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 18q as an early event. The mixture model suggested two independent pathways namely a major pathway with 28p and a less frequent pathway with 19q. The distance-based tree identified three progression pathways, one characterized by 28p, another by 23p and the third by alterations 111q and 17p. Differences were observed in cytogenetic pathways of node-positive and node-negative oral cancers. Nodepositive cancers were characterized by more non-random aberrations (n 5 11) and progressed via 28p or 23p. On the other hand, node-negative cancers involved fewer non-random alterations (n 5 6) and progressed along 23p. In summary, the tree models for oral cancers provided novel information about the interactions between genetic alterations and predicted their probable order of occurrence. ' UICCKey words: oral cancer; CGH; comparative genomic hybridization; oncogenetic tree; progression pathways; genetic progression score Oral squamous cell carcinomas (OSCC), like all solid tumors, are characterized by multiple chromosomal alterations and are genetically complex. 1 Dependencies between the numerous genetic alterations lead to observed karyotypic complexity, which results in the distinct biological behavior of oral cancers. 2 For example, node-positive OSCC are biologically aggressive and have poor prognosis when compared with the node-negative OSCC. 3 This indicates that different genetic pathways of progression exist in oral cancers, leading to the molecular subtypes with distinct clinical outcomes. Hence, it is necessary to identify the genetic alterations and the interactions between them that form multiple progression pathways. This approach may aid in better understanding the biology of oral carcinomas.Comparative genomic hybridization (CGH), a genome-wide profiling technique, has revealed non-random pattern of genetic alterations in oral cancers. 4-9 An early study suggested that genomic alterations in OSCC may be more uniform than those of other solid tumors, 5 but a more recent study demonstrated that the initiation and progression of oral cancers involves divergent pathways. 9 Because, the study used frequency analysis, it could not evaluate interactions between the alterations and provided limited information on genetic pathways. Thus, it is desirable to use additional statistical methods that account for interactions and can estimate genetic pathways of cancer progression from CGH data.Cancer progression has been des...

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.

No abstract