Recurrent chromosomal translocations: Is proximity a rule.

The role of recurrent chromosomal translocations in pathogenesis is well characterized in many leukemia subtypes; however, the factors leading to such preferential gene fusions are yet to be understood. The proximity of the genetic regions is considered important for genetic exchange, and interphase molecular cytogenetic methods can be employed to measure the same. The interphase genomic location of gene pairs taking part in translocations which are non-randomly associated with leukemia subtypes was studied for the extent of proximity by measuring relative distance and radial location. The FISH (Fluorescence In Situ Hybridization) signals corresponding to gene pairs were scored for relative distance and percentage of possible translocation pairs showing proximity which was found higher for BCR-ABL, PML-RARA and AML-ETO. The radial position of the gene pairs was also recorded to see if there is any preferred location in terms of nuclear centre or periphery for translocation partners. The results suggested no preferential location of any of the gene pairs in periphery or centre of the interphase nucleus, rather random distribution was observed for all the three cases. We report here the use of simple interphase FISH method to assess the interphase proximity of gene fusion pairs which can be further employed for other translocations.

Phenotypic spectrum in uniparental disomy: Low incidence or lack of study.

CONTEXT: Alterations in the human chromosomal complement are expressed phenotypically ranging from (i) normal, via (ii) frequent fetal loss in otherwise normal person, to (iii) sub‑clinical to severe mental retardation and dysmorphism in live births. A subtle and microscopically undetectable chromosomal alteration is uniparental disomy (UPD), which is known to be associated with distinct birth defects as per the chromosome involved and parental origin. UPD can be evident due to imprinted genes and/or activation of recessive mutations. AIMS: The present study comprises of data mining of published UPD cases with a focus on associated phenotypes. The goal was to identify non‑random and recurrent associations between UPD and various genetic conditions, which can possibly indicate the presence of new imprinted genes. SETTINGS AND DESIGN: Data mining was carried out using the homepage “http://www.fish.uniklinikum‑jena.de/ UPD.html,” an online catalog of published cases with UPD. MATERIALS AND METHODS: The UPD cases having normal karyotype and with or without clinical findings were selected to analyze the associated phenotypes for each chromosome, maternal or paternal involved in UPD. RESULTS: Our results revealed many genetic conditions (other than the known UPD syndromes) to be associated with UPD. Even in cases of bad obstetric history as well as normal individuals chance detection of UPD has been reported. CONCLUSIONS: The role of UPD in human genetic disorders needs to be studied by involving larger cohorts of individuals with birth defects as well as normal population. The genetic conditions were scrutinized in terms of inheritance patterns; majority of these were autosomal recessive indicating the role of UPD as an underlying mechanism.

Trisomy 8 in leukemia: A GCRI experience.

Trisomy of chromosome 8 is frequently reported in myeloid lineage disorders and also detected in lymphoid neoplasms as well as solid tumors suggesting its role in neoplastic progression in general. It is likely to be a disease-modulating secondary event with underlying cryptic aberrations as it has been frequently reported in addition to known abnormalities contributing to clinical heterogeneity and modifying prognosis. Here, we share our findings of trisomy 8 in leukemia patients referred for diagnostic and prognostic cytogenetic assessment. Total 60 cases of trisomy 8, as a sole anomaly or in addition to other chromosomal aberrations, were reported (January 2005–September 2008). Unstimulated bone marrow or blood samples were cultured, followed by GTG banding and karyotyping as per the ISCN 2005. Patients with +8 were chronic myeloid leukemia (CML) (36), acute myeloid leukemia (AML) (17), and acute lymphoblastic leukemia (ALL) (7). In 7 patients, trisomy 8 was the sole anomaly, whereas in 6 patients +8 was in addition to normal clone, in 47 patients, the +8 was in addition to t(9;22), t(15;17), and others, including 3 with tetrasomy 8. Only one patient showed constitutional +8. The present study will form the basis of further cumulative studies to correlate potential differential effects of various karyotypic anomalies on disease progression and survival following a therapeutic regime. To unravel the role of extra 8 chromosome, constitutional chromosomal analysis and uniparental disomy will be considered.

