PhD Scientific Days 2020

Pathology and Oncology III. Lectures

Comprehensive Mutation Screening by Targeted Next-Generation Sequencing in Pediatric Acute Myeloid Leukemia at Diagnosis

Előadó neve

Dr. Szilvia, Krizsán

Előadó munkahelye

1st Department of Pathology and Experimental Cancer Research, Semmelweis University

Előadó telefonszáma

+36202334232

Előadó e-mail címe

krizsan.szilvia@med.semmelweis-univ.hu

Az előadás címe

Comprehensive Mutation Screening by Targeted Next-Generation Sequencing in Pediatric Acute Myeloid Leukemia at Diagnosis

Szerző(k) neve és munkahelye

Szilvia Krizsán1, Ambrus Gángó1, Endre Sebestyén2, Tibor Nagy3, Lajos Hegyi1, Dániel János Erdélyi4, György Péter5, Marianna Zombori5, Krisztina Csanádi5, Krisztián Kállay6, Gergely Kriván6, Gábor Kovács4, Donát Alpár1*, Csaba Bödör1*
1 MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest
2 Computational Biology Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest
3 Bioinformatics and Functional Genome Analysis Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen
4 Second Department of Pediatrics, Semmelweis University, Budapest
5 Heim Pál National Pediatric Institute, Budapest
6 Pediatric Hematology and Stem Cell Transplantation Unit, Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases, Budapest

Szekció

Pathology and Oncology III. Lectures

Language of the presentation

English

Section, first choice

Pathology and Oncology

Section, second choice

Molecular Sciences

Összefoglaló szövege

Introduction: Recent medical advances dramatically improved the outcome of pediatric cancers, still the prognosis of childhood AML remains unfavorable due to primary therapy resistance and frequent relapses. AML represents the leading cause of childhood leukemia mortality, with a 5-year overall survival (OS) of 60-70%.
Aims: To establish the mutational profiles of 60 Hungarian pediatric AML patients diagnosed in our institute between 2005 and 2019 using next-generation sequencing (NGS).
Method: Diagnostic samples were obtained from bone marrow (n=44), peripheral blood (n=14), skin (n=1) and lymph node biopsy (n=1), with three sequential samples collected at diagnosis and two subsequent relapses from a single patient. Median follow up time was 55 months (range 0.2-179.0 months) with a 5-year OS of 55% representing a relatively low survival rate owing to the high proportion of patients with poor prognosis in this cohort. Targeted NGS analysis of 54 genes recurrently altered in myeloid malignancies was performed using the TruSight Myeloid Gene Panel with the libraries sequenced on a NextSeq500 instrument.
Results: NGS revealed a total of 101 somatic variants in 60 diagnostic samples with an average allelic depth of 7400x across the 54 genes analyzed. On average, 1.7 mutations (range: 0-5) were detected per sample, with an average variant allele frequency of 32.3% (range: 2.0-83.1%), and with ten patients presenting with wild-type genotype for all 54 genes analyzed. The most frequently mutated genes included FLT3 (30%), NRAS (18%) and WT1 (17%). Patients with normal karyotype carried a slightly higher number of variants compared to patients with chromosomal abnormalities (2.5 vs 1.7 variants on average per sample). Interestingly, 53% of patients harbored mutations in genes encoding actionable proteins including FLT3, NRAS and IDH1. Active clonal evolution was documented in one patient carrying NPM1 and FLT3-ITD mutations at diagnosis. At first relapse, elimination of FLT3-ITD was accompanied by the emergence of an ASXL1 mutation, with acquisition of a novel FLT3-TKD mutation by the time of the second relapse.
Conclusion: Targeted NGS using the TruSight Myeloid Sequencing Gene Panel seems to be an efficient, high-throughput assay for the genomic characterization of pediatric AML, with potentially actionable mutations detected in 53% of patients in our cohort.

Additional Information

Supervisor: Csaba Bödör, Donát Alpár

E-mail address: krizsan.szilvia@med.semmelweis-univ.hu

Bemutatás módja

Szóbeli

Kind

Szabad

Status

elfogadva

Accepted presentation method

szóbeli

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

4662

Start

17:00

End

17:15

Authors (legacy)

Szilvia Krizsán1, Ambrus Gángó1, Endre Sebestyén2, Tibor Nagy3, Lajos Hegyi1, Dániel János Erdélyi4, György Péter5, Marianna Zombori5, Krisztina Csanádi5, Krisztián Kállay6, Gergely Kriván6, Gábor Kovács4, Donát Alpár1*, Csaba Bödör1*
1 MTA-SE Momentum Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest
2 Computational Biology Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest
3 Bioinformatics and Functional Genome Analysis Research Group, Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen
4 Second Department of Pediatrics, Semmelweis University, Budapest
5 Heim Pál National Pediatric Institute, Budapest
6 Pediatric Hematology and Stem Cell Transplantation Unit, Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases, Budapest