Dataset Information

Clustering of molecular alterations in gastroesophageal carcinomas.

ABSTRACT: Gene expression levels are regulated at many levels. Integration of genome-wide analyses for the study of DNA and RNA provides a unique tool to detect genetic alterations in the cancer genome. In this study, we generated and integrated DNA amplification data from comparative genomic hybridization (CGH) and serial analyses of gene expression (SAGE) in order to obtain a molecular profile of gastroesophageal junction (GEJ) carcinomas. DNA amplifications mapped to specific chromosomal regions and were frequently seen at 1q, 4q, 5q, 6p, 7p, 8q, 17q, and 20q. Using SAGE, we obtained over 156,432 tags from GEJ adenocarcinomas and normal gastric mucosa. These tags were assigned to UniGene clusters. Chromosomal positions for overexpressed genes were obtained to produce a GEJ carcinoma transcriptome map. A total of 123 genes was significantly overexpressed (more than fivefold; P <.01) in one or more SAGE libraries. This gene overexpression map was integrated and compared to the chromosomal CGH ideogram. Several chromosomal arms that had frequent DNA amplifications showed frequent gene expression alterations such as chromosomes 1 (15 genes), 2 (9 genes), 6 (6 genes), 11 (6 genes), 12 (8 genes), and 17 (13 genes). Despite the relatively large DNA amplification regions, overexpressed genes frequently mapped and clustered to small chromosomal regions at early-replicating (Giemsa light) bands such as 1q21.3 (nine genes), 6p21.3 (five genes), and 17q21 (eight genes). These results provide a comprehensive tool to search for DNA amplifications and overexpressed genes in GEJ carcinoma. The observed phenomenon of the presence of large amplification areas, yet clustering of overexpressed genes to relatively small loci, may suggest a high organization of chromatin and cancer-related genes in the nucleus.

SUBMITTER: Koon N

PROVIDER: S-EPMC1502088 | biostudies-literature | 2004 Mar-Apr

REPOSITORIES: biostudies-literature

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Clustering of molecular alterations in gastroesophageal carcinomas.

Koon Natalie N Zaika Alexander A Moskaluk Christopher A CA Frierson Henry F HF Knuutila Sakari S Powell Steven M SM El-Rifai Wa'el W

Neoplasia (New York, N.Y.) 20040301 2

Gene expression levels are regulated at many levels. Integration of genome-wide analyses for the study of DNA and RNA provides a unique tool to detect genetic alterations in the cancer genome. In this study, we generated and integrated DNA amplification data from comparative genomic hybridization (CGH) and serial analyses of gene expression (SAGE) in order to obtain a molecular profile of gastroesophageal junction (GEJ) carcinomas. DNA amplifications mapped to specific chromosomal regions and we ...[more]

PMID: 15140403

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Project description:BackgroundHer2 expression and amplification occurs in a significant subset of gastro-esophageal carcinomas. Her2 is a client protein of molecular chaperones, e.g. heat shock protein (HSP) 90, rendering targeted therapies against Her2/HSP90 an interesting approach. This study aimed to investigate the role and relationship of Her2 and HSP90 in gastric and gastro-esophageal adenocarcinomas.Material and methodsImmunohistochemical determination of HSP90 and Her2 expression was performed on 347 primary resected tumors. Her2 amplification was additionally determined by fluorescence in situ hybridization for all cases. Expression and amplification results were correlated with pathologic parameters (UICC pTNM category, tumor grading) and survival.ResultsElevated Her2 copy numbers were observed in 87 tumors, 21 of them showing amplification. 174 tumors showed Her2 immunoreactivity/expression. HSP 90 immunoreactivity was found in 125 tumors. There was no difference between gastric carcinomas and carcinomas of the gastroesophageal junction regarding Her2 or HSP90. Both high HSP90 and Her2 expression/amplification were associated with earlier tumor stages (p<0.01), absence of lymph node metastases (p<0.02) and Laurens intestinal type (p<0.001). HSP90 correlated with Her2 expression and amplification (p<0.001 each). Expressions of HSP90 and Her2, but not Her2 amplification were associated with better prognosis (p=0.02; p=0.004; p=0.802). Moreover, Her2 expression was an independent prognostic factor for overall survival in the subgroup of gastric carcinoma patients (p=0.014) besides pT category, pN category and distant metastases.ConclusionHer2 expression and gene amplification occurred in a significant subset of cases. Our results suggest a favorable prognostic impact of Her2 expression. This warrants further investigations regarding the significance of Her2 non-amplified tumors showing Her2 immunoreactivity and the definition of Her2 status in gastric cancers. Moreover, the correlation of Her2 expression with the expression of Her2 chaperoning HSP90 may indicate a synergistic regulation. Targeting HSP90 with or without Her2 may offer additional therapeutic options for gastric carcinoma treatment.

Project description:Adenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival. There are few data directly comparing the frequencies of single nucleotide mutations in cancer-related genes between the two sites. Sequencing of targeted gene panels may be useful in uncovering multiple genomic aberrations using a single test.DNA from 92 gastroesophageal junction and 75 gastric adenocarcinoma resection specimens was extracted from formalin-fixed paraffin-embedded tissue. Targeted deep sequencing of 46 cancer-related genes was performed through emulsion PCR followed by semiconductor-based sequencing. Gastroesophageal junction and gastric carcinomas were contrasted with respect to mutational profiles, immunohistochemistry and in situ hybridization, as well as corresponding clinicopathologic data.Gastroesophageal junction carcinomas were associated with younger age, more frequent intestinal-type histology, more frequent p53 overexpression, and worse disease-free survival on multivariable analysis. Among all cases, 145 mutations were detected in 31 genes. TP53 mutations were the most common abnormality detected, and were more common in gastroesophageal junction carcinomas (42% vs. 27%, p?=?0.036). Mutations in the Wnt pathway components APC and CTNNB1 were more common among gastric carcinomas (16% vs. 3%, p?=?0.006), and gastric carcinomas were more likely to have ?3 driver mutations detected (11% vs. 2%, p?=?0.044). Twenty percent of cases had potentially actionable mutations identified. R132H and R132C missense mutations in the IDH1 gene were observed, and are the first reported mutations of their kind in gastric carcinoma.Panel sequencing of routine pathology material can yield mutational information on several driver genes, including some for which targeted therapies are available. Differing rates of mutations and clinicopathologic differences support a distinction between adenocarcinomas that arise in the gastroesophageal junction and those that arise in the stomach proper.

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Clustering of molecular alterations in gastroesophageal carcinomas.

Publications

Clustering of molecular alterations in gastroesophageal carcinomas.

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