Absence Of Monosomy Research Articles

Predictive and Prognostic Markers in Adults With Acute Myeloid Leukemia: A Single-Institution Experience

BackgroundAcute myeloid leukemia (AML) is a heterogeneous malignancy with diverse genetic abnormalities, clinical presentations, and outcomes. Known predictive and prognostic factors in AML include age, performance status, comorbidities, cytogenetics, and molecular mutations. Identifying prognostic and predictive factors can inform the choice of induction therapy and outcomes prediction. Patients and MethodsA retrospective review was performed of 137 adult AML patients from 2010 to 2015. Predictors of complete remission (CR) and overall survival (OS) were determined for patients treated with 3+7 (3 days of anthracycline and 7 days of cytarabine) or hypomethylating agent. Variables associated with CR or OS were assessed using univariate Cox regression and a multivariate Cox model. ResultsThe average age was 65 years and 91 patients (66%), sample size is 137 patients had primary AML. Patients in the 3+7 induction group were younger, had a higher bone marrow blast percentage, and more de novo AML compared with those in the hypomethylating agent group (P < .001, P < .001, P = .005, respectively). Univariate logistic regression for CR showed a significant association between age (P < .001), choice of induction (P < .001), and monosomy (P = .015), although only induction with 3+7 (P < .001) and absence of monosomy (P = .042) remained significant in multivariate analysis. Univariate Cox regression indicated that age (P = .003), AML status (de novo or secondary; P = .0277), choice of induction (P = .030), and monosomy (P = .010) had a significant association with OS. Only younger age (P = .018) and absence of monosomy (P = .022) were predictive of OS in multivariate Cox analysis. ConclusionPositive predictors of CR in adult AML include absence of monosomy and induction treatment with 3+7; whereas positive predictors of OS are younger age and absence of monosomy.

MEDU-38. NEXT GENERATION MOLECULAR CHARACTERIZATION OF LOCALLY RECURRENT WNT PATHWAY MEDULLOBLASTOMA: A CASE REPORT

Abstract BACKGROUND: Wnt pathway medulloblastoma has high relapse-free survival following standard cranio-spinal irradiation with primary site boost and adjuvant chemotherapy. However, rare patients do develop recurrences. We report a case with comprehensive molecular characterization of both initial and recurrent tumor. CASE REPORT: A seven year old girl had local recurrence of a gross totally resected non-metastatic classic Wnt pathway medulloblastoma, 21 months after receiving 18Gy craniospinal irradiation with primary site boost to 54Gy, with weekly vincristine, followed by a modified maintenance chemotherapy regimen including 9 cycles of vincristine, temozolomide, oral etoposide, alternating with vincristine and carboplatin or cyclophosphamide. The original tumor was YAP-1 and nuclear beta-catenin positive, GAB1 and monosomy 6 negative, cmyc and nmyc non-amplified. Rare tumor cells were noted to be HMB45 or desmin and/or myogenin positive. The recurrent lesion demonstrated classic Wnt pathway medulloblastoma without HMB45 or desmin reactivity or monosomy 6. The child has since received marrow-ablative thiotepa and carboplatin with autologous stem cell rescue. Analysis of both initial and recurrent tumors was performed using Illumina Human Methylation 850K Array. Mutational analysis on tumor DNA was performed via NextGen sequencing on Illumina NextGen platform for 130 brain tumor-related genes. DNA methylation profile of the recurrent tumor demonstrated classic medulloblastoma, Wnt activated. A copy number profile demonstrated several chromosomal aberrations without amplifications. MGMT promoter was unmethylated, while the gene panel sequencing revealed a variant in CTNNB1 (same as the original tumor). Germ line analyses are pending. CONCLUSION: The absence of monosomy 6 in the face of CTNNB1 mutation may highlight a worse prognostic variant of Wnt pathway medulloblastoma. The presence of melanocytic and/or rhabdomyoblastic markers by IHC may also indicate a less optimal prognosis even amongst Wnt pathway activated medulloblastoma.

Acute Lymphoblastic Leukemia Natural History in Neurofibromatosis Type 1 Monozygotic Twins

