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Abstract

Methotrexate (MTX), a cornerstone cancer treatment, has contributed to improved 5-year event-free survival rates but is associated with 20-40% occurrence of mucositis, which is characterized by the development of painful inflammatory lesions largely focused along the alimentary tract that often leads to premature termination of cancer treatment and impacts survival. Previous studies identified individual genetic variants implicated in mucositis development. Considering the complex biological pathways involved in mucositis development highlighted in recent studies, we hypothesize that multiple genetic variants within these shared biological pathways contribute to the onset of MTX-induced mucositis. To identify gene pathways that are likely to impact mucositis risk, we captured genes associated with: (i) methotrexate pharmacokinetics/pharmacodynamics from PharmGKB; (ii) published pathobiological pathways (e.g., WNT/β-catenin signaling) predicted to underlie mucositis development using MSigDB/Enrichr; and novel pathways based on genes previously associated with mucositis from literature using StringDB. To pinpoint pathways highly enriched for genetic variations associated with mucositis development in methotrexate-treated children, we examined the joint association of genetic variants using the raw genome-wide genotyping and patient clinical data for a set of pediatric mucositis cases (n=131) and controls (n=366) treated with intravenous methotrexate across 6 Canadian academic hospitals. A final set of 18 non-redundant pathways with a priori evidence for association with treatment-induced mucositis were selected for analysis. Our study used a phenotypic permutation test to identify significant enrichment in the IL-6 and WNT/β-catenin signaling pathways in patients developing mucositis due to high-dose MTX (> 1000 mg/m2). Using these genetic findings and clinical data, we developed a machine learning algorithm for mucositis risk stratification in patients receiving high-dose IV-MTX and identified key features impacting risk. Our future direction will focus on replicating the findings. If validated, the results can guide clinical care for high-risk patients and inform diagnosis and prescribing decisions. Moreover, the highlighted pathobiological pathways may serve as future therapeutic targets for mitigating mucositis during cancer treatment. Our goal is to minimize MTX-induced adverse reactions and improve patient quality of life during cancer treatment.