Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1942-1949 ◽  
Author(s):  
Ivy H. N. Wong ◽  
Margaret H. L. Ng ◽  
Dolly P. Huang ◽  
Joseph C. K. Lee
Keyword(s):  
Promoter Methylation ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Methylation Status ◽  
Disease Stage ◽  
Acute Leukemias ◽  
Prognostic Implications ◽  
Methylation Patterns ◽  
First Time

Abstract We prospectively analyzed p15 and p16 promoter methylation patterns using methylation-specific polymerase chain reaction (PCR) in patients with adult and childhood acute leukemias and studied the association of methylation patterns with chromosomal abnormalities and prognostic variables. In nearly all French-American-British leukemia subtypes, we found p15methylation in bone marrow or peripheral blood cells from 58% (46/79) of patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute biphenotypic leukemia (ABL). An identical alteration was detected in blood plasma from 11 of 12 of these patients (92%). We also demonstrated for the first time concomitant p16and p15 methylation in 22% (8/37) of adults with AML or ALL, exclusively in those with M2, M4, or L2 subtypes. According to cytogenetic data from 35 patients with ALL, AML, or ABL, 82% (14/17) of those with unmethylated p15 alleles had normal karyotypes or hyperdiploidies associated with a favorable prognosis. Conversely, 44% (8/18) of patients with p15 methylation had chromosomal translocations, inversions, or deletions, suggesting an interplay of these abnormalities with p15 methylation. As a prognostic marker for disease monitoring, p15 methylation appears to be more widely applicable than BCR-ABL, AF4-MLL, andAML1-ETO transcripts, which were detectable in only 8% (4/48) of patients by reverse transcriptase-PCR. Thirty-nine of 43 blood samples (91%) sequentially collected from 12 patients with AML, ALL, or ABL showed p15 methylation status in excellent concordance with morphologic disease stage. Early detection of p15methylation at apparent remission or its acquisition during follow-up may prove valuable for predicting relapse. Overall survival of patients with p15 methylation was notably shortened among 38 adults with AML and 12 adults with ALL. Aberrant p15 methylation may have important prognostic implications for clinical monitoring and risk assessment.

scholarly journals Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 435-439 ◽  
Author(s):  
JA Fletcher ◽  
EA Lynch ◽  
VM Kimball ◽  
M Donnelly ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Intensive Treatment ◽  
First Remission ◽  
Prognostic Implications

Abstract The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)- positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

Co-Existence of Various Sub-Clones in TEL-AML1 Positive Acute Lymphoblastic Leukemia in Association with Sub-Microscopic Deletion of AML1.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1096-1096
Author(s):  
Amos Toren ◽  
Rachel Rothman ◽  
Bella Bielorai ◽  
Malka Reichart ◽  
Ninette Amariglio ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Gene Rearrangement ◽  
Chromosomal Abnormalities ◽  
Residual Disease ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Submicroscopic Deletion ◽  
Minimal Residual

Abstract The TEL/AML1 fusion gene is the most common gene rearrangement in pediatric acute lymphoblastic leukemia (ALL). Although considered to be a low risk leukemia it has a 20% risk of late relapse. The coexistence of different sub clones at diagnosis, based on polymerase chain reaction (PCR) studies of Ig/TCR gene rearrangement, was recently reported in this subtype of ALL. Their different response to chemotherapy may explain the emergence of certain sub clones at relapse, and may serve as a marker for minimal residual disease follow-up. Several chromosomal rearrangements such as t(9;22), t(8;21), inv(16) and rearrangements of the MLL gene are frequently associated with submicroscopic deletions and some of them have prognostic significance. Such deletions were not reported in t(12;21) positive ALL. Bone marrow cells from 76 pediatric patients with ALL at diagnosis were analyzed for the presence of the TEL/AML1 fusion gene by interphase fluorescence in situ hybridization (FISH). We used a new system of combined analysis enabling a very large-scale study of the cells of interest with regard to morphology, FISH and immunophenotyping. Fourteen patients were positive for the translocation. Four of them had several sub clones associated with various combinations of additional chromosomal abnormalities. The most striking was an atypical and unexpected hybridization pattern consistent with a submicroscopic deletion of the 5′ region of the AML1 breakpoint (intron2) not previously reported. We describe the use of a larger probe for AML1 (AML1/ETO) to exclude the possibility of insertion of TEL into the AML1 region without breakage and to reduce the false positivity due to optical fusion. This may enable a better monitoring of minimal residual disease in cases with submicroscopic deletion. All patients had some sub-clones with TEL deletion. Other abnormalities included trisomy and tetrasomy 21 as well as double TEL-AML1 fusion. The analysis of numerous sub-clones at presentation in these patients suggests clonal evolution at an early stage of the disease. These sub-clones may have different sensitivities to chemotherapy, and some of them may reappear at relapse. The frequency of AML1 deletion in t(12;21) in addition to other chromosomal abnormalities, is unknown. The involvement of these findings in the generation of leukemic sub clones, their prognostic significance and role in minimal residual disease follow-up deserves further studies in a large number of patients and a longer follow-up.

