Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization

doi:10.1016/S0165-4608(00)00306-X

Cancer Genetics and Cytogenetics

Volume 123, Issue 1, November 2000, Pages 27-34

https://doi.org/10.1016/S0165-4608(00)00306-X Get rights and content

Abstract

Comparative genomic hybridization (CGH) has been applied to detect recurrent chromosome alterations in 62 primary gastric carcinomas. Several nonrandom chromosomal changes, including gains of 8q (31 cases, 50%), 20q (29 cases, 47%) with a minimum gain region at 20q11.2–q12, 13q (21 cases, 34%) with a minimum gain region at 13q22, and 3q (19 cases, 31%) were commonly observed. The regions most frequently lost included: 19p (23 cases, 37%), 17p (21 cases, 33%), and 1p (14 cases, 23%). High copy number gain (DNA sequence amplification) was detected in 6 cases. Amplification of 8q23–q24.2 and 20q11.2–q12 were observed in 3 cases. Gain of 20q and loss of 19p were confirmed by fluorescence in situ hybridization using corresponding bacterial artificial chromosomes (BAC) clones from those regions. The gain and loss of chromosomal regions identified in this study provide candidate regions involved in gastric tumorigenesis.

Introduction

Gastric cancer is considered to be the second most common cancer worldwide [1], affecting approximately 24,000 persons in the United States in 1994 [2]. The prognosis for gastric adenocarcinoma is very poor, with 5-year survival rates ranging from 5% to 20% [3]. The development of new diagnostic, preventive, and treatment approaches requires a good understanding of the mechanisms of the complex multistep process of tumorigenesis in the gastric cancer. Although several studies have been performed to study the relationship between gastric cancer and known oncogenes and tumor suppressors (e.g., amplification of ERBB-2 [4], K-SAM [5], and C-MET [6], mutations of the TP53 [7], and APC [8] genes], very little information is available detailing recurring chromosome alterations in gastric cancer because of the difficulties in karyotype analysis with conventional chromosome banding techniques.

Comparative genomic hybridization (CGH) is an approach to analyze the entire genome for regional variations of DNA sequence copy number (gain, loss, and amplification of DNA sequences) in a single experiment [9]. In CGH, equal amounts of total genomic DNA from a tumor sample and a normal control tissue are labeled with green or red fluorochromes and simultaneously hybridized to normal metaphase chromosomes. After hybridization, the fluorescence ratio between tumor and normal DNA along each reference chromosome is measured and analyzed. This technique can detect recurrent copy number changes and may highlight chromosomal regions containing genes that contribute to cancer development and/or progression. Since it was developed, CGH has been applied to study genetic alteration in many solid tumors including gastric cancer 10, 11, 12. This report using CGH examines 69 primary gastric carcinomas with several recurring chromosomal alterations that include the gain of 3q, 8q, 13q, 20q, and the loss of 1p, 17p, and 19p. Gain of 20q and loss of 19p were confirmed by interphase fluorescence in situ hybridization (FISH) using corresponding bacterial artificial chromosomes (BAC) clones.

Section snippets

Primary tumor specimens and DNA extraction

All 69 cases in this study were untreated patients from whom primary tumor tissue was collected at the time of surgical resection at the Department of Surgery, Harbin Medical University (Harbin, China), Cancer Hospital, Sun Yat-Sen University of Medical Science (Guangzhou, China), and the Department of Surgery, Norman Bethune Medical University (Changchun, China). The clinical and histopathologic data are summarized in Table 1. Tumor tissue was selected by histopathologic examination on the

Comparative genomic hybridization analysis

Comparative genomic hybridization analysis was carried out on 69 cases of primary gastric cancers. Of 69 cases, 62 showed chromosome imbalances. Three histopathologic subtypes of gastric cancer were analyzed in this study, including adenocarcinoma (44 cases), signet-ring carcinoma (9 cases), and mucin-producing adenocarcinoma (9 cases). All changes in DNA sequence copy number for the entire genome detected in these 62 primary gastric cancers are listed in Table 1 and summarized in Fig. 1. Fig. 2

Discussion

In the present study, 62 primary gastric cancers were analyzed by comparative genomic hybridization. The findings in this study are in general agreement with previous LOH and CGH results. For example, gain of 8q, 20q, and loss of 1p, 17p, and 19p have been detected as frequent chromosomal alterations in gastric cancer in at least one of the previous CGH studies 10, 11, 12.

