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Scott, Erika

University of British Columbia

Adverse drug reactions (ADRs) can have life-altering consequences for patients. Several ADRs occur in the context of chemotherapy as it often involves multiple therapeutics at high doses and the non-specific destruction of actively growing cells. Cisplatin-induced hearing loss (CIHL) and anthracycline-induced cardiotoxicity (ACT) are severe chemotherapy-induced ADRs that can cause permanent hearing loss and congestive heart failure, respectively. It is therefore important to predict these ADRs before treatment is started such that treatment plans can potentially be altered to avoid long-term effects. Several studies have identified genetic predictors for CIHL and ACT; however, these variants do not account for all instances of these ADRs, and the clinical relevance of many identified variants remains unknown. The goal of this dissertation was therefore to investigate the clinical relevance of known, and identify novel, genetic predictors for CIHL and ACT. A systematic review of known genetic associations with CIHL was performed and determined that variants in ACYP2 and TPMT had strong evidence for association with CIHL. For ACT, in a cohort of adult patients treated with anthracyclines, genetic variants in RARG and SLC28A3 were more clinically relevant in a well-characterized subset. Through genome-wide analyses, a variant with a strong, but non-significant, risk effect on ACT was identified (rs34644385; odds ratio=5.09, 95% confidence interval=2.46-10.50, P=1.09x10⁻⁵) and calcium signalling was implicated in the development of ACT in adult patients. Finally, through transcriptome-wide association study analyses in pediatric patients treated with anthracyclines, an association between dysregulated GDF5 and ACT was identified (P=1.70x10⁻⁵), replicated in an independent cohort (P=3.54x10⁻³), and was functionally validated. Genes known to be essential for survival were also implicated in the development of ACT. The results of this dissertation enable development of a new CIHL predictive pharmacogenetic test that includes ACYP2 along with TPMT and recommend early pharmacogenetic testing to prevent CIHL. The additional genetic insight into ACT may also help improve the predictive ability of pharmacogenetic testing for ACT. This dissertation contributes to expanding the pharmacogenetic literature and improving patient care through the investigation and identification of genetic predictors for CIHL and ACT.

Text

2025-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/84105

Medical Genetics

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/