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- Wade Kyono (United States of America)
- Lillian Sung (Canada)
Introduction
- Lillian Sung (Canada)
CLINICAL STUDY OF MAP2K1-MUTATED LANGERHANS CELL HISTIOCYTOSIS IN CHILDREN
- Ying Yang (China)
Abstract
Background and Aims
To analyze the genetic and clinical features of children with MAP2K1-mutated Langerhans cell histiocytosis (LCH).
Methods
The clinical data of patients with MAP2K1-mutated LCH from July 2017 to October 2020 were collected and compared with all patients with either the BRAFV600E mutation or no known mutation of the MAPK pathway at the same period.
Results
Thirteen mutations of the MAP2K1 gene were detected in 37 patients with LCH. The median age of the patients at disease onset was 4.56 (1.54, 9.42) years, and the median follow-up time was 17.67 (4.82, 24.92) months. The mutations of MAP2K1 were mainly concentrated at p.53-62 and p.98-103, and the most common mutation site was c.172_186del (32.4%). The BRAFV600E mutation group and the no known mutation of the MAPK pathway group included 133 and 59 patients, respectively. Compared with the BRAFV600E mutation group, the MAP2K1 mutation group had an older age of disease onset, a lower incidence of multisystem involvement, a higher incidence of single system multiple bone involvement (P<0.05). There was no significant difference in clinical features compared with the no known mutation group. The 2-year progression-free survival (PFS) rate of first-line treatment in MAP2K1-mutated patients was 65.6% ± 9.5%, without a significant difference among the three groups. The 2-year PFS of second-line chemotherapy in the MAP2K1 mutation group was 35.7% ± 26.7%, which was close to that of the BRAFV600E group (P>0.05) but significantly lower than that of the no known mutation group (P=0.011). Lung involvement was an independent risk factor in patients with MAP2K1 mutations [HR (95% CI) = 6.312 (1.769-22.526), P = 0.005].
Conclusions
Compared with the BRAFV600E mutation group, the patients with MAP2K1 mutations were mainly characterized by single system multiple bone involvement, with later disease onset and less involvement of risk organs. The prognosis of MAP2K1-mutated patients with lung involvement may be poor.
CHILDHOOD CANCER SURVIVAL GAP BY HEALTH INSURANCE TYPE IN COLOMBIA: A REPORT FROM VIGICANCER SURVEILLANCE SYSTEM
- Oscar Ramirez (Colombia)
Abstract
Background and Aims
Since 1993, Colombia, a middle-income country, shifted to a universal healthcare system with current coverage of more than 95% of its inhabitants. Herein, we describe pediatric cancer survival gaps by health insurance type in nine large Colombian cities.
Methods
We included prospectively collected data of children (<15 years) from VIGICANCER (Childhood Cancer Outcomes Surveillance System) from nine cities with a mean population of 1.8 million inhabitants (range: 0.35 to 7.7 million). We grouped cities with >100 cases/year (3 cities) or <100 cases/year (6 cities). We used Kaplan-Meier for survival analyses and Cox regression to adjust the hazard ratios (aHR) by covariates (age, sex, ethnicity, residence, city group, and tumoral group).
Results
From 2013 to 2019, 2431 children were registered in the 9 cities. Patients’ median age was 6 years, 56% were male, 36% resided in a province capital, and 8% were afro-Colombians. Ninety-six percent of patients had health insurance coverage. Insurance type was semi-private in 40%, public in 51%, and other (military/police/teachers) in 5%. Cohort 5-year overall survival (OS) was 58% (95% CI: 56, 61); 61% for hematological malignancies, 46% for brain tumors, and 58% for extra-cranial solid tumors. Semi-private vs. public OS gap at 2, 3, and 5 years was 6%, 8%, and 11%, respectively; p<0.001. The aHR of mortality for public compared to semi-private insurance was 1.4 (95% CI: 1.2, 1.7).
Conclusions
We show that the pediatric cancer OS gap by health insurance type in Colombia is a widespread phenomenon despite city size and region. Determinants of pediatric cancer survival are complex and insurance coverage plays a pivotal role. Although achieving universal health coverage is an immense public health advancement, it seems that is not sufficient to improve outcomes and additional measures must be taken to address pediatric cancer survival gaps.