Over-representation of 8q and 20q was the most prominent feature in this study. Gain of 8q was detected in 31/62 cases

Acknowledgements

This study is supported in part by the Leung Kwok Tze Foundation and by a Chinese National Outstading Young Scientist Award (No. 39825511).

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Some additional markers are expounded on in the following sections. Potential biomarkers, such as phospholipase A2, signature profiles of gene expression, or copy number alterations identified may ultimately provide useful prognostic as well as diagnostic information about GC.98,140,141 Elevated tissue levels of certain proteins have been shown to be associated with increased invasiveness of tumor cells, and some even associated with poorer survival, including urokinase-type plasminogen activator (uPA), VEGF, MET, MYC, tie-1 protein tyrosine kinase, CD44v6, PDGF-A, TGF-β1, and cyclin D2.67
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However, gains at 8q23 observed in this study have not been correlated with any of the clinicopathological properties. Gains in 7 have been the second highest among the most common (28%) observed in this study (Figures 1A and 1B) but have not provided enough evidence to support an association with TNM staging, tumor grade, and H. pylori infection status despite the fact that involvement of 7 p gains in gastric cancer has been extensively reported (15,16,18,26–28). In this study, the MOR in gains of 7 has been assigned to 7p21, which has been congruous with the previous studies in gastric cancer, e.g., Morohara et al. reported the gain of 7p21 in differentiated-type gastric carcinomas and showed its association with the intestinal-phenotype (I-phenotype) tumors (29).
Multiple genetic alterations are responsible for development and progression of gastric cancer which is one of the leading causes of cancer-related deaths worldwide. The aim of this study was to identify the genomic imbalances of gains and/or losses in gastric adenocarcinomas from Turkish patients and to investigate their association with development and progression of this type of cancer.
Forty three patients with gastric adenocarcinoma were enrolled in this study and genomic imbalances were analyzed by high-resolution–comparative genomic hybridization (HR–CGH).
In 36/43 cases (84%) of gastric adenocarcinomas, genomic imbalances have involved all chromosomes in various combinations. The mean number of gains was 3.95 ± 4.19 and the most common gains observed were 7q (35%), 8q (35%), 7 p (28%), 1q (26%), 13q (26%), and 20q (21%). The calculated mean number of losses was 3.65 ± 3.55 and the most common losses were found on arms 18q (26%), 5q (21%), and 14q (21%). High-level amplifications involved chromosomes 1, 7, 8, 9, 13, and 16. No significant differences in chromosomal imbalances were observed in different tumor stages, tumor grades, and Helicobacter pylori infection status groups. The most striking result in this study was the involvement of the 13q gains with increased lymph node metastasis (p = 0.046). Late-stage tumors displayed a somewhat significantly higher number of losses than early-stage tumors (p = 0.053).
A series of gains, losses and amplifications concerned with gastric adenocarcinoma identified in this study are presented in detail. In particular, 13q21–q32 was prominent because it has been linked to increased lymph node metastasis.
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Loss of chromosomal region 11q was also one of the most frequent findings in our study. Other studies only rarely identified loss of 11q using CGH or CGH-array in CG tumors [5,17,34,36,37,41]. Inconsistencies regarding the pattern of genetic imbalances in GC between our study and studies involving other populations may be suggestive of distinct gastric carcinogenesis pathways in different ethnic composition or even geographic regions.
