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Microdeletion of 9q22.3 is a rare chromosomal disorder characterized by body overgrowth, facial dysmorphic features and psychomotor delay. The presence of genomic microdeletion or microdu-plication can not be identified by the conventional chromosomal analysis. Microarray comparative genomic hybridization (CGH) is a newly developed molecular cytogenetic technique that enables the identification of minute copy number variation (CNV) in the human genome. Here, we report a case of microdeletion in the 9q22.31-q22.33 region, which included a patched homolog 1 (PTCH1) gene, as detected by CGH and confirmed by fluorescence in situ hybridization (FISH) analyses in a neonate with prenatal onset of macrosomia, dysmorphism, and muscle hypotonia. To the best of our knowledge, this is the first case report of 9q22.3 microdeletion detected by CGH in Korea. [ABSTRACT FROM AUTHOR]

Early gastric carcinoma (GC) is considered to be a curable cancer, as it progresses to the advanced stage following varying durations. Understanding the early stage of GC may provide an insight into its pathogenesis and contribute to reducing the mortality rate of this disease. To investigate the genomic aberrations associated with 22 cases of early GC, high-density microarray comparative genomic hybridization was performed in the present study. The most notable finding was copy number gains (log2 ratio >0.25) on the long arm of chromosome 8, which occurred in 77.3% (17/22) of GC cases, and the delineated minimal common region was 8q22.1-q24.3. More specifically, two amplified (log2 ratio >1) loci in the 8q22.1-q24.3 region were detected in 18.2% (4/22) of GC cases. The first loci covered a region of 102.4-107.9 kb, mapping on 8q22.3-q23.1, and comprised the transcription factor CP2-like 3 gene. The second loci, spanning 128.7-145.7 kb on 8q24.21-q24.3, comprised the representative oncogene of myelocytomatosis. Furthermore, the following possible target genes that were not previously considered to play a pathogenic role in GC were identified: Plasmacytoma variant translocation 1, cysteine/histidine rich 1, kinesin family member C2, forkhead box H1, protein phosphatase 1 regulatory subunit 16A, glutamic-pyruvate transaminase, LOC113655 and RecQ protein-like 4. In the present study, previous findings showing that 8q mutations accumulate early during the multistage pathogenesis of GC were confirmed and expanded upon. The confirmation of previously reported 8q gains and the identification of novel target genes at 8q22.1-q24.3 amplified chromosomal sites should aid in improving our understanding of the molecular mechanisms underlying the tumorigenesis of early GC. [ABSTRACT FROM AUTHOR]

S-1, a novel oral fluoropyrimidine, has shown remarkably good tolerability in Korean gastric and colorectal cancer patients due to its favorable safety profile. Myelosuppression and diarrhea were the events that precluded dose escalation in Japan, whereas gastrointestinal toxicity and skin reaction were the major limiting factors in Western countries. In contrast, the major adverse event in Korean patients was anemia, which appeared early in the S-1 treatment period and varied among patients. Conventional comparative genomic hybridization (CGH) is used to screen for chromosomal copy number variations such as gene gain, loss, amplification, and deletion. This technique can provide information about genetic instability and chromosomal rearrangements. However, the low resolution of 5-10 Mb is a caveat with conventional CGH. cDNA microarray-based CGH is a useful technique for achieving higher resolution for the detection of genomic aberrations. Pharmacogenomic markers, in combination with clinical factors such as initial hemoglobin level, may be useful for predicting S-1 treatment-induced anemia. Prospective genomic and clinical validation of this model may provide a predictive model for the clinical application of S-1 treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND Human female meiosis is particularly error prone, leading to the generation of aneuploidy, a problem which increases dramatically with advancing age. Despite being of great clinical importance, the genesis of oocyte aneuploidy remains poorly understood. Cumulus cells (CCs) surround oocytes in antral follicles and play a crucial role in regulating their maturation. During this investigation, we aimed to obtain an insight into the follicular environment of oocytes that become aneuploid and identify non-invasive markers of oocyte chromosome status and competence. METHODS Microarray comparative genomic hybridization was used to assess oocyte ploidy. Expression of 96 genes was examined via a large real-time PCR experiment in 51 CC samples, whereas an additional 26 CC clumps were used for a more focused real-time PCR experiment assessing just three genes. Gene selection was based on the results of a previous microarray analysis comparing the transcriptome of CCs from normal and aneuploid oocytes. RESULTS Fifty eight of the investigated genes were confirmed to be expressed in CCs. Patterns of expression were generally similar among all CC samples, regardless of the chromosomal status of the corresponding oocyte. However, two genes, SPSB2 and TP53I3, were both significantly down-regulated in CCs from chromosomally abnormal oocytes (P< 0.05). The expression of SPSB2 was also found to display a strong trend towards up-regulation in the CCs of oocytes that produced a healthy live birth (P= 0.054). CONCLUSIONS In the current study, SPSB2 and TP53I3 exhibited highly significant differences in their expression between CCs of normal and chromosomally abnormal oocytes. SPSB2 is involved in intracellular signalling and homeostasis, whereas TP53I3 regulates carbohydrate metabolism and apoptosis. We speculate that both these genes might have the potential to serve as non-invasive markers of oocyte aneuploidy. [ABSTRACT FROM AUTHOR]