Post-Transplant Therapy Is More Important Than Induction Regimen Choice in Autologous Hematopoietic Cell Transplantation (AHCT) Recipients for Multiple Myeloma (MM)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 396-396 ◽  
Author(s):  
Robert Frank Cornell ◽  
Luciano J Costa ◽  
Adetola A. Kassim ◽  
Racquel Inns-Shelton ◽  
Amrita Krishnan ◽  
...  
Keyword(s):  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Chromosomal Abnormalities ◽  
Conditioning Regimen ◽  
Patient Characteristics ◽  
Chromosome 1 ◽  
Disease Stage ◽  
Similar Response ◽  
Induction Regimen

Abstract Background: Modern therapies incorporating bortezomib (V), lenalidomide (R), cyclophosphamide (C) and dexamethasone (D) constitute the most common doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens for transplant eligible MM in the US. These regimens produce an overall response rate of >80% but their impact on longer term post-AHCT outcomes are largely unknown. Patient and Methods: We evaluated the relative impact of pre- and post-AHCT treatment on 693 patients receiving upfront AHCT after induction with RD (178), VD (161), CVD (84) or VRD (270) using data prospectively reported to the CIBMTR from 2008-2013. Analysis was limited to those receiving one line of induction chemotherapy and a single transplant with 200 mg/m2 melphalan as conditioning regimen no later than 12 months from treatment initiation. Survival endpoints were evaluated from time of AHCT and the planned use of post-AHCT maintenance incorporating R or V was also considered. Results: The table shows patient characteristics. Median number of induction cycles were 4 (range, 2 to 16) and median time to transplant was 6.5 months. Median follow up was 36 months (3 to 82) from time of transplant. Age, disease stage, disease status at transplant and cytogenetic risk were similar between the 4 cohorts. Fourteen percent had high-risk chromosomal abnormalities [17pdel, t(4;14), t(14;16), chromosome 1 abnormalities and hypodiploidy]. CVD and VD were used more frequently in patients with renal failure. Doublet use was more common before 2010 (55%) and triplets after 2010 (85%). Use of R or V post-AHCT chemotherapy was higher in with VRD (79%) and CVD (81%) cohorts vs. RD (53%) and VD (67%). No differences in pre- or post-AHCT responses were seen with regard to choice of induction agents. Pre-AHCT responses ≥VGPR were 57% for VRD vs. 45/42/51% for CVD/RD/VD respectively. Corresponding post AHCT responses at day 100 were 65% for VRD and 58/63/65% respectively. In multivariate analysis of relapse, progression free (PFS) and overall survival (OS), there was no overall difference in these outcomes based on induction regimen. High risk cytogenetics (HR = 0.57, p=0.0004 for non-high risk) and absence of planned maintenance (HR=1.55, p=0.0008) were associated with higher risk of relapse. VRD was associated with a marginal benefit in relapse risk vs. CVD (HR=0.68, p=0.04). Non-relapse mortality was similar across cohorts. Those not receiving planned post-AHCT maintenance (HR 1.69, p<0.001) and high-risk MM had higher risk of progression/death (HR in non-high risk 0.58, p<0.001); OS was lower in those with low stage (DSS or ISS I/II) vs. stage III (HR 0.6, p=0.006) and with non-high risk cytogenetics (HR 0.5, p=0.001). Patients receiving planned post-AHCT therapy had significantly improved 3-year PFS vs. no post-AHCT therapy (55% vs. 39%, log-rank p=0.0001) (figure). Conclusions: Modern induction doublets and triplets induce similar response rates and post AHCT outcomes at a median follow-up of 36 mo. Although there is an increase in use of triplets after 2010 in transplant eligible patients, our analysis suggests that the choice of induction regimen is less important than the decision to use vs. not use planned post-AHCT maintenance therapy. Figure 1. Patient characteristics. Figure 1. Patient characteristics. Figure 2. PFS by planned post-AHCT therapy vs. not: Figure 2. PFS by planned post-AHCT therapy vs. not: Disclosures Krishnan: Janssen: Consultancy; BMS: Consultancy; Jazz: Consultancy; Millenium: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau. Gasparetto:Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Hari:Celgene: Consultancy; Takeda: Consultancy; BMS: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy.