Gastric adenocarcinoma is a serious public health concern, especially in northern Brazil. Gastric cancer can be subdivided into diffuse and intestinal types. Genetic imbalances in diffuse-type gastric cancer remain largely unknown. In the present study, we analyzed 24 advanced diffuse-type gastric cancer samples from northern Brazil subjects using high-resolution comparative genomic hybridization. We found chromosomal alterations in 75% of samples. In cancers with aneusomies, the mean genomic copy number alteration was 6.4. Losses of chromosome regions exceeded gains. The most frequent losses were located at chromosome regions 11q and 18q (five samples for each region), 1pq, 3q, 4q, 5q, 13q, and 14q (four samples), followed by 2pq, 7p, 9pq, 11p, and 16p (three samples). Our results confirm that gastric cancer has a complex pattern of chromosomal alterations that can be due to general chromosomal instability related to the advanced stage of gastric carcinogenesis. Loss of 11q and 18q were the most frequent chromosomal changes in diffuse-type gastric adenocarcinoma in individuals from northern Brazil. Frequent loss of 11q chromosome region in this gastric cancer may be peculiar among this population.
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Recurrent chromosomal changes in ovarian carcinoma have been extensively analyzed by comparative genomic hybridization (CGH) with several amplified regions including 3q or parts of 3q, being reported [5–8]. Amplification of 3q also has been detected frequently in other solid malignant tumors including esophageal carcinoma [9], lung carcinoma [10], gastric carcinoma [11], colorectal carcinoma [12] and other neoplasms [13,14], suggesting that human chromosome 3q contains oncogenes related to tumorigenesis and progression of a number of different solid tumors. Using a chromosome microdissection-hybrid selection method, we have previously isolated a novel candidate oncogene, eIF-5A2 (eukaryotic initiation factor 5A2), from a primary ovarian cancer cell line UACC-1598 containing a high-copy-number amplification of 3q26 [15].
Our previous study has suggested an oncogenic role of eIF-5A2 in ovarian tumorigenesis. Abnormalities of eIF-5A2 and its clinical/prognostic significance, however, in ovarian carcinoma are unclear.
In this study, we examined expression of EIF-5A2, using immunohistochemistry, in 30 normal ovaries, 30 ovarian cystadenomas, 30 borderline ovarian tumors and 110 ovarian carcinomas. The amplification status of eIF-5A2 in each ovarian carcinoma was assessed by fluorescence in situ hybridization.
Overexpression of EIF-5A2 was detected in none of the normal ovaries, 7% cystadenomas, 30% borderline tumors, and 53% invasive ovarian carcinomas, respectively. Amplification of eIF-5A2 was detected in 16% of informative ovarian carcinomas. In ovarian carcinomas, significant positive associations were found between overexpression of EIF-5A2 and the tumors ascending grade, later pT/pN and FIGO stages, as well as increased positive rate of Ki-67 (p < 0.05). In univariate survival analysis of the ovarian carcinoma cohorts, a significant association of overexpression of EIF-5A2 with shortened patient survival (mean 39.0 months vs 69.5 months, p < 0.001) was demonstrated. Importantly, EIF-5A2 expression provided significant independent prognostic parameters in multivariate analysis (p = 0.043).
These findings suggest that increased expression of EIF-5A2 in ovarian carcinoma may represent an acquired malignant phenotypic feature of tumor cells, and the overexpression of EIF-5A2, as detected by immunohistochemistry, is an independent molecular marker for shortened survival time of patients with ovarian carcinoma.
Cytogenetic and molecular aspects of gastric cancer: Clinical implications
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Gastric cancer is of major importance world-wide being the second most common cause of cancer-related death in the world. According to Lauren’s histological classification gastric cancer is divided in two groups, the better differentiated intestinal carcinomas and the poorly differentiated diffuse-type cancers. The genetic changes underlying the initiation and progression of gastric cancer are not well defined. Gastric carcinogenesis is a multistep process involving a number of genetic and epigenetic factors. Although it has been proposed that different genetic pathways exist for differentiated and undifferentiated carcinomas, the two histological subtypes of gastric cancer share some common genetic alterations. Currently, tumor histology and pathologic stage are the major prognostic variables used in the clinical practice for gastric cancer patients. However, it is known that tumors with similar morphology may differ in biological aggressiveness, prognosis and response to treatment. Molecular genetic