Influencing Factors Of Quality Of Life And Survival Time Among Lung Cancer Patients Based On Single Nucleotide Polymorphisms

Objective: Lung cancer(LC)is the tumor with highest morbidity and mortality worldwide and in China.The majority of LC patients were diagnosed at advanced stage with poor prognosis and poor quality of life(Qo L).Therefore,the treatment goal for LC patients is not only to prolong survival time,but also to improve the quality of life.The influence factors of Qo L of LC patients are not entirely clear.Few previous studies focused on genetic factors affecting Qo L of LC patients.The objective of this research was to explore the association between single nucleotide polymorphisms(SNPs)of DNA repair genes(excision repair cross complementary gene 1 [ERCC1],excision repair cross complementary gene 2 [ERCC2],breast cancer susceptibility gene 1 [BRCA1])and subjective well-being related genes and the Qo L and survival of LC patients.Some potential factors such as demographic and sociological characteristics,clinical characteristics and cancer disclosure were also included in the study.Methods: In the first part of this study,EORTC QLQ-C30,QLQ-LC13,SAS and SDS were used to assess the Qo L and mental state of 291 patients with non-small cell lung cancer.Demographic and sociological characteristics,clinical characteristics and treatment history of the patients were investigated by questionnaires,and survival time was followed up.Twelve tag SNPs of ERCC1 gene,ERCC2 gene,and BRCA1 gene were calculated by haploview4.2software.The 12 tag SNPs,RAPGEF6 rs3756290 and CSE1 L rs2075677 were detected by i MLDR genotyping technology.The association between SNPs,haplotype and Qo L of LC patients was analyzed by ?2 test,ANOVA and regression analysis.Survival analysis was conducted by Kaplan-Meier method and Cox proportional hazards regression model.In the second part of this study,we explored the association between cancer diagnosis disclosure and the survival time of patients with LC based on baseline and follow-up information of a large sample including 29825 patients.Results:1.SNPs and haplotypes of DNA repair genes were related to different domains of QoL among LC patients.(1)After corrections for multiple testing and environmental factors,ERCC1 rs11615 was related to emotional function domain of Qo L among LC patients.Patients with ERCC1 rs11615 A allele had better emotional function(adjusted Beta = 6.85,95% CI = 2.38-11.31,Bofferoni adjusted P = 0.041).(2)ERCC1 rs762562-rs3212986 haplotype was associated with cognitive function,physical function and dysphagia.Compared with GC haplotype,patients with AA haplotype had worse cognitive function(Beta =-5.34,P= 0.029)and worse physical function(Beta =-5.89,P = 0.014),and severer dysphagia symptom(OR = 3.32,P = 0.044),which suggested that LC patients with ERCC1rs762562-rs3212986 AA haplotype had worse Qo L.(3)ERCC1 rs3212986-rs11615 haplotype was associated with emotional function,cognitive function,physical function,appetite loss and dysphagia.Compared with CG haplotype,patients with AG haplotype had worse cognitive function(Beta =-5.42,P = 0.028),worse physical function(Beta =-6.55,P =0.007),severer appetite loss(OR = 1.67,P = 0.025)and severer dysphagia(OR = 4.43,P =0.019),while patients with CA haplotype had better emotional function(Beta = 6.61,P =0.005),and milder dysphagia(OR = 0.035,P = 0.017).It suggested that patients with ERCC1rs3212986-rs11615 AG haplotype had poor Qo L,and patients with ERCC1rs3212986-rs11615 CA haplotype had good Qo L.(4)BRCA1rs1799966-rs3737559-rs8067269 haplotype was related to physical function,dyspnea and peripheral neuropathy.Compared with TCG haplotype,patients with CCA haplotype had better physical function(environmental correction Beta = 6.21,P = 0.010),while patients with CTA haplotype had severer dyspnea symptom(OR= 2.05,P = 0.031)and severer peripheral neuropathy symptom(environmental correction OR = 3.91,P = 0.030),which suggested that patients with CCA haplotype had better Qo L,and patients with CTA haplotype had worse Qo L.