| Background and objective:Multiple myeloma(MM)is the second most common hematologic malignancies just after lymphoma,which is characterized by the accumulation of malignant plasma cells in bone marrow microenvironment.And in blood or urine,the overproduction of monoclonal immunoglobulin and its fragment(M protein)which is secreted by plasma cells is associated with organ damage,called as CRAB signs.The treatment of MM in new era have changed with the introduction of proteasome inhibitors,immunomodulatory drugs,histone deacetylase inhibitors and monoclonal antibodies,which dramatically improved clinical outcomes of patients and significantly prolonged their survival time.However,MM is still an uncurable disease by so far,most patients eventually die of its progression and recurrence.To better predict the prognosis of the MM patients,IMWG revised International Staging System(ISS)for MM in 2015.They combined other clearly identified prognostic factors,such as chromosomal abnormalities and LDH with ISS,finally formed the new algorithm,the revised ISS(R-ISS).Besides,with the increasingly advances in molecular biological research of MM over recent years,more and more attention were paid to the potential significant prognostic biomarkers.Among the variety of types of DNA damage,the most deleterious is the DNA double-strand break(DSB),normal cells develop into cancer cells when the breaks are not repaired,or repaired improperly.?-H2 AX is an early indicator of DSB,gathered rapidly in the chromatin flanking DSB site once the breaks were occurred,and then the ?-H2 AX foci was formed,serving as a biomarker for aging and cancer.Some studies have verified that ?-H2 AX plays a key role in the progression of tumor proliferation,invasion and metastasis.Moreover,high level of ?-H2 AX expression is associated with poor clinical outcome for cancer patients,it might be used as a novel prognostic factor to evaluate patients' prognosis.Whether ?-H2 AX is highly expressed in the bone marrow of MM patients,and whether it is related to poor prognosis of the disease is not known as yet.Therefore,the main focus of our study is to investigate the expression of ?-H2 AX in the bone marrow and analyze the correlation between ?-H2 AX and the prognosis of patients with MM.Methods:1.Collecting and analyzing the general clinical,pathological and molecular cytogenetic data of newly diagnosed patients with MM from 1st,January,2012 to 31 th,December,2016 in Xijing Hospital.And the bone marrow biopsy specimens of non-hematologic malignancies were also collected as negative control group,which showed no obvious morphological abnormalities supported by the bone marrow smear examination.2.The expression of ?-H2 AX in bone marrow biopsies of cases and controls was detected via immunohistochemical staining.And Microscopic Imaging Amplification System was performed to observe the cellular localization of ?-H2 AX.The mean density(MD)of ?-H2 AX staining for each case was analyzed by image processing software of Image-Pro Plus,which was to quantify the expression of ?-H2 AX.3.According to the quantization results of ?-H2 AX staining in the previous step,we calculated the mean value of MD(`x±s)for all cases and controls respectively,and compared the differences of ?-H2 AX expression between the two groups.4.The patients with MM were divided into two groups according to the mean value of ?-H2 AX expression.Group1 was defined as strong expression of ?-H2 AX,when the results were greater than or equal to the mean value.While the other group was defined as weak expression based on the results which was under the mean level.The clinical and pathological characteristics were compared respectively between the two groups.And the association of ?-H2 AX expression with patients' prognosis was analyzed by the Kaplan-Meier(Log-rank test)for univariate survival analysis and Cox proportional hazard model for multivariate analysis.Results:1.A total of 102 MM patients were collected as the study cohort,and 32 cases as control group.The median age of MM patients was 56.5 years(range,32~77 years),and the male-female ratio was 1.49(61/41).IgG MM was still the most common type of MM,accounting for 41.2%(42/102)of the total cases.2.After 4 cycles of standard chemotherapy of initial treatment,the efficacy of chemotherapy treatment containing bortezomib was obviously better than the other agents(P<0.05).3.The mean value of MD for ?-H2 AX expression in case group was 6.78±3.47,and the control group was 1.10±0.83.Obviously,?-H2 AX expression among MM patients was significantly stronger than the controls(P<0.05).4.There were 49 cases which had strong expression of ?-H2 AX in MM patients,accounting for 48.0%,while 53 patients(52.0%)exhibited weak ?-H2 AX expression.The level of ?-H2 AX expression showed no significant association with any clinical or pathological characteristics of both groups,such as age,gender,the histopathological subtypes,the ISS stage or the results of FISH(P>0.05).And the survival time of MM patients showed significant correlation with ?-H2 AX expression,LDH,FISH results and the treatment effects(P<0.05).Moreover,the high expression of ?-H2 AX was closely related to the poor prognosis of MM patients(P<0.05).Conclusions:The results of our study showed that the level of ?-H2 AX expression was higher among MM patients compared with control group,and the over expression of ?-H2 AX in bone marrow was associated with poor clinical outcome of MM.However,whether ?-H2 AX could severe as a prognostic factor to predict MM patients' survival is still need to be confirmed by large prospective researches. |
PDF Full Text Request