Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles

Abstract

Molecular classification of tumors based on their gene expression profiles promises to significantly refine diagnosis and management of cancer patients. The establishment of organ-specific gene expression patterns represents a crucial first step in the clinical application of the molecular approach. Here, we report on the gene expression profiles of 154 primary adenocarcinomas of the lung, colon, and ovary. Using high-density oligonucleotide arrays with 7129 gene probe sets, comprehensive gene expression profiles of 57 lung, 51 colon, and 46 ovary adenocarcinomas were generated and subjected to principle component analysis and to a cross-validated prediction analysis using nearest neighbor classification. These statistical analyses resulted in the classification of 152 of 154 of the adenocarcinomas in an organ-specific manner and identified genes expressed in a putative tissue-specific manner for each tumor type. Furthermore, two tumors were identified, one in the colon group and another in the ovarian group, that did not conform to their respective organ-specific cohorts. Investigation of these outlier tumors by immunohistochemical profiling revealed the ovarian tumor was consistent with a metastatic adenocarcinoma of colonic origin and the colonic tumor was a pleomorphic mesenchymal tumor, probably a leiomyosarcoma, rather than an epithelial tumor. Our results demonstrate the ability of gene expression profiles to classify tumors and suggest that determination of organ-specific gene expression profiles will play a significant role in a wide variety of clinical settings, including molecular diagnosis and classification.

Figure 1.

PCA of all genes. Four PCA views of the gene expression profiles, generated by stratifying the all of the genes analyzed into four quarters of equal size (see Results). Colon cohort, red; lung cohort, green; and ovary cohort, blue.

Figure 2.

PCA of selected genes. PCA view of the top 60 differentially expressed genes (20 from each tumor type). Arrowheads show the two outlier tumors, one within the colonic group and one distinct from the three tumor groups. Arrows highlight the group of mucinous ovarian tumors that are seen as colon-like. Colon cohort, red; lung cohort, green; and ovary cohort, blue.

Figure 3.

Histopathological and immunohistochemical analysis of colonic (A–C) and ovarian outlier tumors (D–G). A: H&E stain. B: Vimentin immunostain. C: Cytokeratin cocktail immunostain. D: H&E stain. E: CK20 immunostain. F: CK7 immunostain, and G: CEA immunostain. Original magnifications, ×200.