| Purpose:Based on the high-throughput whole-exome sequencing technology to detect the normal cellular gene status of lung cancer patients treated with radiotherapy.Comprehensively detect the susceptibility genes associated with radiation pneumonia.Predict the risk of severe radiation pneumonitis,guide individualized radiotherapy,avoid or reduce radiation pneumonitis.Patients and methods:This study screened 1,027 patients with lung cancer who received radiotherapy from January 2013 to April 2017 in Shandong Cancer Hospital.The patients received regular follow-up and chest CT examination during radiotherapy and within6 months after radiotherapy.According to the CTCAE version 4.0,three radiation oncologists assessed and graded the radiation pneumonia,and recorded the patient's radiation dosimetry factors and clinical factors such as age,gender,KPS,smoking history,histological type,and tumor stage.Patients who received?60Gy of lung radiation without symptomatic radiation pneumonitis?RP 0-1?were included in the control group.Patients who received?66Gy of lung radiation with severe radiation pneumonitis?RP 3-5?were included in the susceptible group.5ml of blood samples were collected from the every patients,DNA was collected for exome sequencing,and gene differences between the two groups were analyzed.Results:77 patients were included in the genetic analysis of the susceptible group,with a median age of 62 years?40-79 years?and a median radiotherapy dose of 60Gy?40-66Gy?;76 patients were included in the gene analysis of the control group,with a median age of 59years?34-84 years?and a median radiotherapy dose of 60Gy?60-75Gy?.Cox univariate and multivariate analysis showed that?65 years was an independent risk factor for grade?3radiation pneumonitis.The whole exome sequencing results showed that there were 140significantly different mutation sites between the two groups,belonging to 85 genes.From the above,we chose a region with significant differences in the two or more analysis methods and the corresponding genome locations are more concentrated??3 sites with significant differences within 100Kb?as positive association regions.There are four,1)chr1:226550741?226589833,a total of 10 significant differences SNPs were observed,the most significant difference SNP is chr1:226576270?PARP1 rs2255403?,P=8.40×10-5;2)chr2:130897559-130948303,a total of 8 significant differences SNPs were observed,the mostsignificantSNPischr2:130930819?SMPD4rs2290295?,P=8.29×10-5;3)chr8:21954973-21965113,a total of 4 significant differences SNPs were observed,the most significant difference SNP is chr8:21955116?FAM160B2 rs11352?,P=1.95×10-4;4)chr19:50909389-50922370,a total of 4 significant differences SNPs were observed,the most significant difference SNP is chr19:50921272?POLD1 rs2445837?,P=1.14×10-4.A functional enrichment analysis was performed on all 85 genes.The results showed that the genes related to DNA repair have higher enrichment multiples and significant difference.The genes involved include PARP1,POLD1,RPS27L,SLK,and UPF1,in which PARP1 and POLD1 are located in the positive region of the above association analysis.Conclusions:1)The frequency of A allele in the PARP1 rs2255403 locus was 69.9%in the pneumonia group and 47.3%in the control group,indicating that PARP1 rs2255403AA/AG has a higher risk of severe radiation pneumonitis than GG.2)SMPD4 rs2290295pneumonia group 45 CC,32 TT/TC,TT/TC probability 41.6%,control group 66 CC,10TT/TC,TT/TC probability 13.2%,indicating SMPD4 rs2290295 TT/TC genotype There is a higher risk of severe radiation pneumonitis than the CC genotype.3)23 TT/TC,54 CCs in FAM160B2 rs11352 pneumonia group,and 70.1%in CC rate,5 TT/TC and 71 CCs in control group,and CC probability 93.4%,indicating that FAM160B2 rs11352 CC genotype ratio is higher than TT/TC genotype There is a lower risk of severe radiation pneumonitis.4)The T allele frequency of PLD1 rs2445837 locus was 92.9%in the pneumonia group and 78.3%in the control group,indicating that the POLD1 rs2445837 TT/TC has a higher risk of severe radiation pneumonitis than the CC.5)Age?65 years is an independent risk factor for severe radiation pneumonitis. |
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