| Purposes:The aims of this study are to investigate the characteristics and prognosis of1p12,1p13.3,1p21.2and1p32.3cytogenetic aberrations in plasma cell tumors of various disease states and to explore clinical detection indicators suitable for1p in MM patients to better guide clinical diagnosis and treatment, and to complement the genetics prognostic datas of our lymphoma center, to provide the basis for establish genetics prognostic stratification standards and individualized treatment system suitable for patients in china.Methods:I-FISH was performed on purified138+plasma cells from265newly diagnosed,90relapsed/refractory MM patients,56CR/PR/VGPR,5pPCL,7sPCL and2MGUS patients by using probes covered1p12,1p13.3,1p21.2and1p32.3regions that contain the FAM46C,AHCYL1,HCDC14A and CDKN2C genes. Cut off value is10%. The features of1p cytogenetic abnormalities in various disease states of plasma cell disorders, clinical relevance and prognostic significance were analysed in myeloma patients.Results:(1) The deletion rates of1p12,1p13.3,1p21.2and1p32.3were13.0%,18.7%,20.8%and9.06%in newly diagnosed MM patients,16.7%,15.2%,23.3%and10.0%in relapsed/refractory patients,28.6%,42.9%,57.1%and57.1%%in sPCL Patients,5pPCL and2MGUS patients did not detect del(1p), The del(1p) rates of sPCL were higher than newly diagnosed MM patients(P=0.239,0.019,0.022,0.000), but no difference between newly diagnosed and relapsed/refractory patients. Some patients had amplication of1p with amp rate of3.04%,2.60%,3.77%and4.15%in1p12,1p13.3,1p21.2,1p32.3, the rates of amplication were significant lower than the rates of deletion(P=0.000,0.000,0.000,0.021).(2)230previously untreated patients patients were detected4loci in1p.57patients existed at least one or more loci deletions, the rate of1p deletion was24.8%, with the percentage of one locus deletion patients accounting for26.3%,22.8%with two loci loss,35.1%with three loci loss,15.8%with four loci loss.The percentage of two or more loci deletion patients accounted for73.7%. The different loci of1p in the same patients can coexist several genetic abnormalities, such as deletion and normal, ampliation and normal, deletion and ampliation, deletion and deletion, amplication and amplication. The percentage of deletion cell in four loci of1p showed significantly positive correlation (P=0.000).(3) Patients with del(1p21,1p32.3and1p13.3) had more deletion rate of del(13q14)(P=0.023,0.033,0.01),1p12,1p13.3,1p21.2,1p32.3deletion were positivly correlated with hige LDH (>220U/L)(P=0.029,0.034,0.026,0.012).1p12,1p13.3,1p21.2deletion were positivly correlated with high percentage of plsma in bone Marrow (P=0.009,0.003,0.001).(4) The results of survival analysis showed the time of PFS and OS were shorter in del (1p) patients compared to patients without del(1p)(P<0.05) in newly diagnosed patients receiving thalidomide-based chemotherapy, but no difference in patients receiving bortezomib-based chemotherapy. In Ip21.2and1p32.3deletion patients, bortezomib-based chemotherapy can improve PFS and OS time of the patients, but not in patients with Ip12and1p13.3deletion.(5) Univariate analysis showed newly diagnosed thalidomide-based chemotherapy group patients with complex karyotype, LDH≥220U/L, del(17p13) and del(1p) had shorter PFS (P=0.005,0.015,0.000,0.002) and OS time(P=0.001,0.003,0.001,0.000). Multivariate analysis showed del(1p) and del(17p13) were independent poor prognostic factors to influence PFS (HR:3.633,95.0%Cl:1.270-10.391, P=0.016; HR:6.189,95.0%Cl:1.122-34.144, P=0.036) and del(1p) was independent poor prognostic factor to influence OS (HR:4.536,95.0%Cl:1.562-13.169, P=0.005).(6) Relapsed/refractory patients with1p21.2deletion had shorter PFS and OS (P=0.025,0.001) and patients with1p13.3had shorter OS (P=0.003), bortezomib-based chemotherapy can improve OS time of the del(1p21.2) patients(P=0.034), but no PFS time (P=0.258).