Background: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features, and to compare results to solid ACC. Methods: Genome wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, four with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), and five solid ACC. In addition, Ki67 index and p53 immunopositivity was assessed. Results: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component. Conclusion: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC. [ABSTRACT FROM AUTHOR]

Background. Sinonasal squamous cell carcinomas (SCCs) are rare tumors with no etiologic link to tobacco and alcohol, as opposed to other SCCs of the head and neck (HNSCC). Little is known about the genetic changes in sinonasal SCC. Methods. DNA copy number changes of sinonasal SCC were analyzed by multiplex ligation-dependent probe amplification (MLPA) and microarray comparative genomic hybridization (maCGH), and results were related to clinicopathologic features. Results. Copy number losses most frequently included genes at 9p21, 13q14, 17p13, 17q21, and 18q11. Frequent gains were observed on 8q24, 11q13, 17q12, 19p13, and 20q11-q13. Conclusion. The genomic profile of sinonasal SCC showed a number of chromosomal regions with copy number changes similar to those known in HNSCC, in spite of the differences in etiology. [ABSTRACT FROM AUTHOR]

Background. Congenital anomalies of the kidneys and urinary tract (CAKUT) are frequently associated with malformations of other organs. Methods. In order to explore the role of DNA microimbalances in syndromal CAKUT, we applied genome-wide array-based comparative genomic hybridization (arrayCGH) in 30 children with various CAKUT phenotypes and at least one additional extrarenal symptom. Results. In three patients, causal imbalances were detected: In one patient with duplex kidney and vesico-ureteral reflux associated with extrarenal stigmata, a terminal 9.52 Mb gain in chromosomal band 2q37.1-q37.3 and a terminal 5.65 Mb loss in 7q36.2-q36.3 were detected, which were due to an unbalanced 2;7-translocation according to FISH analysis. A balanced 2;7-translocation was present in the unaffected mother. In another patient presenting with renal hypoplasia and proximal ureteric stenosis combined with mental retardation, macrocephaly and ear anomalies, a duplication of 2.73 Mb was detected in 1q21.1. The unaffected father had a 1.3 Mb gain in 1q21.1-q21.2 involving the distal part of the patient’s gain, for which benign copy number variation was described. A third patient affected by dysplastic kidney with a strongly dilated ureter and extrarenal abnormalities exhibited a de novo loss of 13.38 Mb in 3q23-q25.1 including the AGTR1 gene. However, no AGTR1 mutations were identified in the remaining allele of this case or in 108 patients with isolated renal dysplasia/hypoplasia. Conclusions. In this study, 10% of patients with syndromic CAKUT were shown to carry DNA microimbalances, and four chromosomal regions presumably associated with the CAKUT phenotype were identified: 1q21.1, 2q37.1-q37.3, 3q23-q25.1 and 7q36.2-q36.3. [ABSTRACT FROM AUTHOR]

