Prognosis Of AhR/ARNT In The Treatment Of Diffuse Large B-cell Lymphoma With Rituximab

Background and purpose:Diffuse large B-cell lymphoma(DLBCL)is one of the most common non-Hodgkin's lymphomas.Although the advent of rituximab has greatly improved its prognosis,it still has about 30%-40% of patients have a poor prognosis.More and more data indicate that DLBCL has different responsiveness to chemotherapy when clinical characteristics,pathological data,and staging are the same.For this kind of heterogeneous disease It is a new molecule that should be explored in our clinical work to propose new molecules that can predict the tumor burden of disease prognosis or predict prognosis.Here,we sought to identify potential biomarkers that might predict the outcome of diffuse large B-cell lymphoma.The AhR(aryl hydrocarbon receptor)and ARNT(aryl hydrocarbon receptor nuclear)studied in this paper are two key markers.The AhR and ARNT explored in this study belong to the PAS subfamily.It is reported in the literature that the activation of AhR and ARNT is closely related to the occurrence of malignant tumors,and it is related to kidney cancer,colorectal cancer,stomach cancer,breast cancer,endometrial cancer and lymphoma,etc.have been reported.This study focused on the relationship between the expression of AhR and ARNT and the prognosis of diffuse large B-cell lymphoma treated with rituximab.Methods:Retrospective analysis of clinical data of 93 patients with lymph node DLBCL who received rituximab in the Cancer Center of Bethune First Hospital of Jilin University from January 2010 to June 2018.The expression of AhR and ARNT protein was detected by immunohistochemistry.Happening.The correlation between the clinical features and the clinical features was analyzed by ?2 test or Fisher's exact probability method,and the effect on survival was determined by Kaplan-Meier curve.Results:1.Expression of AhR and ARNT: In 93 patients with DLBCL who received rituximab,according to the ROC(receiver operating characteristic curve)curve,the positive expression threshold of AhR and ARNT protein was 80%,then the high expression of AhR was(? There were 26 cases(28%),67 cases(72%)with low expression of AhR(<80%),56 cases(60.2%)with high expression of ARNT(?80%),and low expression of ARNT(<80%)There were 37 cases(39.8%).2.Relationship between AhR and ARNT and clinical features:(1)AhR expression was significantly associated with Bcl-6.In Bcl-6 positive patients,AhR was highly expressed(?80%)in 24 cases(92.3%),low expression(<80%)in 48 cases.(71.6%),suggesting that high expression of AhR is more common in patients with Bcl-6 positive(P=0.032).(2)ARNT expression was significantly associated with gender.In male patients,ARNT was highly expressed(?80%)in 36 cases(64.2%),and low expression(<80%)in 15 cases(40.5%),suggesting that ARNT high expression is more common in male patients.(P=0.024).(3)ARNT expression was significantly associated with lactate dehydrogenase.In patients with elevated lactate dehydrogenase,ARNT was highly expressed(?80%)in 41(73.2%),low expression(<80%)in 15(41.7%),suggesting High expression of ARNT was more common in patients with elevated lactate dehydrogenase(P=0.002).(4)ARNT expression was significantly associated with IPI score.In patients with high IPI score(>2),ARNT was highly expressed(?80%)in 25 cases(46.3%),low expression(<80%)in 9 cases(24.3%),suggesting ARNT High expression was more common in patients with high IPI scores(P=0.033).(5)ARNT expression was significantly associated with MUM-1.In MUM-1 positive patients,ARNT was highly expressed(?80%)in 50(89.3%),low expression(<80%)in 27(73%),suggesting high ARNT expression.More common in patients with MUM-1 positive(P=0.041).(6)ARNT expression was significantly associated with Ki67.In Ki67-positive(?90%)patients,ARNT was highly expressed(?80%)in 24 cases(42.9%),low expression(<80%)in 6 cases(16.2%),suggesting that ARNT was high.The expression was more common in patients with Ki67 positive(?90%)(P=0.007).3.AhR,ARNT and survival: the high expression of AhR(?80%)group was significantly shorter than the control group(AhR<80%),which was 46.0 months and not reached(HR=0.458 [0.169-0.920],P=0.034);ARNT high expression(?80%)group mPFS also showed a shorter trend than the control group(50.0 months and did not reach),but the difference between the groups was not statistically significant(HR=0.650 [0.314-1.359],P=0.260).In the subgroup analysis,high expression of AhR(?80%)was a poor prognostic factor for the prognosis of PDL(PFS)with CR(P=0.652,P=0.002)after 4 courses of treatment;high expression of AhR in the GCB subgroup(?80%)The median PFS was significantly worse in the control group(P=0.044),but no similar results were found in the non-GCB group(P=0.139);in addition,in the subgroup analysis of the combined Bcl-2,AhR High expression(?80%)masked the adverse effects of Bcl-2 expression on DLBCL prognosis(PFS)(P=0.650,P=0.036),suggesting that the presence of high expression of AhR(?80%)may impair Bcl-2 Prognostic value.No similar results were observed in the ARNT subgroup analysis,but found that 78.6% and 64.3% of patients with Bcl-2 and low expression(<80%)ARNT had lower PFS and OS than Bcl-2 and ARNT,respectively.The median value of the expression group suggests that ARNT may have important prognostic value independent of Bcl-2.4.Multivariate analysis of prognosis of AhR and ARNT: Whether high expression of AhR and ARNT(?80%)combined with the following factors(including age,gender,serum LDH level,B symptoms,large mass ?5cm,IPI score,CR status after 4 courses)In COX multivariate analysis,AhR and ARNT were not able to independently affect PFS(HR = 0.529 95% CI [0.224-1.245],P = 0.145;HR = 1.145 95% CI [0.486-2.698],P = 0.757)and Prognostic factors for OS(HR = 0.328 95% CI [0.082-1.306],P = 0.114;HR = 0.663 95% CI [0.164-2.685],P = 0.565).Results showed IPI score > 2 points,4 courses After CR was able to independently affect PFS in patients with this group of DLBCL(HR = 0.122 95% CI [0.048-0.312],P = 0.000;HR = 4.777 95% CI [1.889-12.082],P = 0.001)and OS(HR = Independent prognostic factors were 0.059 95% CI [0.01-0.357],P = 0.002;HR = 14.506 95% CI [1.647-127.78],P = 0.016).Conclusion:1.AhR is closely related to ARNT expression,and high expression of both may be a poor prognostic factor in patients with DLBCL.2.High expression of ARNT is closely related to elevated serum LDH,IPI score > 2 points and high expression of Ki-67,suggesting that high expression of ARNT may affect the long-term prognosis of patients by increasing tumor burden.3.High expression of AhR is a poor prognostic factor(PFS)that is independent of GCB subtype,Ki-67 negative,Bcl-2 negative,etc.,while adverse effects of high ARNT expression on prognosis(PFS)are independent of Ki-67 negative patients.