Genomic profiling of gastric cancer predicts lymph node status and survival

Gastric carcinogenesis is driven by an accumulation of genetic changes that to a large extent occur at the chromosomal level. We analysed the patterns of chromosomal instability in 35 gastric carcinomas and their clinical correlations. With microarray competitive genomic hybridization, genomewide chromosomal copy number changes can be studied with high resolution and sensitivity. A genomewide scanning array with 2275 BAC and P1 clones spotted in triplicate was used. This array provided an average resolution of 1.4 Mb across the genome. Patterns of chromosomal aberrations were analysed by hierarchical cluster analysis of the normalized log2 tumour to normal fluorescence ratios of all clones, and cluster membership was correlated to clinicopathological data including survival. Hierarchical cluster analysis revealed three groups with different genomic profiles that correlated significantly with lymph node status (P=0.02). Moreover, gastric cancer cases from cluster 3 showed a significantly better prognosis than those from clusters 1 and 2 (P=0.02). Genomic profiling of gastric adenocarcinomas based on microarray analysis of chromosomal copy number changes predicted lymph node status and survival. The possibility to discriminate between patients with a high risk of lymph node metastasis could clinically be helpful for selecting patients for extended lymph node resection.

[1]  S. Knuutila,et al.  Presence of high-level DNA copy number gains in gastric carcinoma and severely dysplastic adenomas but not in moderately dysplastic adenomas. , 1998, Cancer genetics and cytogenetics.

[2]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[3]  J. Sheu,et al.  Correlation of histologic subtypes and replication error phenotype with comparative genomic hybridization in gastric cancer , 2001, Genes, chromosomes & cancer.

[4]  Ajay N. Jain,et al.  Assembly of microarrays for genome-wide measurement of DNA copy number , 2001, Nature Genetics.

[5]  M. Sasako,et al.  New method to evaluate the therapeutic value of lymph node dissection for gastric cancer , 1995, The British journal of surgery.

[6]  J. Arends,et al.  Colorectal adenoma to carcinoma progression follows multiple pathways of chromosomal instability. , 2002, Gastroenterology.

[7]  M M Weiss,et al.  Comparative genomic hybridisation. , 1999, Molecular pathology : MP.

[8]  P. Laurén,et al.  THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. , 1965, Acta pathologica et microbiologica Scandinavica.

[9]  E. Kuipers,et al.  Distinct chromosomal aberrations in Epstein-Barr virus-carrying gastric carcinomas tested by comparative genomic hybridization. , 2001, Gastroenterology.

[10]  Seung-Moo Noh,et al.  Genetic alterations of gastric cancer: comparative genomic hybridization and fluorescence In situ hybridization studies. , 2000, Cancer genetics and cytogenetics.

[11]  S. Knuutila,et al.  17q12‐21 amplicon, a novel recurrent genetic change in intestinal type of gastric carcinoma: A comparative genomic hybridization study , 1997, Genes, chromosomes & cancer.

[12]  D. Parkin,et al.  Global cancer statistics in the year 2000. , 2001, The Lancet. Oncology.

[13]  P. V. van Diest,et al.  Genetic analysis of 53 lymph node‐negative breast carcinomas by CGH and relation to clinical, pathological, morphometric, and DNA cytometric prognostic factors , 1998, The Journal of pathology.

[14]  E. Lander,et al.  Gene expression correlates of clinical prostate cancer behavior. , 2002, Cancer cell.

[15]  D. Gouma,et al.  Extended lymph-node dissection for gastric cancer. , 1999, The New England journal of medicine.

[16]  P. Riegman,et al.  Molecular cytogenetic evaluation of gastric cardia adenocarcinoma and precursor lesions. , 2001, The American journal of pathology.

[17]  Ash A. Alizadeh,et al.  Towards a novel classification of human malignancies based on gene expression patterns , 2001, The Journal of pathology.

[18]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[19]  W. Kuo,et al.  Quantitative mapping of amplicon structure by array CGH identifies CYP24 as a candidate oncogene , 2000, Nature Genetics.

[20]  J. Coebergh,et al.  Incidence of cancer in the Netherlands. , 2001 .

[21]  Ajay N. Jain,et al.  Fully automatic quantification of microarray image data. , 2002, Genome research.

[22]  H. P. Wang,et al.  Genetic alterations in gastric cancer: relation to histological subtypes, tumor stage, and Helicobacter pylori infection. , 1997, Gastroenterology.

[23]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  L. Hansson,et al.  Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. , 2001, Gastroenterology.

[25]  W. Kuo,et al.  High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays , 1998, Nature Genetics.

[26]  M. Blaser,et al.  Pathogenesis of the transformation from gastritis to malignancy , 1998, Alimentary pharmacology & therapeutics.

[27]  T Takahashi,et al.  Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization , 1999, Genes, chromosomes & cancer.

[28]  J. Trent,et al.  Recurrent chromosome changes in 62 primary gastric carcinomas detected by comparative genomic hybridization. , 2000, Cancer genetics and cytogenetics.

[29]  T. Poggio,et al.  Multiclass cancer diagnosis using tumor gene expression signatures , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[30]  P. Fayers,et al.  Patient survival after D 1 and D 2 resections for gastric cancer: long-term results of the MRC randomized surgical trial , 1999, British Journal of Cancer.