Background: ACC can occasionally undergo dedifferentiation also referred to as high-grade transformation (ACC-HGT). However, ACC-HGT can also undergo transformation to adenocarcinomas which are not poorly differentiated. ACC-HGT is generally considered to be an aggressive variant of ACC, even more than solid ACC. This study was aimed to describe the genetic changes of ACC-HGT in relation to clinico-pathological features and to compare results to solid ACC. Methods: Genome-wide DNA copy number changes were analyzed by microarray CGH in ACC-HGT, 4 with transformation into moderately differentiated adenocarcinoma (MDA) and two into poorly differentiated carcinoma (PDC), 5 solid ACC. In addition, Ki-67 index and p53 immunopositivity was assessed. Results: ACC-HGT carried fewer copy number changes compared to solid ACC. Two ACC-HGT cases harboured a breakpoint at 6q23, near the cMYB oncogene. The complexity of the genomic profile concurred with the clinical course of the patient. Among the ACC-HGT, p53 positivity significantly increased from the conventional to the transformed (both MDA and PDC) component. Conclusion: ACC-HGT may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form in which the poorly differentiated forms (PDC) presents a genetic complexity similar to the solid ACC. [ABSTRACT FROM AUTHOR]

S-1, a novel oral fluoropyrimidine, has shown remarkably good tolerability in Korean gastric and colorectal cancer patients due to its favorable safety profile. Myelosuppression and diarrhea were the events that precluded dose escalation in Japan, whereas gastrointestinal toxicity and skin reaction were the major limiting factors in Western countries. In contrast, the major adverse event in Korean patients was anemia, which appeared early in the S-1 treatment period and varied among patients. Conventional comparative genomic hybridization (CGH) is used to screen for chromosomal copy number variations such as gene gain, loss, amplification, and deletion. This technique can provide information about genetic instability and chromosomal rearrangements. However, the low resolution of 5–10 Mb is a caveat with conventional CGH. cDNA microarray-based CGH is a useful technique for achieving higher resolution for the detection of genomic aberrations. Pharmacogenomic markers, in combination with clinical factors such as initial hemoglobin level, may be useful for predicting S-1 treatment-induced anemia. Prospective genomic and clinical validation of this model may provide a predictive model for the clinical application of S-1 treatment. [ABSTRACT FROM AUTHOR]

Background Intestinal-type sinonasal adenocarcinomas are rare tumors related to professional exposure to wood dust. Little is known about the genetic changes in these tumors. Methods Twenty-two tumors were analyzed by microarray comparative genomic hybridization (CGH). In addition, DNA ploidy was measured by flow cytometry and microsatellite instability (MSI) by multiplex PCR. Results The most frequent gains were, in descending order, as follows: 5p15, 20q13, and 8q24. Losses occurred most frequently at 4q31-qter, 18q12-22, 8p12-pter, and 5q11-qter. MSI was not detected. Seven cases that harbored very few changes were mostly DNA diploid and had more favorable clinicopathological features, such as lack of intracranial invasion, less metastases, and longer overall survival. Conclusion The microarray CGH results enabled to better define hotspots of chromosomal gains and losses for further investigation of genes involved in the tumorigenesis of sinonasal adenocarcinoma. In addition, the data allowed classification of a group of patients with better clinical outcome. © 2008 Wiley Periodicals, Inc. Head Neck, 2009 [ABSTRACT FROM AUTHOR]

Identifying changes in DNA copy number can pinpoint genes that may be involved in tumor development. Here we have defined the smallest overlapping regions of imbalance (SORI) in testicular germ cell tumors other than the 12p region, which has been previously investigated. Definition of the regions was achieved through comparative genomic hybridization (CGH) analysis of a 4559 cDNA clone microarray. A total of 14 SORI were identified, which involved at least five of the 11 samples analysed. Many of these refined regions were previously reported using chromosomal or allelic imbalance studies. The SORI included gain of material from the regions 4q12, 17q21.3, 22q11.23 and Xq22, and loss from 5q33, 11q12.1, 16q22.3 and 22q11. Comparison with parallel chromosomal CGH data supported involvement of most regions. The various SORI span between one and 20 genes and highlight potential oncogenes/tumor suppressor genes to be investigated further (Supplementary material is available at http://www.crukdmf.icr.ac.uk/array/array.html).Oncogene (2004) 23, 9142-9147. doi:10.1038/sj.onc.1208115 Published online 18 October 2004 [ABSTRACT FROM AUTHOR]