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

Elizabeth Ann Coleman, Jeannette Y. Lee, Stephen W. Erickson, Julia A. Goodwin, Naveen Sanathkumar, Vinay R. Raj, Daohong Zhou, Kent D. McKelvey, Senu Apewokin, Owen Stephens, Carol A. Enderlin, Annette Juul Vangsted, Patty J. Reed, Elias J. Anaissie

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)841-849
Number of pages9
JournalSupportive Care in Cancer
Volume23
Issue number3
DOIs
StatePublished - Mar 2015
Externally publishedYes

Keywords

  • Chemotherapy-induced oral mucositis
  • GWAS
  • Genetic variants
  • Multiple myeloma
  • Oral mucositis
  • SNPs

ASJC Scopus subject areas

  • Oncology

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