Coleman Elizabeth Ann, Lee Jeannette Y, Erickson Stephen W, Goodwin Julia A, Sanathkumar Naveen, Raj Vinay R, Zhou Daohong, McKelvey Kent D, Apewokin Senu, Stephens Owen, Enderlin Carol A, Vangsted Annette Juul, Reed Patty J, Anaissie Elias J
College of Nursing, University of Arkansas for Medical Sciences, 4301 W. Markham St, Slot 529, Little Rock, AR, 72205, USA.
Support Care Cancer. 2015 Mar;23(3):841-9. doi: 10.1007/s00520-014-2406-x. Epub 2014 Sep 14.
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.
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.
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 %.
These SNPs may be important for their roles in inflammatory pathways, epithelial healing, and chemotherapy detoxification.
高剂量化疗及自体干细胞移植（ASCT）用于治疗多发性骨髓瘤（MM）和其他癌症时，存在发生口腔黏膜炎（OM）的风险，其后果包括营养和液体摄入受损、疼痛以及感染性并发症。由于这些问题，癌症治疗可能不得不中断或推迟。在本研究中，我们通过全基因组关联研究（GWAS），超越了OM已知的肾功能和马法兰剂量等风险因素，以评估基因变异与临床风险因素相结合是否会影响OM的易感性。
使用Illumina HumanOmni1-Quad v1.0 BeadChip进行基因分型，并进一步评估数据质量。我们在针对新诊断MM的全疗法临床试验（TT2、TT3、TT4）中，对972例接受高剂量马法兰和ASCT治疗的白种人患者，检测了892,589个种系单核苷酸多态性（SNP）与OM的关联。统计分析包括t检验、逐步回归建模和逻辑回归建模，以找出与OM相关的基线临床因素和基因型。
我们发现353例（36.3%）患者发生了2-4级OM。治疗方案类型、基线估计肾小球滤过率、马法兰剂量以及基线血清白蛋白和女性性别可预测43.6%的2-4级OM病例。位于基质金属蛋白酶13、JPH3、DHRS7C、CEP192、CPEB1/LINC00692、FBN2、ALDH1A1和DMRTA1/FLJ35282内部或附近的11个SNP与2-4级OM相关。添加这些SNP后，检测2-4级OM病例的敏感性提高到了52%。
这些SNP可能因其在炎症途径、上皮愈合和化疗解毒中的作用而具有重要意义。