(7) Univariate analysis showed high LDH, extramedullary infiltration were Influencing factors of PFS and OS in relapsed/refractory patients, multivariate analysis showed Del (1p21.2) and high LDH were independent poor prognostic factors to influence PFS (P=0.024,0.001) and OS (P=0.019,0.019), but del (1p13.3) have no independent prognostic significance in multivariate analysis.Conclusion:(1) Chromosome1p abnormalities are complex, various in forms, mainly large size of deletion, rarely amplification.(2) There was no significant difference in deletion rate and the percentage of deletion cells in different states of MM. The deletion rates of sPCL were higher than newly diagnosed MM patients.(3) The percentage of deletion cell in four loci of1p showed significantly positive correlation. Patients with1p13.3,1p21.2,1p32.3deletion had more del(13q14), high LDH(1p12,1p13.3,1p21.2,1p32.3deletion) and more patients with1p12,1p13.3,1p21.2deletion had percentage of plsma in bone marrow≥50%.(4) In newly diagnosed patients receiving thalidomide-based chemotherapy, the time of PFS and OS were shorter in del (1p) patients. Bortezomib-based chemotherapy can improve PFS and OS time of the patients, but not in patients with1p12and Ip13.3deletion. Multivariate analysis showed del(1p)and del(17p13) were independent poor prognostic factors to influence PFS and del(1p) was independent poor prognostic factor to influence OS.(5) Relapsed/refractory patients receiving thalidomide-based chemotherapy with1p21.2and1p13.3deletion had poor prognosis, bortezomib-based chemotherapy can improve OS time of the del(1p21.2) patients. Multivariate analysis showed del(1p21.2) and high LDH were independent poor prognostic factors to influence PFS and OS, but del(1p13.3) had no independent prognostic significance in multivariate analysis.(6) We think untreated patients should be routinely detected the1p21.2locus or/1p21.2and1p32.3two loci. Relapsed/refractory patients should be routinely detected1p21.2locus. Purposes:Multiple myeloma (MM) is an incurable plasma cell malignancy with complex genetic alterations. Cytogenetic abnormalities are well established as the most important prognostic parameter and are used for stratification and treatment decisions in MM.Our objective was to search for the features of12p13.31cytogenetic aberrations and its prognosis in MM patients and to complement the genetics prognostic datas of our lymphoma center, to provide the basis for establish genetics prognostic stratification standards and individualized treatment system suitable for patients in china.Methods:I-FISH was performed on purified138+plasma cells from265newly diagnosed,90relapsed/refractory MM patients,64CR/PR/VGPR,6pPCL,8sPCL and2MGUS patients by using probe covered12p13.31region that contains the CD27gene. Cut off value is10%. The features of12p13.31cytogenetic abnormalities in various disease states of plasma cell disorders, clinical relevance and prognostic significance were analysed in myeloma patients.Results:(1) The deletion rate of12p13.31was10.9%in newly diagnosed MM patients,14.4%in relapsed/refractory patients,10.5%in PR patients,5%in CR/VGPR patients,33.3%in sPCL Patients,8pPCL and2MGUS patients did not be detected del(12p13.31). There was no significant difference in patients with different disease states (P≥0.05). We also detected amp(12p13.31) in some patients, the amplication rate of12p13.31was4.5%in newly diagnosed MM patients,11.1%in relapsed/refractory patients with higher amplication rate compared to newly diagnosed MM patients (P=0.025).