Impact on Disease Development, Genomic Location and Biological Function of Copy Number Alterations in Non-Small Cell Lung Cancer

Lung cancer, of which more than 80% is non-small cell, is the leading cause of cancer-related death in the United States. Copy number alterations (CNAs) in lung cancer have been shown to be positionally clustered in certain genomic regions. However, it remains unclear whether genes with copy number changes are functionally clustered. Using a dense single nucleotide polymorphism array, we performed genome-wide copy number analyses of a large collection of non-small cell lung tumors (n = 301). We proposed a formal statistical test for CNAs between different groups (e.g., non-involved lung vs. tumors, early vs. late stage tumors). We also customized the gene set enrichment analysis (GSEA) algorithm to investigate the overrepresentation of genes with CNAs in predefined biological pathways and gene sets (i.e., functional clustering). We found that CNAs events increase substantially from germline, early stage to late stage tumor. In addition to genomic position, CNAs tend to occur away from the gene locations, especially in germline, non-involved tissue and early stage tumors. Such tendency decreases from germline to early stage and then to late stage tumors, suggesting a relaxation of selection during tumor progression. Furthermore, genes with CNAs in non-small cell lung tumors were enriched in certain gene sets and biological pathways that play crucial roles in oncogenesis and cancer progression, demonstrating the functional aspect of CNAs in the context of biological pathways that were overlooked previously. We conclude that CNAs increase with disease progression and CNAs are both positionally and functionally clustered. The potential functional capabilities acquired via CNAs may be sufficient for normal cells to transform into malignant cells

Fluorescence in situ hybridisation analysis of chromosomal aberrations in gastric tissue: the potential involvement of Helicobacter pylori

In this series of experiments, a novel protocol was developed whereby gastric cells were collected using endoscopic cytology brush techniques, and prepared, such that interphase fluorescence in situ hybridization (FISH) could be performed. In total, 80 distinct histological samples from 37 patients were studied using four chromosome probes (over 32 000 cells analysed). Studies have previously identified abnormalities of these four chromosomes in upper GI tumours. Using premalignant tissues, we aimed to determine how early in Correa's pathway to gastric cancer these chromosome abnormalities occurred. Aneuploidy of chromosomes 4, 8, 20 and 17(p53) was detected in histologically normal gastric mucosa, as well as in gastritis, intestinal metaplasia, dysplasia and cancer samples. The levels of aneuploidy increased as disease severity increased. Amplification of chromosome 4 and chromosome 20, and deletion of chromosome 17(p53) were the more common findings. Hence, a role for these abnormalities may exist in the initiation of, and the progression to, gastric cancer. Helicobactor pylori infection was determined in premalignant tissue using histological analysis and PCR technology. Detection rates were comparable. PCR was used to subtype H. pylori for CagA status. The amplification of chromosome 4 in gastric tissue was significantly more prevalent in H. pylori-positive patients (n=7) compared to H. pylori-negative patients (n=11), possibly reflecting a role for chromosome 4 amplification in H. pylori-induced gastric cancer. The more virulent CagA strain of H. pylori was associated with increased disease pathology and chromosomal abnormalities, although numbers were small (CagA+ n=3, CagA− n=4). Finally, in vitro work demonstrated that the aneuploidy induced in a human cell line after exposure to the reactive oxygen species (ROS) hydrogen peroxide was similar to that already shown in the gastric cancer pathway, and may further strengthen the hypothesis that H. pylori causes gastric cancer progression via an ROS-mediated mechanism

Non-random structural chromosomal changes in ovarian cancer: i(5p) a novel recurrent abnormality

Ovarian cancer represents the leading cause of death among patients with gynecological cancer. The genetic changes underlying the initiation and progression of ovarian cancer have not been well defined. However, non-random structural chromosomal changes have been identified with common chromosomal breakpoints. We have studied cytogenetically 15 cases of ovarian adenocarcinomas by a direct culture of cancer cells and a G-banding technique investigating the presence of recurrent structural aberrations with common chromosomal breakpoints. Among very complex structural rearrangements found, we could recognize recurrent structural aberrations involving according to frequency chromosomal regions 3p 13-14, 11p15, 19q 13, 3q21, 11q23, 11q10, 1p13, 1p36, and 17q24-25. Isochromosomes i(5p), i(17q), i(8q) and i(11q) were also observed. Isochromosome i(5p), rarely reported in ovarian cancer was found in seven cases suggesting that it may be a novel recurrent abnormality. Translocations t(1;11), t(3;19), t(3;17), t(7;11) and t(11;17) were also identified. Conventional cytogenetics continues to be valuable detecting the presence of non-random chromosomal breakpoints and facilitating the identification of genes implicated in tumorigenesis. (c) 2005 Elsevier Ireland Ltd. All rights reserved

Non-random structural chromosomal changes in primary gastric cancer

Gastric cancer is of major importance world-wide representing the second most common cause of cancer related death in the world. Data concerning the chromosomal changes in gastric cancer are limited and no specific change has been identified to date. We have studied cytogenetically 15 cases of primary gastric cancer by direct culture of tumors cells and G-banding technique. We focused on structural aberrations observed in order to identify non-random aberrations presenting common chromosomal breakpoints. Chromosomes most commonly involved were according to frequency 1,11,14,7,17,6,8 and 13. Chromosome 11 was involved as add(11)(p15), while the pericentromeric area of chromosome 14 was constantly participated in aberrations. Isochromosomes i(1q), i(8q), i(13q), i(14q) and i(17q) were constantly found. Furthermore translocations t(1;7), t(7;14), t(6;17) and t(5;14) were identified. Conventional cytogenetics continues to be valuable in cancer study detecting genomic areas potentially candidate for the isolation of genes related to carcinogenesis. (c) 2004 Elsevier Ireland Ltd. All rights reserved

INVOLVEMENT OF CHROMOSOME-5 IN LARGE-BOWEL CANCER

We present here 3 of 30 cases of large bowel cancer cytogenetically studied, with deletion of chromosome 5. One of them presented a terminal deletion and the other two an interstitial deletion of chromosome 5q. In all three cases the segment 5q12-22 was deleted. Our findings may show that the segment 5q12-22 is important for a subgroup of colorectal cancers

Molecular cytogenetic analysis of breast cancer: a combined multicolor fluorescence in situ hybridization and G-banding study of uncultured tumor cells

In six patients with breast cancer, uncultured tumor cells were investigated with G-banding and multicolor fluorescence in situ hybridization (M-FISH). A large number of numerical and structural aberrations could be analyzed. Among other structural abnormalities, reciprocal, hidden and complex translocations were found. Recurrent t(1; 10) and t(6; 16), not previously described, were identified, as well as t(15;22). The latter was also found in additional cases among our unpublished breast carcinomas. The significance of t(15;22) for breast cancer is discussed, taking into account also data drawn from the literature. Reciprocal translocations were a prominent feature in a pseudodiploid lobular carcinoma. Hidden translocations on 6p22similar top24 were detected with M-FISH. Involvement of 6p22similar top24 was observed in five cases. The analysis of various other translocations and different structural abnormalities revealed the following common breakpoints (according to frequency of involvement): 1p34similar top36, 3p12similar top13, 4p13–>q11, 14p–>q11, 1q42, 8p11, 8q24, 10q22, 11q13, 11q23similar toq24, 13q13, and 18psimilar to10similar top11. Loss of 3p and 1p34similar top3–>pter and complete or partial loss of 13q and chromosome 17 were also found. With the combination of G-banding and M-FISH techniques, chromosome misclassification is avoided and the characterization of complex tumor karyotypes is more effective. (C) 2004 Elsevier Inc. All rights reserved