Variant Philadelphia translocations with different breakpoints in six chronic myeloid leukemia patients.

OBJECTIVE: The Philadelphia (Ph) chromosome, consisting of the t(9;22)(q34;q11) translocation, is observed in ~90% of patients with chronic myeloid leukemia (CML). Variant Ph translocations are observed in 5%-10% of CML patients. In variant translocations 3 and possibly more chromosomes are involved. Herein we report 6 CML patients with variant Ph translocations. METHODS: Bone marrow samples were examined using conventional cytogenetic meth ods. Fluorescence in situ hybridization (FISH) with whole-chromosome paints and BCR-ABL 1D probes were used to confirm and/or complement the findings, and identify rearrangements beyond the resolution of conventional cytogenetic methods. RESULTS: Variant Ph translocations in the 6 patients were as follows: t(7;22)(p22;q11), t(9;22;15)(q34;q11;q22), t(15;22)(p11;q11), t(1;9;22;3)(q24;q34;q11;q21), t(12;22)(p13;q11), and t(4;8;9;22)(q11;q13;q34;q11). CONCLUSION: Among the patients, 3 had simple and 3 had complex variant Ph translocations. Two of the presented cases had variant Ph chromosomes not previously described, 1 of which had a new complex Ph translocation involving chromosomes 1, 3, 9, 22, and t(1;9;22;3)(q24;q34;q11;q21) apart from a clone with a classical Ph, and the other case had variant Ph translocation with chromosomes 4, 8, 9, and 22, and t(4;8;9;22)(q11;q13;q34;q11) full complex translocation. Number of studies reported that some patients with variant Ph translocation were poor responders to imatinib. All of our patients with variant Ph translocations had suboptimal responses to imatinib, denoting a poor prognosis also. Variant Ph translocations may be important as they are associated with prognosis and therapy for CML patients.

3p abnormalities in peripheral lymphocytes in small cell lung cancer.

3p abnormalities are the most frequent chromosome abnormalities in small cell lung cancer (SCLC). To date these abnormalities have only been observed in cells derived from tumor tissues. It is thought that cancer-related chromosome abnormalities in peripheral lymphocytes could help to predict cancer development, prognosis, and future metastasis. We report clonal and nonclonal 3p abnormalities in the peripheral lymphocytes of two patients with SCLC. A standard T-lymphocyte culture method and GTL banding technique were applied to the samples, and various clonal and nonclonal chromosome 3 abnormalities, i.e., -3, del(3)(p24), del(3)(p21), del(3)(p11), del(3)(q22), inv(3)(p14q29), and inv(3)(q21q29) were observed. Efforts have been made to understand if there are cancer-related chromosome abnormalities in lymphocytes and the suitability of these abnormalities to predict cancer development or metastases. As far as we know, this is the first report on chromosome 3 abnormalities in lymphocytes. Since 3p abnormalities are specific for SCLC, it is important to show that these cancer-related abnormalities can be found in blood cells.

A Novel and Mosaic WDR45 Nonsense Variant Causes Beta-Propeller Protein-Associated Neurodegeneration Identified Through Whole Exome Sequencing and X chromosome Heterozygosity Analysis.

Beta-propeller protein-associated neurodegeneration (BPAN) is an X-linked rare dominant disorder of autophagy. The role of WDR45 has been implicated in BPAN almost exclusively in females possibly due to male lethality. Characterization of distinctive clinical manifestations and potentially the complex genetic determinants in rare male patients remain crucial for deciphering BPAN and other X-linked dominant diseases. We performed whole exome sequencing (WES) followed by segregation analysis and identified a novel nonsense and mosaic variant in WDR45, namely NM_007075.3:c.873C>G; p.(Tyr291*) in an affected male at the age of 34. His biphasic medical history was compatible with BPAN, which was characterized by delayed psychomotor development, intellectual disability, and progression into dystonia parkinsonism in his twenties. The variant had an apparently mosaic pattern both in whole exome and Sanger sequencing findings. In order to figure out if mosaicism was restricted to this variant or related to a chromosomal level mosaicism, we used our in-house WES data from 129 unrelated individuals to calculate the threshold values of male and female X chromosome heterozygosity (XcHet) in WES data for our pipeline. A background level of heterozygous variants on X chromosome excluding the pseudoautosomal loci is an observed phenomenon in WES analysis and this level has been used as a quality measure. Herein, we suggest utilization of this measure for detection of digital anomalies of the X chromosome in males by potentially observing a higher XcHet value than the threshold value. This approach has revealed a variant level mosaicism in the affected male, which was further supported with cytogenetic analyses.

A childhood acute lymphoblastic leukemia (ALL) case with t(3;17)(q23;p13),t(5;12)(q31;p13),inv(11)(p15q12).

It is known that clonal chromosomal changes in childhood ALL are nonrandom and important markers for diagnosis, prognosis and relaps. In this report we present 4 year-old boy with ALL-L1 who has complex chromosomal rearrangements. Chromosome analysis was performed on bone marrow aspiration sample in relaps after one year from diagnosis and induction chemotherapy. The karyotype was; 46,XY,t(3;17)(q23;p13),t(5;12)(q31;p13),inv(11)(p15q12) [11]/46,XY[8].

t(1;3)(p36;p21): presentation of a patient with MDS/AML (M2) and review of the literature.

t(1;3)(p36;p21) is a recurrent reciprocal translocation found in a subset of myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) characterized by trilineage dysplasia, especially dysmegakaryopoiesis and poor prognosis. In the literature, some authors have suggested that this recurrent translocation is closely associated with prior chemotherapy including alkylating agents in various hematologic malignancies. We identified a recurring translocation, t(1;3)(p36;p21), in our patient with MDS/AML(M2), although she had not been given any kind of treatment previously.