(2) We analysed the correlation between12p13.31deletion and various clinical indicators in newly diagnosed patients, the results showed12p13.31deletion was positively correlated with some high tumor burden clinical indicators:Cr≥177μmol/L (P=0.038),β2-mg≥5.5mg/dL (P=0.007), ISS-Ⅲ (P=0.009), high expression of cytokines IL-2(P=0.000), IL-4(P=0.012) and IL-6(P=0.012). (3) The results of survival analysis showed the time of PFS (12±4.33:23±2.36months) and OS (12±7.34:37.5±7.37months) were shorter in del (12p13.31) patients compared to patients without del(12p13.31)(P=0.025,0.007) in newly diagnosed patients receiving thalidomide-based chemotherapy, but no difference in patients receiving bortezomib-based chemotherapy with PFS (14±5.06:24±5.46months) and OS (23.5±3.75:54±18.35months) in del(12p13.31) and without del(12p13.31) patients (P=0.324,0.151). In25del(12p13.31) patients, the median PFS and OS were14±5.51:12±4.32months,24±3.67:12±7.34months in patients reveiving treatment of thalidomide-based and bortezomib-based chemotherapy, the difference was not statistically significant (P=0.672,0.411). But in bortezomib group, patients with del(12p13.31) had more VGPR therpy efficacy (50%:23.1%) and longer OS time(24±3.67:12±7.34months). So we think that bortezomib can partly improve OS time and therpy efficacy of the patients with del(12p13.31).(4) Patients with del(12p13.31)and hige LDH (≥220U/L), high β2-MG (≥5.5mg/dL) and pathologic fracture had shorter PFS (1.0,12.0and1.0months) and OS (2.0,23.5and1.0months) time compared to patients with del(12p13.31), high LDH or high β2-MG or pathologic fracture alone or without such abnormalities.(5) Univariate analysis showed newly diagnosed thalidomide-based chemotherapy group patients with complex karyotype, LDH≥220U/L, del(17p13) and del(12p13.31) had shorter PFS (P=0.005,0.015,0.000,0.025) and OS (P=0.001,0.003,0.001,0.007) time.But multivariate analysis showed del(12p13.31) was not an independent poor prognostic factor in previously untreated thalidomide group patients and del(17pl3) was an sole independent poor prognostic factor to influence PFS (HR:6.743,95.0%Cl:2.055-22.123, P=0.002) and OS (HR:3.989,95.0%Cl:1.218-13.06, P=0.022).(6)12p13.31deletion had no correlation with various clinical indicators in relapsed/refractory patients, the results of survival analysis showed patients with del(12p13.31) had shorter PFS (4.5±2.62months) time than patients without del(12p13.31)(14±2.87months)(P=0.009). But no difference in OS. Multivariate analysis showed high LDH was the sole influence factor of PFS, high LDH and extramedullary infiltration were independent influence factors of OS in relapsed/refractory patients. (7)12p13.31amplication had no correlation with various clinical indicators and no prognosis significance in previously untreated and relapsed/refractory patients.Conclusion:(1) Del(12p13.31) and amp(12p13.31) can also be detected in MM patients, mainly deletion, relapsed/refractory patients had higher amplication rate than previously untreated patients,but no defference in deletion rate.(2)12p13.31deletion was positively correlated with some high tumor burden clinical indicators:Cr≥177μmol/L (P=0.038),02-mg≥5.5mg/dL (P=0.007), ISS-Ⅲ(P=0.009), high expression of cytokines IL-2(P=0.000), IL-4(P=0.012) and IL-6(P=0.012).(3) Del (12p13.31) was an poor prognosis factor in newly diagnosed patients receiving thalidomide-based chemotherapy, but multivariate analysis showed del(12p13.31) was not independent poor prognostic factor and del(17p13) was an sole independent poor prognostic factor to influence PFS and OS.(4) Patients with del(12p13.31) and hige LDH(≥220U/L), high β2-MG(≥5.5mg/dL) and pathologic fracture had poor prognosis compared to patients with del(12p13.31), high LDH or high β2-MG or pathologic fracture alone or without such abnormalities.(5) Patients with del(12p13.31) had shorter PFS time than patients without del(12p13.31)(P=0.009) in relapsed/refractory MM patients. But no difference in OS.(6)Bortezomib can partly improve therpy efficacy and OS time of the patients with del(12p13.31).(7)12p13.31amplication had no correlation with various clinical indicators and no prognosis significance in previously untreated and relapsed/refractory patients. |
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