| Background and Objective:Small cell lung cancer (SCLC) is an aggressive malignancy neuroendocrine neoplasm characterized by early metastatic and poor prognosis. Platinum-based chemotherapy is the standard therapy for SCLC, while patients with the same clinical diagnose have different therapy response and survival time. Large numbers of studies show that genetic variations significantly influence the individual response and prognosis. Recent studies have found that non-coding region genes play an important role in the development of tumors rather than a desert without any biological function. In addition, RAD52 is a key component in mediating homologous recombination repair which can keep the genome stability and prevent cancer. This study explored the associations between genetic variations of non-coding region genes and RAD52 and therapeutic response or survival in SCLC patients receiving platinum-based chemotherapy.Methods:Our study involved in SCLC patients who received platinum-based chemotherapy in Cancer Hospital, Chinese Academy of Medical Sciences from March 1997 to May 2013. We conducted a high throughput screening study to identify genetic variations of non-coding region genes associated with therapeutic response or survival in 475 individuals with SCLC receiving platinum-based chemotherapy followed by validation in an independent set of 432 individuals with the same disease and the same treatment. In addition, nine tagging single nucleotide polymorphisms (tagSNPs) of RAD52 were genotyped by Sequenom Mass ARRAY methods in 939 SCLC patients with complete response evaluation. Logistic regression model and Cox proportional hazards regression model were used for the association analysis and survival analysis.Results:We found that rs6968202 G>C variation which in the intron of LINC01006 was significantly associated with the chemotherapy response. Compared with patients carrying G allele, patients carrying C allele had a better response and decreased the risk of no-responders (OR= 0.53,95% CI= 0.41-0.69, P= 1.59×10-6). Rs17129504, rs17574506 and rs10916317 variations were associated with patients overall survival in Cox proportional hazards regression model analysis. The hazard ratios (HRs) for patients with rs17129504 AC genotype and CC genotype were 1.27 (95% CI= 1.08-1.50, P= 0.0038) and 1.76 (95%CI= 1.33-2.33, P= 8.49×10-5) compared with the AA genotype. For rs17574506, the HRs for patients with CT and TT genotype were 1.51 (95% CI= 1.26-1.81, P= 9.85×10-6) and 1.66 (95% CI= 1.33-2.09, P= 9.85×10-6) compared with the CC genotype. The HRs for patients with rs10916317 GA and AA genotype were 1.36 (95% CI= 1.15-1.60, P= 2.68×10-4) and 1.45 (95% CI= 1.13-1.87, P= 0.0042) compared with the GG genotype. Meanwhile, rs77910142 A>T variation was associated with the progression free time and overal survival time (HR= 1.51,95% CI= 1.21-1.89, P= 2.80×10-4; HR= 1.38,95% CI= 1.09-1.74, P= 0.0072, respectively). In addition, we found that rs10774474 T>A variation in the 5’-flanking region of RAD52 was significantly associated with the chemotherapy response. Compared with the TT genotype, patients with TA or AA genotype had a worse chemotherapy response and increased the risk of no-responders (OR= 1.59,95% CI= 1.16-2.19, P= 0.0041).Conclusions:These results suggest that genetic variations of non-coding genes are associated with chemotherapy response or survival in SCLC patients receiving platinum-based chemotherapy. RAD52 genetic polymorphism rs10774474 plays an important role on the response to platinum-based chemotherapy. Together, our findings are of importance in better understanding of SCLC therapy and prognosis, and can provide certain data support for the follow-up molecular mechanism study. Furthermore, these identified genetic variations in non-coding region genes and RAD52 may have potential utility in personalized chemotherapy and clinical care of SCLC. |
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