Clinicopathological and prognostic implications of genetic alterations in oral cancers.

This study evaluated the clinicopathological and prognostic implications of genetic alterations characterizing oral squamous cell carcinoma(OSCC). Comparative genomic hybridization(CGH) was used to identify chromosomal alterations present in primary OSCCs obtained from 97 pateints. In this population, tobacco use was a significant risk factor for OSCC. By contrast, all 97 of our samples are negative for human papillomavirus (HPV) DNA integration, which is another known risk factor for OSCC in certain populations. Results of the Fisher's exact test followed by Benjamini-Hochberg correction for multiple testing, showed a correlation of 7p gain and 8p loss with node-positive OSCC (p≤0.04 for both genetic alterations) and association of 11q13 gain with high-grade OSCC (p≤0.05). Univariate Cox-proportional hazard models, also corrected for multiple testing, showed significant association of 11q13 gain and 18q loss with decreased survival (p≤0.05). These findings were supported by multivariate analysis which revealed that 11q13 gain and 18q loss together serve as a strong bivariate predictor of poor prognosis. In conclusion, our study has identified genetic alterations that correlate significantly with nodal status, grade, and poor survival status of OSCC. These potential biomarkers may aid the current TNM system for better prediction of clinical outcome.

Gene Expression Profiling of Gastric Cancer.

Gastric cancer is the second leading cause of cancer death worldwide, both in men and women. A genomewide gene expression analysis was carried out to identify differentially expressed genes in gastric adenocarcinoma tissues as compared to adjacent normal tissues. We used Agilent's whole human genome oligonucleotide microarray platform representing ~41,000 genes to carry out gene expression analysis. Two-color microarray analysis was employed to directly compare the expression of genes between tumor and normal tissues. Through this approach, we identified several previously known candidate genes along with a number of novel candidate genes in gastric cancer. Testican-1 (SPOCK1) was one of the novel molecules that was 10-fold upregulated in tumors. Using tissue microarrays, we validated the expression of testican-1 by immunohistochemical staining. It was overexpressed in 56% (160/282) of the cases tested. Pathway analysis led to the identification of several networks in which SPOCK1 was among the topmost networks of interacting genes. By gene enrichment analysis, we identified several genes involved in cell adhesion and cell proliferation to be significantly upregulated while those corresponding to metabolic pathways were significantly downregulated. The differentially expressed genes identified in this study are candidate biomarkers for gastric adenoacarcinoma.

Construction of oncogenetic tree models reveals multiple pathways of oral cancer progression.

Oral cancer develops and progresses by accumulation of genetic alterations. The interrelationship between these alterations and their sequence of occurrence in oral cancers has not been thoroughly understood. In the present study, we applied oncogenetic tree models to comparative genomic hybridization (CGH) data of 97 primary oral cancers to identify pathways of progression. CGH revealed the most frequent gains on chromosomes 8q (72.4%) and 9q (41.2%) and frequent losses on 3p (49.5%) and 8p (47.5%). Both mixture and distance-based tree models suggested multiple progression pathways and identified +8q as an early event. The mixture model suggested two independent pathways namely a major pathway with -8p and a less frequent pathway with +9q. The distance-based tree identified three progression pathways, one characterized by -8p, another by -3p and the third by alterations +11q and +7p. Differences were observed in cytogenetic pathways of node-positive and node-negative oral cancers. Node-positive cancers were characterized by more non-random aberrations (n = 11) and progressed via -8p or -3p. On the other hand, node-negative cancers involved fewer non-random alterations (n = 6) and progressed along -3p. In summary, the tree models for oral cancers provided novel information about the interactions between genetic alterations and predicted their probable order of occurrence.