Genetic Polymorphisms in Myeloma

描述（由申请方提供）：尽管多发性骨髓瘤在临床上被定义为骨髓中克隆性恶性浆细胞的蓄积，但该疾病在进展和治疗反应方面显示出显著异质性。该提案中提出的假设是，功能性遗传多态性与肿瘤生长控制、药物代谢/解毒和DNA修复机制相关，这些机制将影响化疗毒性和疾病进程。来自东部肿瘤协作组的3项III期临床试验的细胞和DNA库将用于确定药物代谢/转运相关基因中遗传多态性的等位基因频率（细胞色素P450、髓过氧化物酶、谷胱甘肽S-转移酶（M、T、P）、多药耐药1）; DNA修复骨髓瘤相关生长因子（IL-6、IL-1b、IL-1 RA、IL-10、TNa、Lta、TGFb）。改变这些基因产物中每一种功能的已知遗传多态性将与生存、骨疾病、毒性、反应、感染和继发性恶性肿瘤相关。这些相关性将提供重要的遗传标记，从而允许更好的个性化治疗策略。

DESCRIPTION (provided by applicant): Although multiple myeloma is clinically defined as the accumulation of clonal, malignant plasma cells in the bone marrow, the disease shows significant heterogeneity with regard to progression and therapeutic response. The hypothesis addressed in this proposal is that functional genetic polymorphisms are associated with tumor growth control, drug metabolism/detoxification, and DNA repair mechanisms that will influence chemotoxicity and the course of the disease. Cell and DNA banks from 3 phase Ill clinical trials of the Eastern Cooperative Oncology Group will be used to determine allelic frequencies of genetic polymorphisms in genes associated with drug metabolism/transport (cytochrome P450, myeloperoxidase, glutathione S-transferases (M,T,P), multi-drug resistance 1); DNA repair (XRCCC1, ERCC2); and, myeloma related growth factors (lL-6, IL-1b, IL-1RA, IL-10, TNa, Lta, TGFb). Known genetic polymorphisms that alter function of each of these gene products will be correlated with survival, bone disease, toxicity, response, infection, and secondary malignancies. These correlations will provide important genetic markers that will allow better individualized treatment strategies.