Date of Award

1-1-2011

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

College of Natual Science and Mathematics

First Advisor

Phillip B. Danielson, Ph.D.

Second Advisor

Corinne Lengsfeld, Ph.D.

Third Advisor

James Fogleman

Fourth Advisor

Judith Snyder

Fifth Advisor

David Patterson

Keywords

Acute lymphoblastic Leukemia, Cytochrome P450, Genetic polymorphisms, Genotyping

Abstract

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for 30 - 35% of all cancers in children. Significant improvement in the treatment of pediatric ALL has been achieved in recent years. Only 50 years ago, the disease was uniformly fatal with an Overall Survival (OS) rate < 5%. Modern-day, multi-drug chemotherapy is associated with an overall survival rate over 80%. Standard-risk ALL comprises the majority of ALL with an overall survival approaching 90%. Despite this success, children who relapse from this disease accounts for the majority of cancer-related deaths in children. The backbone of treatment protocols have incorporated somatic but not host genetic features in the treatment regimens. The current study examined 12 genetic polymorphisms affecting the pharmacodynamics of antileukemic drugs in an attempt to identify biologic markers related to the risk of disease relapse.

In the current research program, 125 standard-risk ALL patients who were treated at The Children's Hospital were enrolled in a retrospective study. Statistical analysis was performed to evaluate the association between genetic polymorphisms and risk of disease relapse in this study cohort. The GSTM1 null genotype was associated with a decreased risk of disease relapse (HR = 0.394, 95% CI = 0.127 - 1.224, P = 0.107). A combination analysis of the GSTM1 and GSTT1 genotypes revealed a stronger association between the both the GSTM1 and GSTT1 normal genotype and an increased risk of leukemia relapse (HR = 2.73, 95% CI = 0.9 - 7.9, P = 0.063), compared with patients having either the GSTM1 or GSTT1 null genotype. A "drug exposure" model was used in this study. The risk of relapse in individual with a low or intermediate "drug exposure" genotype increased 2.4-fold (HR = 2.39, 95% CI = 0.8 - 6.9, P = 0.107) compared with the high "drug exposure" genotype. No significant associations with relapse were observed for the CYP1A1, CYP2B6, CYP3A4, CYP3A5, MTHFR C667T, MTHFR A1298G, or TYMS polymorphisms. The findings from this single institution study suggest that polymorphisms within genes of the GST superfamily may influence the treatment outcome in standard-risk ALL. They also point to the need of prospective, large multi-institutional studies to validate these findings prior to clinical implementation.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Qi Wei

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

169 p.

Discipline

Molecular biology, Genetics

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