scholarly journals Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia

Blood ◽  
1991 ◽  
Vol 77 (3) ◽  
pp. 435-439
Author(s):  
JA Fletcher ◽  
EA Lynch ◽  
VM Kimball ◽  
M Donnelly ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Bone Marrow Transplantation ◽  
Poor Prognosis ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Intensive Treatment ◽  
First Remission ◽  
Prognostic Implications

The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)- positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

scholarly journals Clinical Characteristics and Outcomes of Newly Diagnosed Patients with Adult T-Cell Acute Lymphoblastic Leukemia (T-ALL) and T-Lymphoblastic Lymphoma (T-LL) with Hypercvad Based Regimens

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2779-2779
Author(s):  
Preetesh Jain ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Rashmi Kanagal-Shamanna ◽  
Joseph D Khoury ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Patient Characteristics ◽  
Lymphoblastic Lymphoma ◽  
Survival Outcomes ◽  
Not Otherwise Specified ◽  
T Lymphoblastic Lymphoma

Abstract Introduction: T-cell ALL and T-LL are considered as different spectra of the same neoplastic clone. In various clinical trials of adult ALL, patients with T-ALL and T-LL were combined when analyzing treatment responses and survival outcomes. We have previously reported the results with HCVAD-based regimens in patients with adult ALL. In this study we addressed whether the initial presentation, treatment response, and survival outcomes of adults with T-LL and T-ALL differed when patients were uniformly treated with frontline HCVAD-based regimens at a single institution. Methods: One hundred and fifty previously untreated patients with T-LL (n=54) and T-ALL (n=96) who were treated with HCVAD-based regimens (1992-2016) were included in this analysis. Patient charts were reviewed for initial characteristics, treatment responses including minimal residual disease (MRD) status and survival outcomes; event free (EFS) and overall survival (OS) were analysed. Results: Among 150 patients with previously untreated adult T-ALL/LL, we identified 54 patients (36%) with T-LL and 96 (64 %) with T-ALL. Among patients with available immunophenotype data (n=104), early T precursor (ETP) phenotype was significantly more frequent among patients with T-ALL compared to patients with T-LL (44% vs 19%; p=0.006). The proportion of early, cortical and mature immunophenotype were 2% vs 6%, 31% vs 49% and 16% vs 12% in T-ALL versus T-LL, respectively. The clinical characteristics, response to therapy and outcomes of patients in T-LL versus T-ALL were compared (Table 1 and Figure-1). Patients with T-ALL were slightly older at presentation (median age 37 years [18-67] versus 31 years [17-78]; p=0.07). Patients with T-ALL had significantly higher white blood cell counts, peripheral blood blasts %, bone marrow blasts %, and serum LDH as compared to patients with T-LL. Distribution of chromosomal aberrations was significantly different among the two groups: Diploid karyotype was more commonly encountered in patients with T-LL while patients with T-ALL had more hyperdiploidy and hypodiploidy. Among patients evaluable for response, complete remission (CR) rates were 85% and 95% (p=0.002) in T-LL and T-ALL, respectively. Overall the median follow up times were 72 months (range, 5-243) and 61 months (range, 1-267). Thirty nine (72%) patients with T-LL and 43 (45%) with T-ALL were alive at the time of last follow-up. Patients with T-LL had better outcomes than patients with T-ALL. The 3-year EFS and OS rates were 78% and 74% in patients with T-LLand 53% (p=0.005) and 50% (p=0.001) in patients with T-ALL (Figure 1). Conclusions: In summary, adult patients with T-LL have better outcomes than patient with T-ALL after treatment with HCVAD-based regimens. Additional studies to characterize the genomic profile in tumoral tissues, as well as the pattern of relapses in patients with adult T-LL and T-ALL are ongoing. Table 1 Summary of patient characteristics according to initial diagnosis - T-lymphoblastic lymphoma (T-LL) vs. T-acute lymphoblastic leukemia (T-ALL) *104 patients had full immunophenotype for classification, nos - not otherwise specified, **On available cytogenetic data (47 in T-LL and 82 in T-ALL), of note 3 patients in T-LL and 22 in T-ALL have miscellaneous chromosomal abnormalities Table 1. Summary of patient characteristics according to initial diagnosis - T-lymphoblastic lymphoma (T-LL) vs. T-acute lymphoblastic leukemia (T-ALL). / *104 patients had full immunophenotype for classification, nos - not otherwise specified, **On available cytogenetic data (47 in T-LL and 82 in T-ALL), of note 3 patients in T-LL and 22 in T-ALL have miscellaneous chromosomal abnormalities Disclosures Konopleva: Calithera: Research Funding; Cellectis: Research Funding. Jain:Incyte: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Infinity: Research Funding; Novimmune: Consultancy, Honoraria; Abbvie: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; BMS: Research Funding. Wierda:Acerta: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