Abstract 2414 Introduction:Neurofibromatosis 1 (NF1) is an autosomal dominant disease, caused by mutation of neurofibromin (NF1) gene, located in the 17q11.2 chromosomal region. Children affected by NF1 have an increased risk to develop tumors, including leukemia. It has been suggested that NF1 aberrancy is a tumor predisposing factor, and that secondary events in somatic cells gives rise to the formation of neoplasm. However, the clonal evolution from NF1 mutation to tumor development has never been elucidated. Monozygotic twins constitute an ideal tool to understand the clonal evolution of leukemia in the context of a common genetic background. Patients:We performed the genomic characterization of a pair of monozygotic twins with diagnosis of NF1, who developed concordant B-cell precursor ALL at the age of 6 (Twin 1, T1) and 6.5 years (T2). The diagnostic and relapse samples showed common and unique lesions, allowing us to hypothesize a model for leukemia clonal evolution. At diagnosis, T1 had common ALL with 45,XX,-7,del(9)(p12),del(10)(q23)[8]/46,XX[12] whereas T2 had common ALL with 45,XX,-7,del(10)(q22)[14]. Both were treated according to AIEOP-BFM ALL 2000 protocol; T1 was classified as MRD high risk (HR), and T2 as MRD Intermediate risk (IR). T1 underwent BMT 8 months after diagnosis, and achieved clinical remission, still persisting, whilst T2 relapsed 13 months after diagnosis with 47,XX,del(9)(p21),+21[11]/46,XX[5]; she entered AIEOP REC 2003 protocol and, after achieving second complete remission and negativity for MRD, underwent allogeneic HLA-compatible BMT; she is in clinical remission 3.5 years after BMT. Results:Genome-wide copy number alteration (CNA) analysis by Cytogenetics Whole Genome 2.7M Arrays (Affymetrix) indicated that T1 and T2 shared a copy number neutral Loss Of Heterozygosity (LOH) of 17q arm, were the NF1 gene is located. At diagnosis, both had chromosome 7 monosomy but showed completely different Ig/TCR rearrangements. Three additional clonal rearrangements were found in T2 relapse sample. By backtracking the rearrangements, the relapse clone was detected in about 1% of T2 diagnostic cells, but not in T1 diagnosis sample.Several twin-specific abnormalities were detected: both had a deletion involving the q arm of chromosome 10, with different extent: del(10)(q23.33) in T1 and del(10)(q23.1) in T2. Moreover, T1 carried hemizygous deletions on chromosome 9 and a focal loss of 6q15 locus, containing the B-cell specific transcriptional regulator BACH2. Genomic analysis of T2 revealed a gain in the telomeric region of chromosome 2 and heterozygous losses in 14q32.13 and 15q21.3 regions, involving BX247990 (human full-length cDNA clone of B cells) and TCF12 (transcription factor 12) genes, respectively. The T2 relapse showed LOH 17q and del(15)(q21.3), as found in her diagnostic sample, and several additional CNAs, including the heterozygous deletions of IKZF1 (7p12.2), ETV6 (12p13.2) and C20orf94 (20p12.2) genes, trisomy of chromosome 21 and LOH of chromosome 20. Discussion:This is the first study that describes the natural history of events in NF1 patients (with 17q LOH) who developed ALL.The unique feature common to both twins in diagnosis and relapse samples was 17q LOH, that probably arose prenatally in a common hematopoietic progenitor (before somatic recombination) of one twin and spread to the other twin through intraplacental circulation. After birth, an independent clonal evolution is sustained by different Ig/TCR rearrangements as well as specific and different oncogenetic lesions. This model support a preleukemic state followed by at least-two-step mechanism for progression to leukemia. The absence of monosomy 7 at relapse indicates an independent and postnatal acquisition of this lesion; and that relapse in T2 occurs from a pre-leukemic clone before monosomy 7, which further evolved through acquisition of additional abnormailities, commom in BCP-ALL (i.e. ETV6 and Ikaros deletions).The role of BACH2 and TCF12 gene deletions in NF1 and ALL must be further explored. BACH2 is a human B-cell specific transcriptional repressor already described as tumor suppressor gene, involved in IgH@ translocations. TCF12 (also named HEB) is a basic helix-loop-helix transcription factor involved in B and T cell commitment. The altered expression of these genes could contribute to the differentiation arrest and the uncontrolled proliferation of leukemic blasts. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Monosomal Karyotype In Myelodysplastic Syndromes, with or without Monosomy 7 or 5, Is Prognostically Worse Than An Otherwise Complex Karyotype

AbstractAbstract 2918 Background:Monosomal karyotype (MK) is defined as the presence of two or more distinct autosomal chromosome monosomies or a single autosomal monosomy associated with at least one structural abnormality (Breems DA et al. J Clin Oncol 2008; 26: 4791). In acute myeloid leukemia (AML), MK has been associated with a worse prognosis than otherwise complex karyotype, regardless of the specific type of autosomal chromosome involved (Breems DA et al. J Clin Oncol 2008; 26: 4791). Whether or not these observations also hold true for myelodysplastic syndromes (MDS) is currently unknown. Objective:To determine if MDS with complex karyotype can be prognostically sub-stratified further based on the presence or absence of MK and if prognosis in MDS with MK is in addition affected by the presence or absence of monosomy 7 or monosomy 5. Methods:The Mayo Clinic database for MDS was used to identify consecutive patients with complex karyotype, defined as the presence of three or more numerical or structural cytogenetic abnormalities. World Health Organization (WHO) criteria were used for MDS diagnosis and leukemic transformation (Vardiman JW et al. Blood 2009; 114: 937). Overall and leukemia-free survivals were calculated from the time of initial cytogenetic studies documenting complex karyotype. Results:A total of 127 MDS patients (median age 70 years; 79 males) with complex karyotype were identified. Amongst them, 106 (83%) met the above-stipulated criteria for MK and 21 (17%) had complex karyotype without monosomies. The MK in the 106 patients included monosomy 7 and/or monosomy 5 in 73 cases. The three complex karyotype subsets (i.e. complex without monosomies vs. MK that included monosomy 7 and/or 5 vs. MK excluding monosomy 7 or 5) were not significantly different in terms of age and sex distribution, hemoglobin level, leukocyte or platelet count, bone marrow blast percentage or International Prognostic Scoring System (IPSS) risk score. However, survival was significantly inferior in patients with MK compared to those with complex karyotype without monosomies (p=0.01; HR 1.9, 95% CI 1.1–3.3). Multivariable analysis identified MK (p=0.002), advanced age (p=0.0004), increased bone marrow blast percentage (0.04), but not IPSS risk category (p=0.34), as independent risk factors for survival. Interestingly, there was no difference in survival among MK patients further sub-stratified by the presence or absence of monosomy 7 and/or monosomy 5 (Figure 1). Although not statistically significant, leukemia-free survival was also worse in patients with MK compared to those with complex karyotype (p=0.11; HR 2.7, 95% CI 0.8–9.0); none of the aforementioned variables significantly affected leukemia-free survival. Conclusions:Monosomal karyotype in MDS identifies a prognostically worse subgroup of patients with complex karyotype. Furthermore, in the context of MK, autosomal monosomies other than monosomy 7 or monosomy 5 are prognostically as detrimental. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Monosomal karyotype in myelodysplastic syndromes, with or without monosomy 7 or 5, is prognostically worse than an otherwise complex karyotype

Monosomal karyotype (MK) refers to the presence of two or more distinct autosomal monosomies or a single monosomy associated with a structural abnormality. In acute myeloid leukemia, MK has been shown to be prognostically worse than an otherwise complex karyotype. The current study examines whether the same holds true for myelodysplastic syndromes (MDS). A total of 127 MDS patients (median age 70 years) with a complex karyotype were considered; 106 (83%) met the above-stipulated criteria for MK and 21 (17%) had a complex karyotype without monosomies. Survival was significantly inferior in patients with MK compared with those with a complex karyotype without monosomies (P=0.01; HR 1.9, 95% confidence interval (95% CI), 1.1-3.3). Multivariable analysis identified MK (P=0.002), advanced age (P=0.0004) and bone marrow blast percentage (0.04) as independent risk factors for survival. There was no difference in survival among MK patients further substratified by the presence or absence of monosomy 7 and/or monosomy 5. Although not statistically significant, leukemia-free survival was also worse with MK compared with complex karyotype without monosomies (P=0.09; HR 2.7, 95% CI 0.8-9.0). MK in MDS identifies a prognostically worse subgroup of patients with a complex karyotype, regardless of whether monosomy 7 or 5 is part of the MK component.

Monosomy 3 in uveal melanoma: correlation with clinical and histologic predictors of survival.

To correlate monosomy 3 in uveal melanoma with clinical and histologic prognostic variables and death caused by metastatic disease. Loss of heterozygosity (LOH) on chromosome 3 was investigated by PCR-based microsatellite analysis in 105 tumors and related to large basal tumor diameter (LBD), ciliary body (CB) involvement, tumor cell type, periodic acid-Schiff (PAS)-positive loops, and death related to metastatic disease. A model relating monosomy 3 to these was created with forward-stepwise logistic regression and used to derive a prognostic index. Monosomy 3 occurred in 54 (51%) tumors and regional chromosome 3 LOH in another six (6%) tumors. Monosomy 3 was associated with epithelioid cells (chi(2) test, P < 0.001), PAS-positive loops (chi(2), P = 0.001), LBD (Mann-Whitney test, P = 0.002), CB involvement (chi(2) test, P = 0.008), and metastasis-related death (log rank analysis, P = 0.0003). The regression coefficients indicated that epithelioid histology was 15 times as influential with each millimeter of increase in LBD. A prognostic score was derived: one point for each LBD category (<7.4, 7.5-12.4, 12.5-17.4, and >17.4 mm) and three points for epithelioid histology. The prevalence of monosomy 3 increased with score, from 0% in 18 tumors scoring less than 4 to 95% in 21 tumors scoring 7. Monosomy 3 correlates with survival but can be predicted only in patients with large epithelioid tumors. The absence of monosomy 3 is predictable only in patients who have small, spindle-cell tumors. In most patients, prediction of monosomy 3 according to tumor size and histology is unreliable.