPO1-MLLT10 that have not been reported in AML before
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Interestingly, all cases belonged to the FAB-M7 subtype and did not carry other AML-related driver variants, suggesting that the fusion gene may be a novel AML-M7 driver variant, and its pathogenic mechanism requires further experimental studies
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 Mapping of fusion genes in AML in Chinese children
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(a) Circos plot showing the newly discovered and reproducible fusion genes in this study (b) XPO1-TNRC18 and XPO1-MLLT10 structures showing the author next by comparing the TARGET AML mutation data representing Western children to find different genetic backgrounds There were significant differences in gene mutation frequency and gene mutation co-occurrence among children with AML
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Nearly half (47.
6%, n=10) of the 21 driver genes or hotspot regions with mutation frequencies higher than 4% in the SCMC or TARGET cohorts showed significant frequency differences, mainly from 3-14 years old of AML patients
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Notably, the mutation frequency of the RAS signaling pathway was significantly lower in Chinese children than in Western populations
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Differences in driver genomic mutations among Eastern and Western children with AML
The authors first report findings consistent with known reports in Chinese children with AML, such as children with CBFB-MYH11 fusions, CEBPA, NPM1, and GATA2 mutations have relatively better prognosis, while NUP98-KDM5A/NSD1, FUS-ERG, Fusion genes such as CBFA2T3-GLIS2, RUNX1 mutation and FLT3 ITD mutation are associated with poor prognosis
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In addition, the authors found that in Chinese children with AML, the 5-year event-free survival (EFS) rate of RUNX1-RUNX1T1, a previously reported subtype with a better prognosis, was only 55.
3% (CI 44.
8–68.
2%), which was poorer than reported.

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The patients with KMT2A rearrangement did not have a very poor prognosis, with a 5-year EFS of 56.
1% (CI 42.
9 –73.
3%)
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Further analysis found that after excluding known poor prognostic factors (such as FUS-ERG fusion, FLT3 ITD, complex karyotype, etc.
), remission after a course of treatment was a key factor affecting the prognosis of children, and CSF3R and CSF3R were identified.
KIT-E17 mutation was significantly coexisted in patients with RUNX1-RUNX1T1 fusion who had a course of remission and was a risk factor for poor prognosis
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Finally, the researchers revised the 2017 version of the European LeukemiaNet (ELN) risk stratification model according to the driving variants and clinical correlations established in this study, and established a risk stratification model based on the results of clinical genomic analysis of Chinese children with AML—— SCMC-pAML
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Compared with the 2017 ELN model, SCMC-pAML can more effectively distinguish children with high-risk and low-risk AML
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Optimizing an AML risk stratification model based on Chinese childhood-driven variants
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(a) Flow chart of the optimized SCMC-pAML risk stratification model
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(b) Comparison of risk stratification results of Chinese children with AML according to SCMC-pAML model, ELN model on the left and SCMC-pAML model on the right (c) SCMC-pAML (dotted line) and ELN model (solid line) Comparison of event-free survival after stratification
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In conclusion, this study describes the unique genomic map of Chinese childhood acute myeloid leukemia in detail, and the results show that genetic background is an important factor in clinical precision medicine based on genomic variation, which suggests the establishment of risk stratification for Chinese children with leukemia necessity of the system
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The corresponding author of the article, Dr.
Shen Shuhong, director of the Department of Hematology and Oncology at the National Children's Medical Center/Shanghai Children's Medical Center, said: "Our work is only the beginning of the precise and individualized treatment of childhood leukemia in China, and more in-depth research is needed in the future.
Explore, stratify the risk of AML in children more precisely, and conduct in-depth research on new targets to carry out precise treatment of treatable stratification factors, fundamentally improve the efficacy of AML in children, improve long-term prognosis and survival of children However , these works need
to
work together to carry out multi-center clinical research and translational research
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" "Transcriptome sequencing is currently the most cost-effective analysis method for the detection of genomic variants carried by childhood leukemia
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Combined with the analysis methods developed and optimized by the team, We have achieved three-dimensional analysis of a single transcriptome data, and further improved its detection performance for different types of clinically relevant variants, proving the value of this method in assisting the clinical diagnosis and treatment of childhood leukemia
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” Co-corresponding author of the article, Department of Pediatrics, Shanghai Children’s Medical Center Liu Yu from the Institute of Translational Medicine said
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Editor in charge Production and layout | Sheila proofreading | uuExtended reading What are the similarities and differences between childhood acute myeloid leukemia and adult types?
Jiang Hua/Xu Ling team discovered a new prognostic marker for pediatric acute myeloid leukemia
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The purpose of this article is to share the cutting-edge results of pediatric oncology research, not to recommend treatment options
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▼Scroll to see more ▼Abstract Studies have revealed key genomic aberrations in pediatric acute myeloid leukemia (AML) based on Western populations.
It is unknown to what extent the current genomic findings represent populations with different ethnic backgrounds.
Here we present the genomic landscape of driver alterations of Chinese pediatric AML and discover previously undescribed genomic aberrations, including the XPO1-TNRC18 fusion.
Comprehensively comparing between the Chinese and WesternAML cohorts reveal a substantially distinct genomic alteration profile.
For example, Chinese AML patients more commonly exhibit mutations in KIT and CSF3R, and less frequently mutated of genes in the RAS signaling pathway.
Thesedifferences in mutation frequencies led to the detection of previously uncharacterized co-occurring mutation pairs.
Importantly,the distinct driverprofile is clinically relevant.
We propose a refined prognosis riskclassification model which better reflected the adverse event risk for ChineseAML patients.
These results emphasize the importance of genetic background inprecision medicine.
DOI: 10.
1038/s41467-022-29336-y👇Click here directly to the original