N-PhenoGENICS: Neurocognitive-Phenome, Genome, Epigenome and Nutriome In Childhood Leukemia Survivors (NPG)

To find possible therapeutic targets to help prevent long-term brain and behavioural side effects in survivors of childhood leukemia that may have been caused by chemotherapy (Treatment-Related late Adverse Neuro-Cognitive Effects: TRANCE). The study hypothesis is that genetic variations of the elements in the folate-related cycles and methotrexate disposition networks are associated with the deficit phenotype (TRANCE) of childhood leukemia survivors.

Study Overview

• Status: Completed
• Conditions: Childhood Leukemia Survivors

Detailed Description

Hypothesis Genetic variants of the elements in the folate-related cycles and methotrexate disposition networks are associated with the TRANCE phenotype of childhood leukemia survivors.

Objectives

1. To identify TRANCE phenotypes of the childhood leukemia survivors.
2. To characterize the folate and vitamin B12 levels of these children
3. To identify DNA methylation patterns associated with TRANCE trait in the leukemia survivors
4. To identify SNPs associated with the TRANCE trait in the leukemia survivors.
5. To identify the "deficit genotype" associated only with the TRANCE leukemia survivors, but not with general population children who show developmental phenotypes similar to TRANCE: TRANCE-unique deficit variant
6. To replicate the association between the TRANCE-unique deficit variants and the TRANCE trait in a population of childhood leukemia survivors.
7. To evaluate the importance of rare genetic variants in the TRANCE trait in the leukemia survivors.

Study design: A case-control study of leukemia survivors

Analyses

1. Leukemia survivors will be characterized by their status of neurocognitive function, and categorized into the Deficit case and the non-deficit Control case.

2. They will be also characterized by the following attributes

   1. Pathway-based genetic variant status (folate and PK-related genes)
   2. Folate and vitamin B12 status
   3. Epigenetic markers
3. Comparative analyses between neuro-cognitiive deficit phenotype (TRANCE) and Control on those parameters

• Study Type: Observational
• Enrollment (Actual): 204

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 20 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Childhood leukemia survivors

Description

Inclusion Criteria:

• Past diagnosis of acute lymphoblastic leukemia
• 8 years : 0 months - 20 years : 11 months old at the time of their study visit
• At least 2 years : 0 months from the last treatment for acute lymphoblastic leukemia at the time of their study visit
• Continuous complete remission and undergone no bone marrow transplantation or cranial radiation therapy
• Fluent in English (a subject and one parent) for test completion
• Signed informed consent

Exclusion Criteria:

• Inability to complete the phenotyping tests
• Down Syndrome diagnosis

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Leukemia survivors with neurocognitive deficit; Leukemia survivors with neuro-cognitive deficit phenotype. Based on DIVERGET and other phenotyping tools, we will identify those with the deficit phenotype. This will be treated as "case".
Leukemia survivors without neurocognitive deficit; Leukemia survivors who did not show impaired neurocognitive function, compared to the Control group defined above.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DIVERGET	This is a short battery of tests that has been shown to be predictive of both global and academic impairment in survivors of childhood cancer. All neuro-cognitive tests are done on a same day.	Within 6 months from the enrolment
Stop Signal Task (SST)	Response inhibition, disturbed by behavioral inattention, will be characterized using our task-based computer program, the Stop Signal Task (SST). All neuro-cognitive tests are done on a same day.	Within 6 months from the enrolment
CONNERS 3	To characterize behavioural aspects, we will administer the standard measure based on parent report. All neuro-cognitive tests are done on a same day.	Within 6 months from the enrolment
Pathway-based gene variant status	In the hypothesis-driven genome-wide approach, we will focus on the candidate pathways/regions including (but not limited to): a) Folate/methionine cycle genes and transporters; b) drug metabolizing enzymes and transporters (including families of CYP, SLC and ABC transporters); c) epigenetic modifying factors; and d) neuro-regeneration and tissue repair.	Within 3 months from the end of enrolment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
WISC-IV	In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will include tests of general cognitive function (WISC-IV). All neuro-cognitive tests are done on a same day.	Within 6 months from the enrolment
WIAT-III numerical operations and math fluency composite score	In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will include tests of general cognitive function: WIAT-III numerical operations and math fluency composite score. All neuro-cognitive tests are done on a same day.	Within 6 months from the enrolment
Brief Rating Inventory of Executive Function (BRIEF)	In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will administer Brief Rating Inventory of Executive Function (BRIEF), which is designed to assess executive functioning in the home environment. All neuro-cognitive tests are done on a same day.	Within 6 months from the enrolment
N-Back Task	In order to confirm validity of DIVERGT in our sample, and provide the data source for future studies, we will administer N-Back Task, which is a continuous performance computerized task used to measure aspects of working memory. All neuro-cognitive tests are done on a same day.	Within 6 months from the enrolment
Folate, vitamin B12 and iron intake	Folate and other vitamin intakes vary among individuals. Folic acid fortification in Canadian food product has changed the Canadian population norm of folate status, virtually eliminating folate deficiency status. However, a large inter-individual variation still remains. We will use a Supplement Questionnaire to capture information on all and any supplements that participants may be currently taking.	Within 6 months from the enrolment
Folate status	In order to complement the Supplement Questionnaire (above), we will measure the folate concentration in plasma and red blood cells.	Within 6 months from the enrolment
Serum vitamin B12	Vitamin B12 and folate pathways interact to maintain biochemical homeostasis. To complement the intake assessment (above), we will measure serum vitamin B12.	Within 6 months from the enrolment
Iron status	Iron status affects cognitive function of children. In addition to the intake assessment (above), we will estimate iron status by measuring hemoglobin and soluble transferrin receptor.	Within 6 months from the enrolment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Epigenetics marker	DNA methylation signals represent one of the most stable epigenetic markers, which are known to be affected by environmental factors including drugs and nutrients such as folate. Environmental information conveyed through these factors is translated into gene expression changes mediated by DNA methylation. Although this may contribute to neuro-cognitive deficits of the leukemia survivors, there is no prior data in this regard. Therefore, the aim of this exploratory analysis is to determine if there is any indication that DNA methylation patterns are altered in the participants. DNA will be isolated from each of the blood, buccal swab, and saliva samples and modified using sodium bisulfite, which will then be used to determine DNA methylation patterns.	Within 3 months from the end of enrolment

Collaborators and Investigators

• Sponsor: The Hospital for Sick Children
• Collaborators: Canadian Institutes of Health Research (CIHR); Canadian Cancer Society (CCS); C17 Council; Garron Family Cancer Centre; Pediatric Oncology Group of Ontario
• Investigators: Principal Investigator: Dr. Shinya Ito, MD, The Hospital for Sick Children; Principal Investigator: Dr. Sharon Guger, The Hospital for Sick Children; Principal Investigator: Dr. Johann Hitzler, The Hospital for Sick Children; Principal Investigator: Dr. Deborah L O'Connor, The Hospital for Sick Children; Principal Investigator: Dr. Russell Schachar, The Hospital for Sick Children; Principal Investigator: Dr. Brenda Spiegler, The Hospital for Sick Children; Principal Investigator: Dr. Rosanna Weksberg, The Hospital for Sick Children

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2013
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): June 1, 2019

Study Registration Dates

• First Submitted: July 29, 2013
• First Submitted That Met QC Criteria: July 29, 2013
• First Posted (Estimate): July 31, 2013

Study Record Updates

• Last Update Posted (Actual): October 8, 2020
• Last Update Submitted That Met QC Criteria: October 6, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Methotrexate; Leukemia; Pharmacogenetics; Cognitive; Folate; Acute lymphoblastic leukemia; Cognitive late effects; Neurotoxicity; Childhood leukemia survivors; Late effects; Blood folate; N-PhenoGENICS
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia
• Other Study ID Numbers: 1000033923