Cover Image

Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali

Acute lymphoblastic leukaemia is the most prevalent cancer in children under 14 years of age in Malaysia, with an incidence rate of approximately 35 per one million children. Several potential environmental and lifestyle factors associated with the risk of childhood leukaemia have been investigated,...

Full description

Saved in:
Bibliographic Details
Main Author: Razali, Rizal Husaini
Format: Thesis
Language:English
Published: 2021
Subjects:
Cancer
RJ Pediatrics
Online Access:https://ir.uitm.edu.my/id/eprint/60816/1/60816.pdf
https://ir.uitm.edu.my/id/eprint/60816/
Tags: Add Tag
No Tags, Be the first to tag this record!
id my.uitm.ir.60816
record_format eprints
spelling my.uitm.ir.608162022-06-02T00:02:59Z https://ir.uitm.edu.my/id/eprint/60816/ Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali Razali, Rizal Husaini Cancer RJ Pediatrics Acute lymphoblastic leukaemia is the most prevalent cancer in children under 14 years of age in Malaysia, with an incidence rate of approximately 35 per one million children. Several potential environmental and lifestyle factors associated with the risk of childhood leukaemia have been investigated, such as infections, pesticides, traffic air pollution, industrial pollutant, diet, parental occupation and smoking habit. The study aimed to determine relationships between two SNPs; rs10821936 (ARID5B) and rs25487 (XRCC1), and risk associated in childhood ALL, as well as four SNPs; rs717620 (ABCC2), rs4948496 (ARID5B), rs1801133 (MTHFR) and rs4149056 (SLCO1B1), with the serum levels and toxicity of MTX. The study also sought to investigate the metabolic alterations associated with MTX and to determine the potential metabolic markers and pathway for drug responses. Genomic DNA was isolated from blood, and the polymerase chain reaction analysis was performed for the genotyping study. The variants were then annotated and analysed utilising Variant Effect Predictor (VEP), Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping version 2 (PolyPhen-2). In addition, the Agilent 1200 Infinity HPLC system coupled with the Agilent 6460 triple-quadrupole (QQQ) and Agilent 6520 Accurate-Mass (Q-TOF) mass spectrometers were employed to measure serum concentrations of MTX and to identify the potential metabolic markers, respectively. Eighty-one per cent of the patients have genotypes CC and CT of rs10821936 (ARID5B) were associated with 2.5 – 2.1 increase in the risk of developing ALL. The rs717620 ABCC2 genotype was significantly associated with MTX serum levels at 48 hours post-treatment (p = 0.017, Kruskal-Wallis Test). Patients with CT and TT of rs717620 (ABCC2) and TC and CC of rs4948496 (ARID5B) were significantly associated with grade I – IV leukopenia (Fisher Exact Test; p = 0.03 and 0.02, respectively). The metabolomics study found that thirteen metabolites significantly discriminated the pre- and post-MTX group. Out of the thirteen metabolites identified, the four metabolites with VIP scores of more than 1 were xanthine, alpha-linolenic acid, (9Z)-hexadecenoic acid and cholic acid. The findings revealed that xanthine was the most significant metabolic marker in childhood ALL with an AUC value of 0.88 (95%, CI = 0.84 – 0.92). Our results demonstrate that by pre-screening of ALL patients would identify whose patients at risk and therefore help a paediatric oncologist to personalize chemotherapy drugs for precision health. 2021-07 Thesis NonPeerReviewed text en https://ir.uitm.edu.my/id/eprint/60816/1/60816.pdf Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali. (2021) PhD thesis, thesis, Universiti Teknologi MARA.
institution Universiti Teknologi Mara
building Tun Abdul Razak Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Teknologi Mara
content_source UiTM Institutional Repository
url_provider http://ir.uitm.edu.my/
language English
topic Cancer
RJ Pediatrics
spellingShingle Cancer
RJ Pediatrics
Razali, Rizal Husaini
Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali
description Acute lymphoblastic leukaemia is the most prevalent cancer in children under 14 years of age in Malaysia, with an incidence rate of approximately 35 per one million children. Several potential environmental and lifestyle factors associated with the risk of childhood leukaemia have been investigated, such as infections, pesticides, traffic air pollution, industrial pollutant, diet, parental occupation and smoking habit. The study aimed to determine relationships between two SNPs; rs10821936 (ARID5B) and rs25487 (XRCC1), and risk associated in childhood ALL, as well as four SNPs; rs717620 (ABCC2), rs4948496 (ARID5B), rs1801133 (MTHFR) and rs4149056 (SLCO1B1), with the serum levels and toxicity of MTX. The study also sought to investigate the metabolic alterations associated with MTX and to determine the potential metabolic markers and pathway for drug responses. Genomic DNA was isolated from blood, and the polymerase chain reaction analysis was performed for the genotyping study. The variants were then annotated and analysed utilising Variant Effect Predictor (VEP), Sorting Intolerant from Tolerant (SIFT) and Polymorphism Phenotyping version 2 (PolyPhen-2). In addition, the Agilent 1200 Infinity HPLC system coupled with the Agilent 6460 triple-quadrupole (QQQ) and Agilent 6520 Accurate-Mass (Q-TOF) mass spectrometers were employed to measure serum concentrations of MTX and to identify the potential metabolic markers, respectively. Eighty-one per cent of the patients have genotypes CC and CT of rs10821936 (ARID5B) were associated with 2.5 – 2.1 increase in the risk of developing ALL. The rs717620 ABCC2 genotype was significantly associated with MTX serum levels at 48 hours post-treatment (p = 0.017, Kruskal-Wallis Test). Patients with CT and TT of rs717620 (ABCC2) and TC and CC of rs4948496 (ARID5B) were significantly associated with grade I – IV leukopenia (Fisher Exact Test; p = 0.03 and 0.02, respectively). The metabolomics study found that thirteen metabolites significantly discriminated the pre- and post-MTX group. Out of the thirteen metabolites identified, the four metabolites with VIP scores of more than 1 were xanthine, alpha-linolenic acid, (9Z)-hexadecenoic acid and cholic acid. The findings revealed that xanthine was the most significant metabolic marker in childhood ALL with an AUC value of 0.88 (95%, CI = 0.84 – 0.92). Our results demonstrate that by pre-screening of ALL patients would identify whose patients at risk and therefore help a paediatric oncologist to personalize chemotherapy drugs for precision health.
format Thesis
author Razali, Rizal Husaini
author_facet Razali, Rizal Husaini
author_sort Razali, Rizal Husaini
title Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali
title_short Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali
title_full Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali
title_fullStr Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali
title_full_unstemmed Genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / Rizal Husaini Razali
title_sort genetic risks of childhood lymphoblastic leukaemia and the interpatient variation of methotrexate responses among patients / rizal husaini razali
publishDate 2021
url https://ir.uitm.edu.my/id/eprint/60816/1/60816.pdf
https://ir.uitm.edu.my/id/eprint/60816/
_version_ 1735389659513487360
score 13.211869

Similar Items