URINARY 3-METHOXYTYRAMINE IS A BIOMARKER FOR MYC ACTIVITY IN PATIENTS WITH NEUROBLASTOMA
- Yvette A. Matser (Netherlands)
Abstract
Background and Aims
Elevated urinary 3-methoxytyramine (3MT) level at diagnosis was recently put forward as an independent risk factor for poor prognosis in neuroblastoma. Here, we investigated the biological basis underlying the putative association between elevated 3MT levels and poor prognosis.
Methods
Urinary 3MT levels and prognosis were investigated in both retrospective Italian (n=90) and prospective Dutch (n=95) cohorts. From the previously published retrospective Dutch cohort (n=301), patients with matched urinary 3MT measurements and gene expression data were used to generate a 3MT gene signature. The 3MT gene signature score was then used to predict survival outcome in the Children’s Oncology Group (n=247) and the German Pediatric Oncology Group (n=498) and compared to other known gene signatures. Immunohistochemistry of MYCN and dopamine β-hydroxylase (DBH) proteins was performed on primary tumors.
Results
Elevated urinary 3MT levels were associated with poor prognosis in both retrospective Italian and prospective Dutch cohorts. Moreover, elevated urinary 3MT levels were associated with eight differentially expressed genes, providing a 3MT gene signature that successfully predicted poor clinical outcome. Even among low-risk patients, high 3MT signature score was associated with poor 5-year overall survival (72% vs. 99% among low-risk patients with a low 3MT signature score), and the 3MT signature score was correlated with MYC activity in the tumor (R=82%, P<0.0001). Finally, a strong MYCN and weak DBH staining of tumors derived from patients with elevated urinary 3MT levels was observed, linking MYC activity in the tumor to both catecholamine biosynthesis and elevated urinary 3MT levels.
Conclusions
Elevated urinary 3MT is a promising biomarker for poor prognosis and reflects increased MYC activity in the tumor. Therefore, urinary 3MT levels should be measured at diagnosis and may assist in assessing risk.
THE ASSOCIATION OF NEIGHBORHOOD EFFECTS AND FRAILTY IN CHILDHOOD CANCER SURVIVORS: A REPORT FROM THE ST. JUDE LIFETIME COHORT STUDY
- Lindsay Schwartz (United States of America)
Abstract
Background and Aims
Childhood cancer survivors experience reduced physiologic reserve, known as frailty, earlier and at higher rates than their peers. A survivor’s residence may affect their individual health behaviors and overall health status. The association between these “neighborhood effects” and the development of frail states in survivors has not yet been investigated.
Methods
Participants in the St. Jude Lifetime Cohort Study with geocoded residential addresses were included for analysis (N=3,911, 47.2% female, 81.2% white, mean age at assessment 33.5±9.9 years). Pre-frail/Frail states were defined as having 2/≥3 of sarcopenia, muscle weakness, poor endurance, slow walking speed, and exhaustion obtained from direct assessments. Survivors completed questionnaires regarding individual health behaviors. Neighborhood effects were characterized at the census tract level using publicly-available geospatial health data and methodology (e.g., rurality/urbanicity, access to exercise opportunities and healthy food, and neighborhood socioeconomic status). A series of nested multivariable logistic regression models identified associations between neighborhood effects and pre-frailty/frailty, adjusting for physical activity, diet, smoking, treatment exposures, and chronic medical conditions.
Results
Compared to non-frail survivors (n=2,941, 75.7%), pre-frail (n=720, 18.5%) and frail survivors (n=226, 5.8%) were more likely to live in neighborhoods with reduced access to exercise opportunities (45.2% vs 89.2% vs 97.0%, P<0.0001), lower neighborhood socioeconomic status (46.6% vs 53.8% vs 59.7%, P<0.0001), and that were considered rural (13.1% vs 15.4% vs 20.8%, P=0.0026). Survivors had a 13.3% (95% CI 6.9-20.1%) increase in the odds of being frail/pre-frail if they lived in a resource-poor neighborhood as opposed to a resource-rich neighborhood when accounting for other variables such as demographics, individual health behaviors, treatment exposures, and chronic medical conditions.
