De novo triplication at 1p36.23p36.22 further refines the dosage sensitive region of overlap in Setleis syndrome (focal facial dermal dysplasia type III).

Setleis syndrome (SS), or focal facial dermal dysplasia type III (FFDD3, MIM #227260), is an autosomal recessive condition caused by biallelic loss-of-function variants in TWIST2. It is characterized by bitemporal atrophic skin lesions and distinctive facial features. Individuals with de novo or inherited duplication or triplication of the chromosomal region 1p36.

The clinical utility of integrative genomics in childhood cancer extends beyond targetable mutations.

We conducted integrative somatic-germline analyses by deeply sequencing 864 cancer-associated genes, complete genomes and transcriptomes for 300 mostly previously treated children and adolescents/young adults with cancer of poor prognosis or with rare tumors enrolled in the SickKids Cancer Sequencing (KiCS) program. Clinically actionable variants were identified in 56% of patients. Improved diagnostic accuracy led to modified management in a subset.

The Clinical Landscape of NRAS- mutated Juvenile Myelomonocytic Leukemia-like Myeloproliferation Includes Children With Costello Syndrome.

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive pediatric disorder characterized by pathologic myeloproliferation because of alterations in RAS pathway genes. NRAS -mutated JMML encompasses a broad range of clinical severity. Herein we describe 4 unique cases of NRAS -mutated JMML and JMML-like myeloproliferation, 2 with somatic mutations and 2 with germline mutations.

Building the What Comes Next Cohort for and testing: a descriptive analysis.

Background: Our understanding of how testing for and mutations of the and genes affect cancer risk and the use of risk-reduction strategies comes largely from studies of women recruited from specialized genetics clinics. Our aim was to assemble a generalizable cohort of women who underwent testing (the What Comes Next Cohort), irrespective of test result, to enable study of health care utilization and outcomes after testing.

Methods: This descriptive study included adult women (≥ 18 yr) who met at least 1 of 13 provincial criteria for / testing and who underwent genetic testing at sites in Ontario, Canada, from 2007 to 2016.

Practice patterns of prenatal and perinatal testing in Canadian cytogenetics laboratories.

Objective: To survey patterns of practice in Canadian cytogenetics laboratories and evaluate whether newer technologies have influenced testing algorithms for the detection of common aneuploidies and other genomic imbalances in the prenatal and perinatal settings.

Methods: Cytogenetics laboratories across Canada were invited to participate in two patterns-of-practice surveys: one in 2016 and one in 2019. They were asked to identify the prenatal and perinatal specimen types tested at their facility and which testing methods were used for initial testing and for follow-up.

Assessing copy number aberrations and copy-neutral loss-of-heterozygosity across the genome as best practice: An evidence-based review from the Cancer Genomics Consortium (CGC) working group for chronic lymphocytic leukemia.

The prognostic role of cytogenetic analysis is well-established in B-cell chronic lymphocytic leukemia (CLL). Approximately 80% of patients have a cytogenetic aberration. Interphase FISH panels have been the gold standard for cytogenetic evaluation, but conventional cytogenetics allows detection of additional abnormalities, including translocations, complex karyotypes and multiple clones.

Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR).

PurposeThe purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the BRCA1 and BRCA2 genes as a case study.MethodsBRCA1 and BRCA2 variant data were uploaded and shared through the Canadian Open Genetics Repository (COGR; http://www.opengenetics.

Will a peripheral blood (PB) sample yield the same diagnostic and prognostic cytogenetic data as the concomitant bone marrow (BM) in myelodysplasia?

In patients with myelodysplastic syndromes (MDS), chromosome anomalies are detected by conventional cytogenetic studies (CCS) and/or interphase fluorescence in situ hybridization (FISH) of bone marrow (BM) samples and provide prognostic and diagnostic information, which can direct therapy. Whether peripheral blood (PB) can be substituted for bone marrow in these cases and can provide the same information remains unknown. Concurrent BM and PB specimens collected from 100 patients with recently diagnosed MDS were studied using both CCS and FISH.

The detection of chromosome anomalies by QF-PCR and residual risks as compared to G-banded analysis.

