GWAS of 972 autologous stem cell recipients with multiple myeloma identifies 11 genetic variants associated with chemotherapy-induced oral mucositis

Abstract

Purpose High-dose chemotherapy and autologous stem cell transplant (ASCT) to treat multiple myeloma (MM) and other cancers carries the risk of oral mucositis (OM) with sequelae including impaired nutritional and fluid intake, pain, and infectious complications. As a result of these problems, cancer treatment may have to be interrupted or delayed. In this study we looked beyond OM's known risk factors of renal function and melphalan dose with a genome-wide association study (GWAS) to evaluate whether genetic variants in conjunction with clinical risk factors influence predisposition for OM. Methods Genotyping was performed using Illumina HumanOmnil-Quad vl.O BeadChip and further assessed for data quality. We tested 892,589 germline single-nucleotide polymorphisms (SNPs) for association with OM among 972 Caucasian patients treated with high-dose melphalan and ASCT in Total Therapy clinical trials (TT2, TT3, TT4) for newly diagnosed MM. Statistical analyses included t tests, stepwise regression modeling, and logistic regression modeling to find baseline clinical factors and genotypes associated with OM. Results We found that 353 (36.3 %) patients had grades 2–4 OM. Type of treatment protocol, baseline estimated glomerular filtration rate, and melphalan dose along with baseline serum albumin and female gender predicted 43.6 % of grades 2–4 OM cases. Eleven SNPs located in or near matrix metalloproteinase 13, JPH3, DHRS7C, CEP192, CPEB1/LINC00692, FBN2, ALDH1A1, and DMRTA1/FLJ35282 were associated with grades 2–4 OM. The addition of these SNPs increased sensitivity in detecting grades 2–1 OM cases to 52 %. Conclusions These SNPs may be important for their roles in inflammatory pathways, epithelial healing, and chemotherapy detoxification.

Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa

“…The two recent GWAS studies on patients that received HSCT identified SNPs near the locus of MMP and other genes related to inflammation, but none related to HLA-DR [17, 18]. Other recent studies found a major role for MMPs in mucositis pathology [57].…”

“…Recent genome-wide association studies (GWAS) of patients that underwent HSCT have implied that UM development is associated with a genetic predisposition, primarily related to immune function [17, 18]. One study included 153 patients with miscellaneous malignancies that underwent HSCT, with the aim of building a predictive network for UM, based on 82 selected single nucleotide polymorphisms (SNPs) [17].…”

“…A later study included 972 patients with MM that underwent HSCT, and they identified 11 SNPs located near the matrix metalloproteinase gene that were associated with UM and several known clinical risk factors. The sensitivity of predicting UM was 52% [18]. Apart from the low sensitivity, those studies were limited by their failure to identify phenotypes or causal relationships.…”

Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality

“…Four of the ten toxicities investigated by GWAS were represented by a single study (29,64,65,72), and only one of those four studies incorporated participants of non-European descent (Figure 2A) (65). Of the 28 total studies, 16 utilized cohorts of entirely European descent, compared to 6 that were entirely East Asian, and 6 studies with diverse cohorts (Figure 2B).…”

“…Such clinical heterogeneity confounds analyses unless rigorous care is taken during data collection and analysis. A number of studies evaluated in this review displayed heterogeneity of agents within a class, multiple primary agents, or multiple toxic drugs (55,63,68,72,73,76,77). Problems with accurately assessing phenotype and clinical heterogeneity are particularly troublesome when choosing and properly applying replication sets.…”