Association between Single Nucleotide Polymorphisms (SNPs) and Toxicity of Advanced Non-Small-Cell Lung Cancer Patients Treated with Chemotherapy

Abstract

New therapeutic approaches are being developed based on the findings that several genetic abnormalities underlying non-small-cell lung cancer (NSCLC) could influence chemosensitivity. In this study, we assessed whether polymorphisms in genes of nucleotide excision repair (NER) pathway, including ERCC5, ERCC6, MMS19L, CCNH, XPC, RRM1, can affect the tolerability of platinum-based chemotherapy in NSCLC patients. We used AllGloTM probe to assess genotyping and polymorphisms in 388 stage IIIB and IV NSCLC patients treated with platinum-based chemotherapy. MMS19L might be associated with the adverse events of chemotherapy in NSCLC, especially for all grade leucopenia (P = 0.020), all grade jaundice (P = 0.037) and all grade creatinine increasing (P = 0.013). In terms of grade 3/4 adverse events, MMS19L was related with total grade 3/4 adverse events (P = 0.024) and grade 3/4 thrombocytopenia (P = 0.035), while RRM1 was related with total grade 3/4 adverse events (P = 0.047) and grade 3/4 vomiting (P = 0.046). ERCC5 was related with more infection (P = 0.017). We found that some SNPs in NER pathway genes were correlated with toxicity treated with double chemotherapy in advanced NSCLC patients, especially for SNPs of MMS19L, RRM1 and ERCC5.

Polymorphisms of p53 and MDM2 genes are associated with severe toxicities in patients with non-small cell lung cancer

“…SNPs have been suggested to be predictive markers of treatment response, toxicity and survival in lung cancer patients. 8,24,25 In this study, 3 investigated SNPs of p53 p. Pro72Arg, MDM2 c. 14C 309T > G and MDM2 c.¡461C > G were not associated with ORR and CBR in NSCLC patients during platinum-based chemotherapy. We found a statistically significant difference in clinical response to chemotherapy between subgroups of 57 and above 57 y ( Table 2).…”

“…A considerable number of studies have focused on the association between chemotherapy-related toxicity and polymorphisms in DNA repair genes. 8,24,25 Here, we focused on the association between incidence of toxicities in patients treated with platinumbased combination chemotherapy and polymorphisms of the p53 and MDM2 genes, which are involved in p53-mediated apoptosis in normal bystander cells suffering from platinum-based regimens.…”

“…4 A growing number of studies suggest that individual variations in treatment, clinical outcome and toxicities of platinum-based combination chemotherapy for lung cancer are associated with gene polymorphisms, which in turn affect drug-metabolizing, drug-transporting and DNA repair enzymes. [5][6][7][8] Here, we chose to focus on the MDM2 polymorphisms in the pathway of p53-mediated apoptosis in patients treated with platinum-based combination chemotherapy.…”

XPG polymorphisms are associated with prognosis of advanced non-small cell lung cancer treated with platinum-based doublet chemotherapy

“…Several studies have reported an association between XPG polymorphisms and clinical outcomes of advanced NSCLC patients, but the results are inconsistent (Zienolddiny et al, 2006;Bartolucci et al, 2009;Sun et al, 2009;Butkiewicz et al, 2011;Zhang et al, 2012). Zhang et al (2012) conducted a study in China to investigate the association between 5 SNPs in XPG and the prognosis of NSCLC patients.…”

“…Zhang et al (2012) conducted a study in China to investigate the association between 5 SNPs in XPG and the prognosis of NSCLC patients. They reported that rs1047768 C/T and rs2296147 C/T correlated with clinical outcomes of NSCLC patients treated with platinum-based chemotherapy.…”