Conclusions
The neighborhood in which a childhood cancer survivor resides as an adult is associated with pre-frailty/frailty. This study provides valuable information for creating and implementing interventions that use community factors to mitigate frailty and improve health outcomes in survivors.
BETA-CATENIN MUTATION DETECTING SYSTEM IN SERUM CFDNA IN CHILDREN WITH HEPATOBLASTOMA
- Masato Kojima (Japan)
Abstract
Background and Aims
In pediatric live tumors (PLTs) , especially, hepatoblastoma, activation of Wnt/β-catenin signaling is mainly attributed to the somatic mutations in the exon 3 of β-catenin gene. Accordingly, the alterations in β-catenin may be used as markers in the diagnosis and prognosis of PLTs. Circulating cell-free DNA (cfDNA) has been described in various malignancies as a diagnostic and prognostic biomarker. We tried to establish the screening system for detection of these mutation using real time PCR or digital PCR.
Methods
Cf DNA and tumor DNA were isolated from 30 patients with HB. Cf DNA was also isolated from the serum of 5 healthy individuals. CfDNA and tumor DNA samples were analyzed by the following two methods: 1) Detection of point mutations: digital PCR system using two different fluorescent probes to CTNNB1 exon 3. 2)Detection of deletion of exon3: bridged nucleic acid-clamp real-time PCR (BNA-clamp PCR) using PNA for exon 3. The CTNNB1gene of tumor DNA samples were analyzed by Sanger sequencing.
Results
In a total of 30 cfDNA samples of HB patients were analyzed, all 9 of whom had a point mutation in CTNNB1 exon 3 in tumor DNA were detectable by digital PCR system. In the remaining 21 cases, CTNNB1 deletion was detected in 16 tumor DNA samples by Sanger sequencing. In these 16 cases, CTNNB1 deletion was detectable in 13 cfDNA samples by BNA-clamp PCR. Three cfDNA samples whose deletion was undetectable by BNA-clamp PCR harbored the large deletion beyond the PCR lesion. The 5 cfDNA of healthy volunteers showed no mutation and deletion signals.
Conclusions
Our results indicate that digital PCR and BNA-clamp PCR using cfDNAs of HB patients detects somatic mutations and deletions in CTNNB1 with high accuracy. This cfDNA analysis might become one of the useful liquid biopsy tools and also a useful monitoring marker for relapse/recurrence of HB.
HIGHLY SENSITIVE DETECTION METHOD OF RETINOBLASTOMA GENETIC PREDISPOSITION AND BIOMARKERS
- Lisa Golmard (France)
Abstract
Background and Aims
Retinoblastoma is a malignant tumor of the retina affecting infants and young children. Nearly half of patients are predisposed to retinoblastoma by a germline RB1 pathogenic variant. Non-hereditary retinoblastoma is mainly caused by inactivation of both RB1 alleles at a somatic level. Several polymorphisms have been reported as biomarkers of retinoblastoma risk, aggressiveness or invasion. The most informative genetic testing is obtained from tumor DNA. For long, access to tumor DNA has been warranted by the frequent indication of enucleation, which has decreased due to advances in conservative approaches. Recent studies showed that tumor cell-free DNA can be analyzed in aqueous humor from retinoblastoma patients. Here we describe a next generation sequencing method relying on unique molecular identifiers for a highly sensitive detection of retinoblastoma genetic predisposition and biomarkers in a single analysis.
Methods
A custom gene panel analysis was performed with SureSelect XT-HS2 enrichment (Agilent) and sequencing on NextSeq 500 (Illumina). It is adapted for genomic DNA extracted from peripheral blood, or tumor DNA extracted from tumor fragment, aqueous humor or plasma.
Results
The gene panel was evaluated on 30 samples from 23 retinoblastoma patients. It enabled the detection of RB1 point variants, including low-level mosaic variants, large genome rearrangements and loss of heterozygosity, and biomarker analysis such as MYCN amplification.
Conclusions
The access to tumor cell-free DNA improves the diagnosis of genetic predisposition in case of conservative ocular therapy and provides access to biomarkers guiding the treatment strategy. The analysis of a gene panel is cost-effective and can be easily implemented in diagnostic laboratories.