Objective: To determine the detection rate of clinically significant chromosome abnormalities using quantitative fluorescent polymerase chain reaction (QF-PCR) of fetal DNA in comparison with G-banded analysis of cultured amniotic fluid cells and determine the residual risk if QF-PCR were performed alone for low-risk cases.

Methods: Amniotic fluid samples were prospectively categorized based on the likelihood of the fetus having a chromosome anomaly. QF-PCR results were compared with the G-banded findings.

Euchromatic 9q13-q21 duplication variants are tandem segmental amplifications of sequence reciprocal to 9q13-q21 deletions.

Background: There are four known pericentromeric euchromatic variants of chromosome 9 in the literature that are increasingly being observed in diagnostic cytogenetic laboratories. These variants pose diagnostic and counselling dilemmas, especially in prenatal settings, as distinction of a pathogenic alteration from a euchromatic variant is difficult. The molecular characterisation of three of these four variants has been reported.

Prospective validation of quantitative fluorescent polymerase chain reaction for rapid detection of common aneuploidies.

Purpose: To prospectively validate a quantitative fluorescent polymerase chain reaction (PCR) assay as a method of rapid prenatal aneuploidy detection for chromosomes 13, 18, 21, X, and Y.

Methods: A commercial quantitative fluorescent PCR kit was validated on 200 known, blinded, prenatal DNA specimens. The kit was then validated prospectively on 1069 amniotic fluid specimens, and the results were compared with the karyotype results and the results of interphase fluorescence in situ hybridization testing, when performed in the course of standard care.

Implementation of standardized international karyotype scoring practices is needed to provide uniform and systematic evaluation for patients with myelodysplastic syndrome using IPSS criteria: An International Working Group on MDS Cytogenetics Study.

Karyotype status and complexity are key components of the IPSS; however, emerging data suggest the use of cytogenetics at disease presentation is not applied uniformly among MDS patients. To investigate the degree of consistency of scoring karyotypes, the International Working Group on MDS Cytogenetics (IWGMC) conducted a survey of 32 abnormal karyotype challenges carried out in two phases: (a) an initial survey without any specified karyotype counting guidelines and (b) a second survey conducted after the development of IWGMC consensus guidelines for scoring karyotype complexity. Results indicate that IWGMC guidelines were simple and clear for the cytogeneticists in scoring karyotype complexity, but not as clear for the hematologists.

Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts.

Purpose: The purpose of the study was to investigate the associations between uptake of (111)In-DTPA-trastuzumab, tumour HER2 density and response to trastuzumab (Herceptin) of human breast cancer (BC) xenografts in athymic mice.

Materials And Methods: The tumour uptake of (111)In-DTPA-trastuzumab in athymic mice bearing BC xenografts with increasing HER2 density (0 to 3+) was evaluated. Specific uptake ratios were established in biodistribution (SUR) and imaging studies (ROI-SUR) using (111)In-labeled mouse IgG ((111)In-DTPA-mIgG).

Outcome of patients who develop acute leukemia or myelodysplasia as a second malignancy after solid tumors treated surgically or with strategies that include chemotherapy and/or radiation.

Background: Evaluation of therapeutic outcomes and risk factors was undertaken for patients with primary solid tumors (PST) developing acute leukemia or myelodysplasia (MDS) as a second malignancy.

Methods: In all, 131 consecutive patients presenting to a single institution with leukemia or MDS after treatment for PST with surgery or chemotherapy/radiotherapy were examined. Management of the secondary acute leukemia and MDS consisted either of intensive therapy including allogeneic blood and marrow transplants or supportive measures.

Src promotes estrogen-dependent estrogen receptor alpha proteolysis in human breast cancer.

Estrogen drives both transcriptional activation and proteolysis of estrogen receptor alpha (ER alpha; encoded by ESR1). Here we observed variable and overlapping ESR1 mRNA levels in 200 ER alpha-negative and 50 ER alpha-positive primary breast cancers examined, which suggests important posttranscriptional ER alpha regulation. Our results indicate that Src cooperates with estrogen to activate ER alpha proteolysis.

Characteristics and outcomes of acute myelogenous leukemia patients with very late relapse (>5 years).

The clinical characteristics and outcome of 15 patients with acute myelogenous leukemia (AML) who experienced relapse at least 5 years after induction of complete remission (very late-relapse AML) are described. This subgroup represented 3% of all relapsed patients seen at this institution over the same time period. There were eight males in this cohort and the median age at diagnosis was 48 years (range 13 - 77 years).