analysis of gastric cancer revealed a number of associations of certain genetic changes with pathological features, tumor biological behavior and prognosis of gastric cancer patients, suggesting that these genetic abnormalities might play an important role in gastric tumorigenesis. Increasing evidence suggests that the molecular genetic changes could be helpful in the clinical setting, contributing to prognosis and management of patients. Regarding epigenetic events in gastric tumorigenesis, a number of methylating markers have been proposed for risk assessment, prognostic evaluation and as therapeutic targets. However, further research is required in order to systematically investigate the genetic changes in gastric cancer estimating also their usefulness in the clinical practice. A good understanding of the genetic changes underlying gastric carcinogenesis may provide new perspectives for prognosis and screening of high risk individuals. Some of the genetic alterations could definitely improve tumor classification and management of gastric cancer patients. Also, based on molecular data identified in gastric cancer novel therapeutics might help to improve the treatment of this disease.
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Our previous study has suggested an oncogenic role of eIF-5A2 in ovarian tumorigenesis. Abnormalities of eIF-5A2, however, in colorectal carcinoma are unclear. In this study, amplification and overexpression of eIF-5A2 in colorectal carcinoma were studied by fluorescence in situ hybridization and immunohistochemistry using colorectal carcinoma tissue microarrays, including 139 primary colorectal carcinomas and their adjacent normal mucosa, 22 paired premalignant adenomas, and 42 metastatic tumors. The immunohistochemistry results showed that overexpression of EIF-5A2 was detected in none of normal epithelial mucosa, 35.3% of colorectal adenomas, 53.2% of primary colorectal carcinomas, and 67.6% of metastases. Amplification of eIF-5A2 was detected in 15.8% (16/101) of informative colorectal carcinomas, and most of them showed overexpression of EIF-5A2. In primary colorectal carcinomas, the frequency of EIF-5A2 overexpression was significantly higher in colorectal carcinomas with lymphovascular invasion (61.2%) than that in colorectal carcinomas without lymphovascular invasion (36.6%, P < .05). In addition, significant positive associations were found between EIF-5A2 overexpression and the tumors' later pN and pM stages, as well as increased tumor cell proliferation (P < .05). These findings suggest that overexpression of EIF-5A2 in colorectal carcinomas may be important in the acquisition of a metastatic phenotype and plays an important role in colorectal carcinoma development and progression.

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¹: These authors contributed equally to this work.

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Original articlesRecurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization

Abstract

Introduction

Section snippets

Primary tumor specimens and DNA extraction

Comparative genomic hybridization analysis

Discussion

Acknowledgements

Estimates of the worldwide frequency of sixteen major cancers in 1980

Int J Cancer

Cancer statistics 1994

CA Cancer J Clin

Genetics of gastric cancer

Anticancer Res

Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by amplification of the v-erbA homologue

Oncogene

The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer

Cancer Res

Aberrant expression of c-met mRNA in human gastric carcinomas

Int J Cancer

Detection of frequent p53 gene mutations in primary gastric cancer by cell sorting and polymerase chain reaction single-strand conformation polymorphism analysis

Cancer Res

K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes

Proc Natl Acad Sci USA

Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors

Science

17q12–21 amplicon, a novel recurrent genetic change in intestinal type of gastric carcinomaa comparative genomic hybridization study

Genes Chromosom Cancer

Mapping of chromosomal imbalances in gastric adenocarcinoma revealed amplified protooncogenes MYCN, MET, WNT2, and ERBB2

Genes Chromosom Cancer

Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization

Genes Chromosom Cancer

Original articles
Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization