Welcome to SIOP 2022 Interactive Programme
The Congress will officially run on CET time zone (Central European Time, Barcelona)
- Carla R. Macedo (Brazil)
DISCUSSANT
- Marcio H. Malogolowkin (United States of America)
BEYOND SINGLE GENETIC ABERRATIONS: AN INTEGRATIVE COPY NUMBER ALTERATION-DRIVEN SCORING GUIDE TO REFINE CYTOGENETIC RISK STRATIFICATION IN PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
- Bálint Egyed (Hungary)
Abstract
Background and Aims
Recently, numerous leukemia-relevant copy number alterations (CNAs) were assessed as patient stratification tools in pediatric acute lymphoblastic leukemia (ALL). In our multicentric study of the Hungarian Pediatric Leukemia Molecular Profiling Program, we aimed to integrate classical cytogenetic risk factors with CNA profiles for survival prediction.
Methods
Diagnostic bone marrow samples from 260 children with precursor B-cell ALL were comprehensively screened by digital multiplex ligation-dependent probe amplification (digitalMLPA, MRC Holland) using ALL-specific D007 probemixes on Illumina MiSeq platform. Bioinformatic analysis was performed using the Coffalyser software (MRC Holland).
Results
On average, 5.4 CNAs (gross chromosomal and subchromosomal aberrations) were detected per patient with a mean of 2.5 subchromosomal alterations. Among patients with high hyperdiploid (HHD) karyotype, the concurrent gain of chromosome 4 and 6 proved to be a highly favorable predictor (5-year EFS: 93.2%, other HHD patients: 60.4%; p=0.0005). Several subchromosomal CNAs in disease-relevant genes were identified (e.g. CDKN2A/B in 45.6% of patients, PAX5 13.4%, IKZF1 11.5%). Prognostic categories defined by CNAs in IKZF1 and related genes (normal or deleted IKZF1, IKZF1plus) were refined considering the cytogenetic risk groups suggested by Moorman et al., which resulted in a more accurate risk stratification (IKAROS-low vs. IKAROS-intermediate, p=0.002; IKAROS-intermediate vs. IKAROS-high, p=0.048). Finally, we created a novel integrated score system by proportionally weighting individual cytogenetic aberrations and subchromosomal CNAs (e.g. harboring ETV6-RUNX1 counts +1.5 points; TP53 deletion: -0.25 points). Patient-specific cumulative scores generated from the prognostic value of single lesions distinguished two favorable (60% of patients; excellent and low risk, 96.1% and 87.9% 5-year EFS; p=0.041) and two unfavorable (40% of patients; high and ultra-poor risk, 64.3% and 30.6% 5-year EFS; p=0.004) prognostic groups.
Conclusions
DigitalMLPA offers a fast and standardizable DNA copy number analysis, which is implementable in the diagnostic workflow of pediatric ALL and expands genetics-based risk prediction perspectives.
UNIQUE PROGNOSTIC ASSOCIATIONS OF COPY NUMBER CHANGES OF GENOMIC LOCI IN ASIAN WILMS TUMOR
- Amos H. Loh (Singapore)
Abstract
Background and Aims
In Asians, Wilms tumors display uniquely low incidence and favorable biological features. Having previously shown that 1p/16q co-loss of heterozygosity (LOH) was not prognostic in Asians, we sought to study the association of copy number changes in other genomic loci with relapse and ethnicity in a multiracial population-based cohort.
Methods
Multiplex ligation-dependent probe amplification assay was adapted for formalin-fixed specimens and validated against matched frozen tissues and genotyping methods, then applied to 61 tumors from 55 Asian and non-Asian patients treated with National Wilms Tumor Study regimens in Singapore hospitals from 2001-2022, and a validation set (n=14) from a separate Asian population. Log2 copy number ratios and LOH (defined as gain/loss of ≥2 consecutive loci) were correlated with clinical variables.
Results
Clustering analysis identified a subgroup of predominantly non-Asian and relapsed patients with 1p, 16q loss, and 1q gain, while a subgroup (21%) with predominantly Asian ethnicity, low stage and few relapses was characterized by MYCN exon 2 with/without PAX3 gain, and minimal 1p/1q/16q aberrations. Overall, 23.0% of Singapore cases, and 37.5% of a Vietnamese validation cohort had MYCN exon 2 gain. Univariate t-test verified that PAX3 and MYCN gain were significantly associated with Asian ethnicity (P=0.02, P=0.001, respectively); among Asians, PAX3 loss was associated with relapse (P=0.02). WT1 LOH was associated with older age and metastases (P=0.02, P=0.03, respectively), and TP53 LOH with older age, metastases and anaplasia (P=0.04, P=0.004, P<0.001, respectively). Notably, 1q gain, but not 1p/16q LOH, was associated with relapse (P=0.001). Correspondingly, relapse was associated with older age (P<0.05), higher stage and unfavorable histology (P<0.01).
Conclusions
In Asian Wilms tumor patients, LOH of 1q, but not 1p and 16q, is prognostic for relapse. Gain of MYCN and its downstream target PAX3 is frequent in Asian populations and may uniquely represent a marker of favorable outcome that demands further study.
TRANSCRIPTOME ANALYSIS REVEALS ASSOCIATION OF NEW LONG NONCODING RNAS WITH POOR CLINICAL PROGNOSIS IN PEDIATRIC ADRENOCORTICAL TUMORS
- Luis Fernando P. Nagano (Brazil)
Abstract
Background and Aims
Pediatric adrenocortical tumors (pACT) are rare and aggressive adrenal gland neoplasms. However, molecular markers and therapeutic targets for prognosis and treatment of pACTs are scarce. Considering that lncRNAs are arising as central regulators in oncogenesis and several hallmarks of cancer, the identification of deregulated lncRNAs in this pediatric tumor is of great interest, and new candidates for prognostic markers may emerge.
Methods
We performed RNA sequencing (RNA-seq) of 14 pACTs samples and analyzed the data from an additional pACTs cohort to search for lncRNAs associated with prognosis in pACTs. For the RNA-seq experiment, our cohort was subdivided into two groups: patients with death or relapse events (poor prognosis, n=5) and patients without events (good prognosis, n=9), once there is no consensus on molecular subgroups for pACTS. This criteria was also used for the additional pACTs cohort (public dataset: GSE76019, n=34). All correlation tests were performed based on Spearman’s coefficient. Positive and negative correlated genes were submitted to pathways enrichment using the Reactome database.
Results
Transcriptome analysis of our in house generated RNA-seq and GSE76019 revealed four common differentially expressed lncRNAs between the good and poor prognostic samples, using log2 fold change > 1 or < −1 & adj. p-value < 0.05 as threshold for both analysis. LINC01138, CRNDE, PD6G-AS1 were up-regulated while LINC00400 was down-regulated in poor prognosis pACTs. Nineteen common differentially expressed mRNAs were shown to be LINC01138 predicted targets and negatively correlated with it. In addition, LINC01138 demonstrated to be highly correlated with the cell proliferation marker MKI67 and co-regulated genes of LINC01138 involved in cell cycle regulation and MHC Class I processing and presentation.
Conclusions
In summary, our study showed associations between lncRNAs profiles and pACTs prognosis, in addition to candidate lncRNAs that can be used in future studies related to diagnosis/prognosis or as targets for pACTs treatment. (Grant FAPESP: 2014/20341-0; Grant CNPQ: 140305/2020-3).
ULTRA RARE SOFT PART SARCOMAS IN YOUNG PATIENTS: ARE THEY DIFFERENCES ACCORDING TO AGE OF OCCURRENCE? THE FRENCH NATIONAL NETSARC+ NETWORK EXPERIENCE
- Anne-Laure Genevois (France)
Abstract
Background and Aims
Some soft tissue sarcomas are considered ultra-rare in children [0-18 year, y], as liposarcoma (LPS), leïomyosarcoma (LMS) and alveolar soft part sarcoma (ASPS). No standardized therapeutic guidelines are available for this population. This study aimed to compare their clinical presentation and behavior with their counterparts in young adults [19-30 y].
Methods
National retrospective comparative multicenter study of patients (0-18 vs. 19-30 y) with LPS, LMS, or ASPS included in the "ConticaBase" Sarcoma database, treated between 2010 and 2019. All diagnosis have been reviewed by expert pathologists’ members of the Netsarc+ network.
Results
Overall, 184 patients were identified: 35 children (19%) and 149 adults (81%). Tumor type distribution was: 14 LPS , 6 LMS and 15 ASPS in the [0-18y], 92 LPS, 40 LMS and 17 ASPS in the [19-30y] group (p<0.001). In children, LPS were smaller (median, 5cm vs. 10cm; p=0.005) and LMS were more frequently localized in limbs (83% vs. 30%; p=0.02). ASPS characteristics were similar. The proportions of high-grade tumors were similar for LPS (7% vs. 5%; P=1.00) and for LMS (17% vs. 32%; P= 0.74). After median follow-up of 54 months (range: 0-138), children with LPS and ASPS had similar outcome in term of pattern of relapse, but pediatric patients with LMS developed less distant metastasis [fll1] (0% vs.52%; p=0.025). Three-year overall survival in children vs. adults was 82% [95%CI, 62-100] vs.98% [64-100, p=0.13] for LPS, 100% [100-100] vs. 78% [68-94, p=0.13] for LMS and 92% [79-100] vs.92% [79-100, p=0.52] for ASPS. Three-year overall survival in children vs. adults was 82% [95%CI, 62-100] vs.98% [64-100, p=0.13] for LPS, 100% [100-100] vs. 78% [68-94, p=0.13] for LMS and 92% [79-100] vs.92% [79-100, p=0.52] for ASPS.
Conclusions
These preliminary results suggest that LPS and ASPS have quite comparable presentation and outcomes regardless of age, whereas LMS have more favorable outcomes in children.