Inv (11)(p15q21) in donor-derived Ph-negative cells in a patient with chronic myeloid leukemia in relapse successfully treated with imatinib mesylate post allogeneic stem cell transplantation.

Imatinib mesylate (IM) is the standard first-line treatment for patients with chronic myeloid leukemia (CML). Surprisingly, 2-15% of patients achieving a complete cytogenetic response develop cytogenetic abnormalities in Philadelphia (Ph)-negative cells. Following hematopoietic stem cell transplantation (HSCT), IM induces complete molecular responses (CMR) in approximately 70% patients with relapsed CML, and no IM-related cytogenetic abnormalities in Ph-negative donor-derived cells have been described after HSCT.

A single nucleotide polymorphism chip-based method for combined genetic and epigenetic profiling: validation in decitabine therapy and tumor/normal comparisons.

Progress on several unresolved issues in cancer epigenetics will benefit from rapid and standardized methods for profiling DNA methylation genome-wide. In the area of epigenetic therapy, the demethylating drug decitabine (5-aza-2'-deoxycytidine) is increasingly used to treat acute myelogenous leukemia and myelodysplastic syndrome, but the mechanisms of its anticancer activity have remained unclear. Given the clinical efficacy of decitabine and the uncertainties about its mode of action, it will be useful to optimize methods for following DNA methylation as a biochemical response in individual patients.

Nonmyeloablative stem cell transplantation for myelodysplastic syndrome or acute myeloid leukemia in patients 60 years or older.

We analyzed the outcomes of 24 consecutive patients aged >or=60 years with poor-prognosis myelodysplastic syndrome or acute myeloid leukemia undergoing transplantation with nonmyeloablative conditioning using fludarabine (125 mg/m2) and low-dose total body irradiation (2 Gy) followed by allogeneic peripheral blood stem cell grafts from HLA-identical sibling donors. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil. The median age of the patients was 64 years (range, 60-71 years).

Progression of myelodysplasia to acute lymphoblastic leukaemia: implications for disease biology.

Myelodysplastic syndrome (MDS) comprises a group of clonal haematopoietic disorders characterized by peripheral blood cytopenias, bone marrow hypercellularity, and abnormal blood cell differentiation. Approximately 30% of cases of MDS eventually progress to acute myelogenous leukemia (AML), while progression of MDS into acute lymphoblastic leukemia (ALL) is rare. In this report, we describe a case of MDS that progressed to ALL, and review the 21 previously reported cases of MDS to ALL transformation.

Disease biology rather than age is the most important determinant of survival of patients > or = 60 years with acute myeloid leukemia treated with uniform intensive therapy.

Background: The objectives of the current study were to evaluate the outcome of patients > or = 60 years with acute myeloid leukemia (AML) treated uniformly with high-dose daunorubicin containing induction and modified high-dose cytosine arabinoside containing postremission therapy, and to identify factors predictive of complete disease remission (CR) and survival.

Methods: Between 1998 and 2002, the authors treated 117 newly diagnosed patients (acute promyelocytic leukemia excluded) with AML > or = 60 years (median, 67 years; range, 60-82 years). Karyotype (Medical Research Council classification) at diagnosis was categorized as good risk (n = 3), intermediate risk (n = 69), adverse risk (n = 26), and suboptimal/not done (n = 19).

Small-molecule XIAP inhibitors derepress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells.

We tested the effects of small-molecule XIAP antagonists based on a polyphenylurea pharmacophore on cultured acute myelogenous leukemia (AML) cell lines and primary patient samples. X-linked inhibitor of apoptosis protein (XIAP) antagonist N-[(5R)-6-[(anilinocarbonyl)amino]-5-((anilinocarbonyl){[(2R)-1-(4-cyclohexylbutyl)pyrrolidin-2-yl]methyl}amino)hexyl]-N-methyl-N'-phenylurea (1396-12), but not a structurally related control compound, induced apoptosis of primary leukemia samples with a lethal dose (LD50) of less than 10 microM in 16 of 27 (60%) samples. In contrast, XIAP antagonist 1396-12 was not lethal to the normal hematopoietic cells in short-term cytotoxicity assays.