Search

Microarray methodologies, to include array comparative genomic hybridization and single-nucleotide polymorphism-based arrays, are innovative methods that provide genomic data. These data should be correlated with the results from the standard methods, chromosome and/or fluorescence in situ hybridization, to ascertain and characterize the genomic aberrations of neoplastic disorders, both liquid and solid tumors. Over the past several decades, standard methods have led to an accumulation of genetic information specific to many neoplasms. This specificity is now used for the diagnosis and classification of neoplasms. Cooperative studies have revealed numerous correlations between particular genetic aberrations and therapeutic outcomes. Molecular investigation of chromosomal abnormalities identified by standard methods has led to discovery of genes, and gene function and dysfunction. This knowledge has led to improved therapeutics and, in some disorders, targeted therapies. Data gained from the higher-resolution microarray methodologies will enhance our knowledge of the genomics of specific disorders, leading to more effective therapeutic strategies. To assist clinical laboratories in validation of the methods, their consistent use, and interpretation and reporting of results from these microarray methodologies, the American College of Medical Genetics and Genomics has developed the following professional standard and guidelines.

Cytogenetic studies of bladder cancer have helped to define two clinically distinct subtypes: benign tumors with few genetic mutations and a stable karyotype and aggressive cancers with chromosomal instability and many non-random cytogenetic aberrations. While the cytogenetic data does not provide complete information, these studies have been important for suggesting pathways for bladder carcinoma initiation and its progression. In addition, molecular cytogenetic studies have proven useful for diagnosing bladder cancer and for monitoring patients for cancer recurrence. More detailed molecular genetic studies and expression array analyses are needed to fully comprehend the biologic processes associated with urothelial cancers, but cytogenetics studies have laid the foundation for further investigation., (Copyright (c) 2007 S. Karger AG, Basel.)

Context: Cytogenetic heteromorphisms (normal variants) pose diagnostic dilemmas. Common Giemsa-band heteromorphisms are not described in the literature, although Giemsa-banding is the method most frequently used in cytogenetic laboratories., Objective: To summarize the responses from more than 200 cytogeneticists concerning the definition and reporting of cytogenetic heteromorphisms, to offer these responses as a reference for use in clinical interpretations, and to provide guidance for interpretation of newly defined molecular cytogenetic heteromorphisms., Design: The Cytogenetics Resource Committee of the College of American Pathologists and the American College of Medical Genetics administered a proficiency testing survey in 1997 to 226 participant cytogenetic laboratories. Supplemental questions asked whether participants considered particular Giemsa-banded chromosomal features to be heteromorphisms and if these would be described in a cytogenetic clinical report., Results: Responses were obtained from 99% of participants; 61% stated they would include selected heteromorphism data in a clinical report. More than 90% considered prominent short arms, large or double satellites, or increased stalk length on acrocentric chromosomes to be heteromorphisms; 24% to 36% stated that they would include these in a clinical report. Heterochromatic regions on chromosomes 1, 9, 16, and Y were considered heteromorphisms by 97% of participants, and 24% indicated they would report these findings. Pericentric inversions of chromosomes 1, 2, 3, 5, 9, 10, 16, and Y were considered heteromorphisms with more than 75% of respondents indicating they would report these findings., Conclusions: Responses were not unanimous, but a clear consensus is presented describing which Giemsa-band regions were considered heteromorphisms and which would be reported.

A number of clinical reports have described children with a variety of congenital anomalies in association with uniparental disomy (upd) of chromosome 14, suggesting that at least some genes on chromosome 14 are subject to parent of origin, or imprinting, effects. However, little else is known about this putative imprinting of chromosome 14. Both maternal and paternal upd have been observed, but a consistent phenotype has only been suggested for the former. Here we report on a child with developmental delay, microcephaly, distinct facial findings, and who has a duplication of 14q24.3q31. The same cytogenetic abnormality was found in her phenotypically normal father. We hypothesize that this segment of chromosome 14 contains maternally silenced genes, and that this duplicated segment defines an imprinted region on chromosome 14. Alternatively, this cytogenetic duplication may be unrelated to the girl's phenotypic anomalies, and this duplication may contain genes that are not subject to dosage effect.

The abnormal phenotype and/or mental retardation seen in persons with small marker X (mar(X)) chromosomes has been hypothesized to be due to the loss of the X inactivation center (XIC) at Xq13.2, resulting in two active copies of genes in the pericentromeric region. In order to define precisely the DNA content of mar(X) chromosomes and to correlate phenotype with karyotype, we studied small mar(X) chromosomes, using FISH with probes in the juxtacentromeric region. One of the probes was a 40-kb genomic cosmid for the XIST gene, which maps to the smallest interval known to contain the XIC and is thought to be involved in X inactivation. Our findings reveal that small mar(X) chromosomes do not include the XIC and therefore cannot be subject to X inactivation, supporting the premise that abnormal dosage of expressed genes in the pericentromeric region of the X generates the aberrant phenotype seen in patients with small mar(X) chromosomes.

We describe the first de novo inverted duplication of 18q. Due to the difficulty of identifying de novo chromosome abnormalities based solely on cytologic studies, precise definition of the 18q duplication was attempted by integrating cytogenetic and clinical findings with biochemical and molecular dosage studies. The combined results demonstrated that the proposita had a duplication of 18q21-->q22 with a karyotype of 46,XX,-18, + inv dup(18) (pter-->q12.1::q22-->q21::q12.1-->qter). The duplication of this specific chromosome region does not result in the typical 18 phenotype, supporting the hypothesis that various loci on chromosome 18 may interact to produce the manifestations of this syndrome.

To test the hypothesis that Robertsonian translocation may lead to altered crossing-over on both chromosomes involved in the rearrangement (intrachromosomal effects) and other chromosomes in the cell (interchromosomal effects), we initiated this pilot study utilizing molecular markers (RFLPs) to determine the frequency and approximate location of crossovers on chromosomes 21 of human Robertsonian translocation carriers. Analysis of intrachromosomal effects in five families with Robertsonian translocations involving a chromosome 21 demonstrated an elevation in the amount of crossing-over on chromosomes 21 of the female translocation parent. Several of the crossovers were localized proximal to 21q21.2, suggesting that Robertsonian translocations may lead to an alteration of both the frequency and location of crossing-over. In an assessment of interchromosomal effects in five additional families with a non-21 Robertsonian translocation, no effect could be demonstrated on chromosome 21. The initial data imply that Robertsonian translocation influences the number and position of exchanges on chromosomes 21 involved in the rearrangement, which may be associated with an increased tendency for nondisjunction due to prolonged synapsis of 21. This pilot study demonstrates the utility of this approach in the assessment of intra- and interchromosomal effects of Robertsonian translocations on recombination.

Spontaneous and clastogen induced chromosomal damage was evaluated in lymphocytes of 10 patients with scleroderma and 21 controls. Peripheral blood lymphocytes from patients with scleroderma not only had elevated rates of spontaneous chromosomal damage (p = 0.002), but also bleomycin induced (p = 0.041), streptonigrin induced (p = 0.035), and 4-nitroquinoline-1-oxide induced (p = 0.032) chromosomal breakage. Our findings suggest that scleroderma lymphocytes may have a generalized susceptibility to DNA damage caused by free radicals.