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

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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 HumanOmni1-Quad v1.0 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 2–4 OM cases to 52 %.

Conclusions

These SNPs may be important for their roles in inflammatory pathways, epithelial healing, and chemotherapy detoxification.

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Conflict of interest

The authors have no conflict of interest to report. Author/COI Disclosure Forms were submitted along with the manuscript.

Author contributions

EJ Anaissie, EA Coleman, JY Lee, JA Goodwin, CA Enderlin, and VR Raj are responsible for the conception and design; N Sanathkumar, EA Coleman, EJ Anaissie, and JA Goodwin for the collection and verification of clinical data; VR Raj, O Stephens, and SW Erickson for the generation and verification of GWAS data; JY Lee, SW Erickson, EA Coleman, D Zhou, VR Raj, JA Goodwin, and N Sanathkumar for data analysis and interpretation; PJ Reed for the administrative support; KD McKelvey for serving as a consultant on medical genetics; EA Coleman, JY Lee, D Zhou, SW Erickson, JA Goodwin, VR Raj, N Sanathkumar, S Apewokin, and AJ Vangsted for writing the manuscript; and EA Coleman, JY Lee, SW Erickson, JA Goodwin, N Sanathkumar, D Zhou, KD McKelvey, VR Raj, S Apewokin, O Stephens, CA Enderlin, AJ Vangsted, PJ Reed, and EJ Anaissie fo the final approval of the manuscript.

Financial support

Primary support was given by the National Institutes of Health (NIH)/National Institute of Nursing Research (NINR) 5 RC2NR011945, and for the additional support, the Translational Research Institute at UAMS (grant #1UL1RR029884) and the Elizabeth Stanley Cooper Chair in Oncology Nursing.

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Authors and Affiliations

  1. College of Nursing, University of Arkansas for Medical Sciences, 4301 W. Markham St, Slot 529, Little Rock, AR, 72205, USA

    Elizabeth Ann Coleman, Carol A. Enderlin & Patty J. Reed

  2. UAMS Medical Center, University of Arkansas for Medical Sciences, 4301 W. Markham St, Slot 721-13, Little Rock, AR, 72205, USA

    Julia A. Goodwin

  3. Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Jeannette Y. Lee & Stephen W. Erickson

  4. Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Naveen Sanathkumar, Senu Apewokin & Owen Stephens

  5. Department of Genetics, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Vinay R. Raj

  6. Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    Daohong Zhou

  7. Department of Hematology, Roskilde University Hospital, Roskilde, Denmark

    Kent D. McKelvey & Annette Juul Vangsted

  8. College of Medicine, University of Cincinnati, Cincinnati, OH, USA

    Elias J. Anaissie

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  1. Elizabeth Ann Coleman
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  14. Elias J. Anaissie
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Correspondence to Julia A. Goodwin.

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Coleman, E.A., Lee, J.Y., Erickson, S.W. et al. GWAS of 972 autologous stem cell recipients with multiple myeloma identifies 11 genetic variants associated with chemotherapy-induced oral mucositis. Support Care Cancer 23, 841–849 (2015). https://doi.org/10.1007/s00520-014-2406-x

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  • DOI: https://doi.org/10.1007/s00520-014-2406-x

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