scholarly journals Reporting Subclonal Immunohistochemical Staining of Mismatch Repair Proteins in Endometrial Carcinoma in the Times of Ever-Changing Guidelines

2021 ◽  
Author(s):  
Ashley Scheiderer ◽  
Courtney Riedinger ◽  
Kristopher Kimball ◽  
Larry Kilgore ◽  
Amila Orucevic
Keyword(s):  
Genetic Testing ◽  
Endometrial Carcinoma ◽  
Mismatch Repair ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Nuclear Staining ◽  
Mlh1 Promoter ◽  
History Of ◽  
The Times

Context.— The current College of American Pathologists reporting guideline for mismatch repair protein (MMRP) immunohistochemistry for Lynch syndrome (LS) screening considers the presence of any positive nuclear staining as intact MMRP expression. This would include tumors with combined areas of subclonal retention and loss of MMRP staining. Objective.— To evaluate the clinical significance of reporting subclonal staining patterns of MMRP immunohistochemistry in endometrial carcinoma. Design.— We retrospectively reviewed 455 consecutive MMRP immunohistochemistry results of endometrial carcinoma in hysterectomy specimens from 2012 through 2017 and identified cases with subclonal MMRP staining. These results were correlated with the patient's personal and family history of LS-associated carcinoma, MLH1 promoter methylation status, and LS genetic testing. Results.— Subclonal staining of MMRP was seen in 48 of 455 cases (10.5%) on review. Thirty cases demonstrated isolated subclonal staining and were reported by pathologists as follows: subclonal (n = 5), complete MMRP loss (n = 4), and intact MMRP (n = 21). Eighteen cases had subclonal staining in combination with complete loss of other MMRP. Cases reported as subclonal or complete MMRP loss had appropriate clinical follow-up. Two of 2 cases with isolated subclonal MSH6 loss tested positive for LS. One of 3 cases with isolated subclonal MLH1/PMS2 loss was negative for MLH1 promoter methylation; LS genetic testing was not performed because of cost. Conclusions.— Our study reveals that LS germline mutation can be detected in endometrial carcinoma patients whose tumors display sole subclonal MMRP staining. Our results stress the importance of reporting subclonal staining patterns to ensure appropriate clinical follow-up.

scholarly journals Prognostic importance of structural chromosomal abnormalities in children with hyperdiploid (greater than 50 chromosomes) acute lymphoblastic leukemia

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1963-1967 ◽  
Author(s):  
CH Pui ◽  
SC Raimondi ◽  
RK Dodge ◽  
GK Rivera ◽  
LA Fuchs ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Treatment Failure ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Male Gender ◽  
Newly Diagnosed ◽  
Favorable Prognosis ◽  
Prognostic Importance ◽  
Predict Treatment Failure

Abstract Approximately one fourth of children with newly diagnosed acute lymphoblastic leukemia (ALL) have hyperdiploid (greater than 50 chromosomes) blasts and a relatively favorable prognosis. Nonetheless, a substantial proportion of these patients fail therapy. We studied 138 children (70 male, 68 female) with hyperdiploid greater than 50 ALL to assess initial clinical and cytogenetic features that might predict treatment failure. In 85 of these cases (62%), structural chromosomal abnormalities were also present; clinical and laboratory features in this group did not differ from those of the 53 cases with only numeric abnormalities. However, of the 28 failures seen at a median follow-up of 4 years, 22 occurred in cases with structural chromosomal abnormalities (P = .03 by Breslow test). In a multivariate analysis, only the presence of structural chromosomal abnormalities and male gender were independently associated with treatment failure. Structural chromosomal abnormalities in cases of ALL with greater than 50 chromosomes may define a biologically different form of leukemia characterized by increased likelihood of drug resistance.

Comprehensive Molecular Profiling of T-Cell Acute Lymphoblastic Leukemia Identifies Mutations in 76 (97.4%) of 78 Patients

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2548-2548
Author(s):  
Vera Grossmann ◽  
Alexander Kohlmann ◽  
Sandra Weissmann ◽  
Susanne Schnittger ◽  
Valentina Artusi ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Methylation Status ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Employment Equity ◽  
Equity Ownership

Abstract Abstract 2548 Introduction: At present, the diagnosis of T-ALL is based on immunophenotyping and specific chromosomal rearrangements. However, the knowledge about recurrent somatic mutations is limited. Patients and Methods: We studied a cohort of 78 adult T-ALL cases (n=33 early, n=33 cortical, n=2 mature T-ALL, n=10 subtype not available), including 57 males and 21 females. Age ranged from 18.8–87.7 yrs (median: 42 yrs). A deep-sequencing assay was used to investigate for specific molecular alterations in genes involved in transcriptional regulation: NOTCH1, FBXW7, CDKN2A, DNMT3A, FLT3-ITD, FLT3-TKD, NPM1, PTEN, and RUNX1. Further, chromosome banding analysis and FISH with probes for DNMT3A (2p23), SEC63 (6q21), MYB (6q23), CDKN2A (9p21), PTEN (10q23), CDKN1B (12p13) and TP53 (17p13), as well as CDKN2B promoter methylation analyses were performed. Results: Cytogenetic data was available in 68 patients: normal karyotype: n=22 (2 of these harbored a PICALM-MLLT10-rearrangement), SIL-TAL1-rearrangement: n=3, t(5;14)(q35;q32): n=2, t(10;14)(q24;q11)/t(7;10)(q34;q24): n=9, t(10;11)(p13;q21): n=3, other abnormalities n=29. Importantly, molecular mutations were detected in 67/78 patients (85.6%). In detail, NOTCH1 was the most frequently mutated gene (55/77 cases, 71.4%). Other alterations were detected in DNMT3A (16/78; 20.5%); RUNX1 (13/78; 16.6%); FBXW7 (11/75; 14.6%); PTEN (7/78; 10.0%); CDKN2A (3/58; 5.2%); FLT3-ITD (2/78; 2.5%); and FLT3-TKD (1/70; 1.4%). By FISH analyses, heterozygous deletions of the following loci were observed: DNMT3A (1/43; 2.3%), SEC63 (7/43; 16.3%), PTEN (1/32, 3.1%), CDKN1B (8/43; 18.6%) and TP53 (3/43; 7.0%). CDKN2A deletions were detected in 30/72 (41.6%) cases: n=14 heterozygous, n=15 homozygous, n=1 showed a clone with a heterozygous and a subclone with a homozygous deletion. Further, the CDKN2B promoter methylation status was analyzed. Here, 36/74 (48.6%) cases demonstrated hypermethylation. As such, when combining molecular mutations, CDKN2A deletions, and CDKN2B hypermethylation, in median 2 alterations per case were observed (range 1–5). Moreover, almost every patient (76/78) harbored at least one aberration resulting in a mutation rate of 97.4%. Interestingly, considering alterations in the group of cyclin-dependent kinase inhibitors (CDKN2A/1B deletions, CDKN2A mutations, and CDKN2B hypermethylation), 61/78 (78.2%) cases carried at least one such alteration. With respect to associations amongst molecular mutations, no specific pattern was observed except for a strong correlation between RUNX1 and DNMT3A mutations, i.e. 6/13 RUNX1 mutated cases concomitantly harbored DNMT3A mutations (p=0.021). Furthermore, we observed that DNMT3A and RUNX1 alterations were associated with higher age (DNMT3A: mean±SD 60.9±16 vs. 39.6±16 years; p<0.001; RUNX1: mean±SD 55.4±18 vs. 41.7±18 yrs; p=0.013) whereas PTENmut were associated with younger age (mean±SD 32.9±10 vs. 45.0±19 yrs; p=0.019). With regard to cytogenetics, DNMT3A was significantly correlated with normal karyotype (9/23, 39.1% vs. 6/45, 13.3%; p=0.028). Moreover, RUNX1mut were associated with lower WBC count (mean±SD 26.4±41 vs. 63.4±90 cell count G/L; p=0.025). With respect to immunophenotypes, cases with RUNX1mut showed a trend to be associated with early T-ALLs (9/23, 39.1% vs. 6/45, 13.3%; p=0.082). CDKN2B hypermethylation was significantly correlated with early T-ALLs (21/32, 65.6% vs. 10/31, 32.2%; p=0.012). In contrast, FBXW7mut were associated with the cortical subgroup (1/32, 3.1% vs. 9/32, 28.1%; p=0.013). With regard to clinical outcome, patients with RUNX1mut had a shorter overall survival (OS) compared to RUNX1wt patients (alive at 2 yrs: 44.4% mutated vs. 64.0% wild-type, p=0.011). Further, for NOTCH1mut cases (alive at 2 yrs: 67.4% mutated vs. 33.6% wild-type, p=0.060) a trend towards a better OS was detectable. Conclusions: 1. T-ALL is characterized by a high number of genetic alterations since 46/68 (67.6%) showed cytogenetic aberrations. In addition, at least one molecular alteration was observed in 76/78 (97.4%) patients. 2. The most frequent alterations observed were mutations in NOTCH1, DNMT3A, RUNX1 and FBXW7. 3. The cyclin-dependent kinase inhibitors were altered by deletion, mutation or hypermethylation in 78.2% of cases. 4. RUNX1 mutations are associated with shorter and NOTCH1 mutations with longer OS. Disclosures: Grossmann: MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Weissmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Artusi:MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Stadler:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Cohesin RAD21 Gene Promoter Methylation in Patients with Chronic Lymphocytic Leukemia

