Association Of Matrix Metalloproteinase Pathway Polymorphism With Platinum Chemotherapy In Advanced Non - Small Cell Lung Cancer

Part I Association of Matrix Metalloproteinase Gene Polymorphisms with Response and Survival in Non-Small Cell Lung Cancer Patients Treated with Platinum-based ChemotherapyPlatinum-based chemotherapy has been widely used as first-line treatment for advanced non-small cell lung cancer (NSCLC). These platinum-based regimens bring modest benefits and prolong survival in NSCLC patients. Studies have suggested that chemotherapy efficacy vary greatly between individuals.The cytotoxicity of platinum is primarily ascribed to its interaction with DNA to form interstrand and intrastrand crosslink adducts, which inhibit DNA synthesis and induce cell apoptosis. Matrix metalloproteinases(MMPs), the main physiologicmediator of extracellular matrix (ECM) degradation, as well as important in cell proliferation, apoptosis, and angiogenesis, is playing an increasingly critical role in both cancer developmentandchemotherapy cytotoxicity.In this study, we assume that MMP genetic variants may affect individual response to chemotherapy and survival of NSCLC patients. We selected104single nucleotide polymorphisms (SNPs) from12critical genes in MMP pathway, and investigated the association of genetic variants with treatment efficacy in663Chinese stage Ⅲ-Ⅳ NSCLC patients receiving first-line platinum-based chemotherapy.We found that TIMP-2gene haplotype showed significant association with objective response of platinum-based chemotherapy (χ2test P=2.0×10-4, significance remained after applying10,000-time permutation tests, Psim=0.003). We also found TIMP-3polymorphisms rs135025and rs130275were significantly associated with clinical benefit of NSCLC patients. Moreover, MMP-9missense variants rs17577and rs17576showed significant influences on progression-free survival of NSCLC patients after platinum-based treatment, with consistent result in haplotype analysis (log-rank P=0.037). Both MMP-11polymorphism rs131451and TIMP-1polymorphism rs4898displayed significant correlations with overall survival of advanced NSCLC patients (rs131451, log-rank P=0.006; rs4898, log-rank P=0.027).In this study, we found several genetic variants in MMP genes showed predictive role of treatment efficacy in NSCLC patients receiving platinum-based chemotherapy. It can help patients select the most optimal regimen, thus being of significant benefit for NSCLC individualized treatment in the future. Part II Association of Matrix Metalloproteinase Gene Polymorphisms with Severe Toxicity in Non-Small Cell Lung Cancer Patients Treated with Platinum-based ChemotherapyPlatinum-based chemotherapy brings modest benefits for NSCLC patients, but also induces adverse effects which may cause distressing symptoms and prevent further therapies. Adverse effects caused by platinum vary greatly between individuals, and many biological and clinical studies have suggested that genetic variants played critical roles in this process.Matrix metalloproteinases are well known for their critical roles in cell proliferation and apoptosis. They also play important roles in hematopoietic recovery after chemotherapy-induced myelosuppression. We suggested that MMP genetic variants may affect individual chemotherapy toxicity of NSCLC patients treated with platinum-based regimen. In this study, we investigated the association of MMP gene polymorphisms with severe toxicity occurrence (gastrointestinal toxicity, hematologic toxicity, neutropenia, anemia, and thrombocytopenia) in663stage Ⅲ-Ⅳ NSCLC patients receiving first-line platinum-based chemotherapy.We observed polymorphisms rs494379in MMP-1gene, rs17099562in MMP-10gene, and rs6518799in TIMP-3gene, showing significant associations with severe gastrointestinal toxicity incidence. What is more, we found seven polymorphisms in MMP-2gene displaying significant associations with grade3or4neutropenia incidence. The variant homozygotes of rs12934241exhibited the most significant risk effect on severe neutropenia occurrence (OR=8.33, P=8.8×10-5, remaining significant after Bonferroni correction). Stratified analyses showed that rs12934241exhibited a much stronger influence in the cisplatin-gemcitabine regimen subgroup than the other regimens, leading to an incidence rate which increased from3.3%(C/C) to80.0%(T/T)(OR=8.39, P=1.6×10-4, P for interaction=0.003). Consistent results were observed in haplotype and diplotype analyses. In addition, genetic variants in MMP-3,-7,-8,-10also showed significant correlations with severe neutropenia occurrence. Our results indicate that MMP gene polymorphisms (especially MMP-2) may play important roles in adverse effects prediction in NSCLC patients treated with platinum-based chemotherapy.