Bioinformatic analysis reveals an association of HOXB7 gene expression withoncogenic pathways and phenotypic properties in cancer
Authors: Sami K. Kilpinen, Reija Autio, Sampsa Hautaniemi, Outi Monni, Olli Kallioniemi
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

4799 

Expression monitoring using microarrays is a tool for characterizing gene function in cancer. We hypothesized that a mathematical approach that emphasized the underlying data structure would aid in mapping specific groups of genes to particular sample classes. Our objective was to evaluate our new tool designed to mine large scale multi dimensional data, termed, Sorting Points Into Neighborhoods (SPIN) ., We used the Affymetrix U133A GeneChip to study 144 microdissected samples from patients with colon cancer for whom clinical, pathological and outcome information is available. The samples included: 47 primary carcinomas; 24 adenomas; 22 normal colons; 16 liver metastasis; 19 lung metastasis; 11 normal liver; and 5 normal lung. SPIN utilizes traits of distance matrices to order data in a way that highlights their underlying structure. For gene array experiments SPIN provides two-way sorting, using the genes to order the samples and vice versa . Graphical output generated by SPIN includes a two-way sorted expression matrix, sorted distance matrices and PCA images colored according to the order suggested by the algorithm. SPIN’ s advantage over traditional methods (e.g., hierarchical clustering) is that the color-coded images allow the user to infer not only the partition into clusters, but also observe their shapes and relative relationships. After log-transformation and variance filtration, thousands of genes and the 144 samples were sorted by SPIN . The reordered expression matrix clearly separates the samples according to tissue types (colon, lung, liver), and also tumors from normal tissue, and adenomas from adenocarcinomas. Genes partition into several clusters; some are tissue-specific and others are associated with clinical and pathological disease state. Colon tissue that was isolated from liver metastases arrayed into an elongated, ellipsoid cluster extending from colon samples towards liver samples (a similar picture is seen for lung metastasis). The genes that induced the elongation were characteristic of liver (or lung), suggesting that this pattern reflects admixture of the metastasis samples with cells from the liver or lung. With appropriate calibration, the proportion and origin of contaminating cells can be specified. SPIN also revealed that normal colon samples arrayed in an elongated cluster. The genes responsible for this shape represented residual non-epithelial tissue. Primary colon tumor samples exhibit this pattern of elongation to a lesser extent (less admixture); however, their cluster is extended in an orthogonal direction, encompassing many cell-cycle genes. This variation apparently captures the relative quantities of proliferating cells in the samples, which are significantly higher in the tumors. Therefore, SPIN can also be utilized to estimate the proportion and type of abnormal cells in a complex mixture and to associate particular sample groups with specific changes in gene expression.