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. 2008 Oct;30(10):1273-83.
doi: 10.1002/hed.20871.

Molecular signatures of metastasis in head and neck cancer

Stefano Colella  1 , Kristy L Richards, Linda L Bachinski, Keith A Baggerly, Spiridon Tsavachidis, James C Lang, David E Schuller, Ralf Krahe
Affiliations

Molecular signatures of metastasis in head and neck cancer

"VSports在线直播" Stefano Colella et al. Head Neck. 2008 Oct.

Abstract

Background: Metastases are the primary cause of cancer treatment failure and death, yet metastatic mechanisms remain incompletely understood. VSports手机版.

Methods: We studied the molecular basis of head and neck cancer metastasis by transcriptionally profiling 70 samples from 27 patients-matching normal adjacent tissue, primary tumor, and cervical lymph node metastases. V体育安卓版.

Results: We identified tumor-associated expression signatures common to both primary tumors and metastases. Use of matching metastases revealed an additional 46 dysregulated genes associated solely with head and neck cancer metastasis. However, despite being metastasis-specific in our sample set, these 46 genes are concordant with genes previously discovered in primary tumors that metastasized. V体育ios版.

Conclusions: Although our data and related studies show that most of the metastatic potential appears to be inherent to the primary tumor, they are also consistent with the notion that a limited number of additional clonal changes are necessary to yield the final metastatic cell(s), albeit in a variable temporal order. VSports最新版本.

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Figures

FIGURE 1
FIGURE 1
Analyses of expression profiles generated from the 4509 pseudo probe set genes. (A) Principal component analysis (PCA) showing all 70 samples plotted for the first 3 principal components derived using the expression matrix. The expression values for each gene were log-transformed and centered before computing the principal components. Green dots are normals, yellows are primary tumors, and reds are metastases; lines also join matched primary tumors and metastases. There is a clear separation between the genetically matching normal adjacent samples and tumor samples (primary tumors and metastases). Most metastases are closer to their corresponding primary tumors than to other metastasis profiles. (B) Pairwise distance matrix (PDM) between all 70 samples, using Euclidean distance applied to robust multichip average (RMA) quantifications of all 4509 pseudo probe set genes. The order of normals (N), primary tumors (P), and metastases (M) is the same within blocks. Distances between normals and tumors of all types are greater than distances between normals and other normals, or between tumors and other tumors. The comparison of primary tumors with metastases provided evidence for a tumor-specific signature indicated by shorter distances from primary tumors to their corresponding metastases compared with other metastases. This closer relatedness is visible as a darker blue diagonal in the primary tumor versus lymph node metastasis comparison in the upper left corner of the block of distances between primary tumor and lymph node metastasis.
FIGURE 1
FIGURE 1
Analyses of expression profiles generated from the 4509 pseudo probe set genes. (A) Principal component analysis (PCA) showing all 70 samples plotted for the first 3 principal components derived using the expression matrix. The expression values for each gene were log-transformed and centered before computing the principal components. Green dots are normals, yellows are primary tumors, and reds are metastases; lines also join matched primary tumors and metastases. There is a clear separation between the genetically matching normal adjacent samples and tumor samples (primary tumors and metastases). Most metastases are closer to their corresponding primary tumors than to other metastasis profiles. (B) Pairwise distance matrix (PDM) between all 70 samples, using Euclidean distance applied to robust multichip average (RMA) quantifications of all 4509 pseudo probe set genes. The order of normals (N), primary tumors (P), and metastases (M) is the same within blocks. Distances between normals and tumors of all types are greater than distances between normals and other normals, or between tumors and other tumors. The comparison of primary tumors with metastases provided evidence for a tumor-specific signature indicated by shorter distances from primary tumors to their corresponding metastases compared with other metastases. This closer relatedness is visible as a darker blue diagonal in the primary tumor versus lymph node metastasis comparison in the upper left corner of the block of distances between primary tumor and lymph node metastasis.
FIGURE 2
FIGURE 2
Two-way hierarchical cluster analysis of gene expression profiles generated on pseudo probe set gene expression data. Hierarchical clustering of all 70 samples (cell lines to the side) from both chip types using Euclidean distance and complete linkage applied to robust multichip average (RMA) quantifications of the 338 pseudo-probe sets passing the rank filter. Normals (N) cluster to the left, tumors to the right. Of particular interest is that most primary tumors (P) and lymph node metastases (M) from the same patient show pairing (9 of 14, 64% highlighted by thicker lines). Two primary tumor samples obtained from the same patient before and after treatment (P13 and P3) are also very near in the hierarchical samples cluster, suggesting a patient-specific tumor signature.
FIGURE 3
FIGURE 3
Expression levels for specific genes in sets of genetically matching normal adjacent mucosae (●), primary tumors (□), and metastatic lymph nodes (*). The data plotted for different sample sets (S) show considerable variation in expression levels across individual sets for the same gene in the same tissue types. For each patient sample set, the general trend of dysregulation (overexpression or underexpression) is in the same direction, whereas levels across all patient sets overlap. The plots highlight the utility of the matched-based analysis approach, which improves the sensitivity of the analysis. Representative genes (A) overexpressed (OSF-2) or (B) underexpressed (KER4) in primary tumor and lymph node metastasis relative to their genetically matched normal adjacent tissue sample, in ascending order of expression in the normal tissue. Representative genes (C) overexpressed (CYP1B) or (D) under-expressed (MMP3) in lymph node metastasis relative to their genetically matched primary tumor sample, in ascending order of expression in the primary tumor.
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