(5)ERCC2 rs13181-rs3916874-rs238416 haplotype was related to emotional function,pain in other parts,chest pain and dysphagia.Compared with TCT haplotype,patients with GCC haplotype had better emotional function(Beta = 7.60,P = 0.035),patients with TGC haplotype had milder chest pain(OR = 0.42,P = 0.02),while patients with TCC haplotype had severer pain in other parts(OR = 1.88,P = 0.014)and severer dysphagia(OR =2.82,P = 0.048).2.Education level,clinical stage,smoking and chemotherapy times were associated with different domains of Qo L of LC patients.The patients with higher education level had better global health status(standard Beta = 0.128,P = 0.029).However,the patients with higher education level had severer insomnia symptom than those with low education level(university level vs.primary/middle school level: 46.87 ± 34.76 vs.27.78 ± 30.40,P = 0.003).The advanced clinical stage was associated with severer nausea and vomiting symptom(standard Beta = 0.151,P = 0.010).Smoking increased the risk of chest pain(OR = 2.824,95% CI = 1.150-6.934,P = 0.024).The chemotherapy times was related to financial difficulty(standard Beta = 0.146,P = 0.013)and dysphagia(OR = 0.126,95% CI = 0.016-0.978,P =0.048).3.SNPs and Qo L had influence on anxiety and depression status of LC patients.(1)After corrections for multiple testing and environmental factors,ERCC1 rs3212986 was significantly associated with anxiety score.The anxiety score of ERCC1 rs3212986 CA and AA genotype was higher than that of CC genotype(adjusted Beta = 3.41,95% CI = 1.23-5.57,Bofferoni adjusted P = 0.032).(2)ERCC1 rs3212986-rs11615 haplotype was associated with anxiety score.Compared with CG haplotype,patients with CA haplotype had lower anxiety score(Beta =-2.25,P = 0.014;environmental factors adjusted Beta=-2.18,adjusted P =0.023),which suggested that patients with ERCC1 rs3212986-rs11615 CA haplotype had less anxiety.(3)ERCC2 rs13181-rs3916874-rs238416 haplotype was associated with anxiety state.Compared with TCT haplotype,the patients with GCC haplotype had lower risk of anxiety(OR = 0.28,P = 0.018,environmental factors adjusted OR = 0.23,adjusted P = 0.009).(4)Almost all domains of Qo L were significantly associated with anxiety and depression of LC patients(P < 0.05).Patients with better global health,better functional domains and lighter symptoms had lower anxiety and depression scores.It meant that patients with better Qo L had less anxiety and less depression.Logistic regression model showed that anxiety of LC patients was mainly affected by global health(OR = 0.482),emotional function(OR = 0.340),insomnia(OR = 3.110)and dysphagia(OR = 6.826).Depression of LC patients was mainly affected by global health(OR = 0.548),nausea and vomiting(OR = 2.371)and dysphagia(OR = 4.428,P < 0.05 for all).4.BRCA1 rs1799966,BRCA1 rs8067269,BRCA1 rs1799966-rs37559-rs8067269 haplotype,pain in other parts,clinical stage and age were significantly associated with survival time of LC patients(P < 0.05).The patients with BRCA1 rs1799966 CC genotype had longer survival time than those with TC and TT genotype(MST = 74.86,61.63,36.47,respectively,P < 0.05).The patients with BRCA1 rs8067269 AA genotype had longer survival time than those with GA and GG genotype(MST = 72.21,61.63,35.03,respectively,P<0.05).The patients with BRCA1 rs1799966-rs37559-rs8067269 CCA/CCA haplotype had significantly longer survival time than those with other haplotypes(P < 0.05).CCA/CCA haplotype was protective factor for LC survival(HR [95% CI] = 0.107 [0.015-0.770],P =0.026).Severe symptom of pain in other parts(HR [95% CI] = 1.770 [1.100-2.847],P =0.019),clinical stage III-IV(HR [95% CI] = 3.928 [1.422-10.846],P = 0.008),age ? 60 years(HR = 1.583,95% CI = 1.032-2.429,P = 0.035)were risk factors for survival time of LC patients.5.Knowing their cancer diagnosis contributed to longer survival time in patients with LC.Among 29825 registered LC patients,patients that knew their cancer diagnosis had longer survival time than those who did not(MST [95% CI]: 18.33 [17.60-19.07] vs.8.77[8.51-9.02],P < 0.001).Stratified by sex,age,pathological type,clinical stage,operation,hospital grade and occupational factors,patients that knew their cancer diagnosis had longer survival time in each subgroup(P<0.001,all subgroups).Cox regression analysis showed that knowing their cancer diagnosis was an independent influencing factor for survival in patients with LC(HR [95% CI] = 0.826 [0.802-0.851],P < 0.001).Conclusion: This study made clear the effect of SNPs and haplotypes of ERCC1,ERCC2 and BRCA1 gene on Qo L of LC patients for the first time.Combined with the impact of demographic and clinical characteristics on the prognosis of LC,the results are helpful to identify the patients at risk of poor Qo L and poor survival.In addition,Knowledge of cancer diagnoses may contribute to better survival in patients with LC in the long term.Psychological support and psychological intervention should be given more attention in clinical practice in order to improve Qo L and prognosis of LC patients.