AML-M2 with der(18)t(1;18)(q2?;p11.3) in addition to t(8;21) and del(9q).

We report a case of Acute Myeloid Leukemia with clinical features suggestive of AML-M3 and 46,XX,t(8;21),del(9q),der(18)t(1;18) karyotype leading to the final diagnosis AML-M2 in light of t(8;21). The Deletion (9q) is a frequent secondary anomaly to the t(8;21)(q22;q22) in AML-M2. In addition to these two AML-M2 related rearrangements we also observed der(18)t(1;18)(q2?;p11.3) which may be an unusual rearrangement. This rearrangement resulted into partial trisomy of chromosome #1(q2?) without the loss of any part of chromosome 18, morphologically. Rearrangements of long arm of chromosome 1 that result in complete or partial trisomy for 1q mostly involved the region q25-q32, which may confer a proliferation advantage.

Loss of sex chromosome in acute myeloid leukemia.

Loss of sex chromosomes has been reported in normal and malignant marrows and its frequency increases with age in both situations. It is not clear whether the sex chromosome loss is a critical mutational event for neoplastic transformation or a genetic change related to ageing. The present study was undertaken to analyze incidence of loss of sex chromosomes in leukemia patients. Karyotypic analysis in bone marrow cells was carried out in total 270 AML patients registered at G.C.& R.I. during January 2000 to October 2003. Out of 270, 22 patients had loss of sex chromosome in addition to other disease specific chromosomal abnormalities. Out of 22 patients, 50% (11 of 22) were of the pediatric age (up to 14 years), and only 10% (3 of 22) patients were above the age of 50 years, maximum age being 65 years. On follow-up, only in patients with pathological remission normal 46XX/XY karyotypes were seen. Whereas in patients with persistent leukemic activity, clones with loss of sex chromosome were observed. The results indicate that sex chromosome loss in these cases may be equivalent of a clonal cytogenetic process rather than related to ageing process.

An Increased Incidence Of C-Band Heteromorphism In Hereditary Breast Cancer Patients and Their Healthy Blood Relatives An Indian Experience.

Healthy blood relatives (HBR) of the hereditary breast cancer (HBC) patients are considered to be at higher risk to develop cancer. However, all of them do not suffer from same. This may indicate the possibility of association with genetic polymorphism among them. We have studied this genetic polymorphism in terms of C-band heteromorphism among 11 HBC patients, 36 HBR and results were compared with 22 control females. Significantly higher incidence (p < 0.001) of C-band heteromorphism has been observed among the HBC patients and their HBR as compared to the control females. At the same time, however, the difference in incidence of C-band heteromorphism among HBC patients and their HBR were not statistically significant. The findings indicate possibilities of (i) an association between C-band heteromorphism and hereditary breast cancer, and (ii) C-band heteromorphism may be one of the important factors conferring HBR at an elevated risk to develop the breast cancer.

Constitutive Heterochromatin Polymorphism In Pediatric Cancer Patients.

Incidence of constitutive C-band heteromorphism (CBH) is reported to be higher in patients with malignancy by some studies, while in others no difference is reported between control and malignant conditions. We have studied incidence of CBH in pediatric cancer patients in terms of > 25% size difference between the homologues of chromosome #1, #9 and #16 and compared it with (i) age-matched controls, (ii) controls with minimum 60 years of age and (iii) parents/siblings of pediatric cancer patients and overall prevalence of CBH was comparable between patients and three groups of control subjects. Statistically significant difference was observed between the total lengths of C-band of chromosome #1 for pediatric cancer patients and first degree relatives group (p < 0.01). 17 families of pediatric cancer patients were studied for the pattern of CBH. In three patients, CBH analysis, more number of cancer families and normal pedigrees will be more informative. The problem still remains unresolved and should be analyzed qualitatively using techniques of molecular cytogenetics.