2018 ◽  
Vol 154 (3) ◽  
pp. 126-131 ◽  
Author(s):  
Agapi Ioannidou ◽  
Sophia Zachaki ◽  
Maria Karakosta ◽  
Aggeliki Daraki ◽  
Paraskevi Roussou ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Promoter Methylation ◽  
Chromosomal Abnormalities ◽  
Methylation Status ◽  
Cpg Islands ◽  
Gene Promoter ◽  
Common Type ◽  
Lymphocytic Leukemia ◽  
Cytogenetic Abnormalities ◽  
Epigenetic Processes

Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and is characterized by the presence of specific cytogenetic abnormalities. CLL research has been focused on epigenetic processes like gene promoter methylation of CpG islands. In the present study, the methylation status of the RAD21 gene is studied and associated with cytogenetic findings in CLL patients in order to investigate its possible implication in CLL pathogenesis and the formation of CLL chromosomal abnormalities.

scholarly journals Promoter Methylation and mRNA Expression of Response Gene to Complement 32 in Breast Carcinoma

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Ebrahim Eskandari-Nasab ◽  
Mohammad Hashemi ◽  
Firoozeh Rafighdoost
Keyword(s):  
Mrna Expression ◽  
Promoter Methylation ◽  
Methylation Status ◽  
Methylation Pattern ◽  
Response Gene ◽  
Expression Levels ◽  
Promoter Methylation Status ◽  
Normal Tissues ◽  
A Cell ◽  
Methylation Patterns

Background. Response gene to complement 32 (RGC32), induced by activation of complements, has been characterized as a cell cycle regulator; however, its role in carcinogenesis is still controversial. In the present study we comparedRGC32promoter methylation patterns and mRNA expression in breast cancerous tissues and adjacent normal tissues.Materials and Methods. Sixty-three breast cancer tissues and 63 adjacent nonneoplastic tissues were included in our study.Design. Nested methylation-specific polymerase chain reaction (Nested-MSP) and quantitative PCR (qPCR) were used to determineRGC32promoter methylation status and its mRNA expression levels, respectively.Results. RGC32 methylation pattern was not different between breast cancerous tissue and adjacent nonneoplastic tissue (OR = 2.30, 95% CI = 0.95–5.54). However, qPCR analysis displayed higher levels ofRGC32mRNA in breast cancerous tissues than in noncancerous tissues (1.073 versus 0.959;P=0.001), irrespective of the promoter methylation status. The expression levels and promoter methylation ofRGC32were not correlated with any of patients’ clinical characteristics (P>0.05).Conclusion. Our findings confirmed upregulation of RGC32 in breast cancerous tumors, but it was not associated with promoter methylation patterns.

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