title: GWAS of 972 autologous stem cell recipients with multiple myeloma identifies 11 genetic variants associated with chemotherapy-induced oral mucositis.
abstract: OBJECTIVE
  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.
authors.affiliation: College of Nursing, University of Arkansas for Medical Sciences, 4301 W. Markham St, Slot 529, Little Rock, AR, 72205, USA.
authors.forename: Elizabeth Ann
authors.initials: EA
authors.lastname: Coleman
authors.forename: Jeannette Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Erickson
authors.forename: Julia A
authors.initials: JA
authors.lastname: Goodwin
authors.forename: Naveen
authors.initials: N
authors.lastname: Sanathkumar
authors.forename: Vinay R
authors.initials: VR
authors.lastname: Raj
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
authors.forename: Kent D
authors.initials: KD
authors.lastname: McKelvey
authors.forename: Senu
authors.initials: S
authors.lastname: Apewokin
authors.forename: Owen
authors.initials: O
authors.lastname: Stephens
authors.forename: Carol A
authors.initials: CA
authors.lastname: Enderlin
authors.forename: Annette Juul
authors.initials: AJ
authors.lastname: Vangsted
authors.forename: Patty J
authors.initials: PJ
authors.lastname: Reed
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Anaissie
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects*; D003131:Combined Modality Therapy; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000706:statistics & numerical data; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy / Q000009:adverse effects; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D013280:Stomatitis / Q000139:chemically induced* / Q000235:genetics*; D014182:Transplantation, Autologous
chemical_list: D000970:Antineoplastic Agents; D008558:Melphalan