Clinicopathological and prognostic implications of genetic alterations in oral cancers

Abstract

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.

Figure 1

Kaplan-Meier estimates for (A) 11q13 gain and (B) 18q loss. In both cases, the survival rate was significantly higher in the group lacking alterations. (A) For patients with 11q13 gain, the median survival time was 12.9 months, while (B) for patients with 18q loss, it was 11.4 months. The survival time compares to a half-life of 46.4 months in the absence of either alteration.

Figure 1

Kaplan-Meier estimates for (A) 11q13 gain and (B) 18q loss. In both cases, the survival rate was significantly higher in the group lacking alterations. (A) For patients with 11q13 gain, the median survival time was 12.9 months, while (B) for patients with 18q loss, it was 11.4 months. The survival time compares to a half-life of 46.4 months in the absence of either alteration.

Figure 2

LASSO method estimates of the risk co-efficients in the Cox proportional hazards model. Co-efficients of high-level CNAs are shown as a function of the shrinkage parameter (straight lines). A shrinkage parameter of 1 denotes the unconstrained model. The first two non-vanishing co-efficients are those of +11q and −18q, followed by +3q and +9q. An evaluation of the generalized cross validation statistic (dashed line) reveals that it is minimal for a shrinkage parameter of 0.05. Only +11q and −18q contribute to the overall risk, making this combination an ideal multivariate marker.

Figure 3

Kaplan-Meier plot of the multivariate predictor with +11q13, −18q, +9q and +7p as determined by BIC. Four cohorts defined by the 25, 50, 75 and 100% quantiles of the risk function of the Cox proportional hazards model are shown. As expected, survival was shortest in the high-risk group and longest in the low-risk group. With the exception of one outlier, the lowest risk quantile had complete survival, whereas in the highest risk cohort the half-life was <10 months.

Figure 4

Bivariate predictor based on +11q13 and −18q as yielded by the LASSO method. The fraction lacking the two CNAs exhibited the lowest risk, whereas the cohort with the two alterations had the highest risk. The median survival time in the high-risk group was only 11.4 months, with 29% of the patients surviving after 24 months. By contrast, 95% of patients survived in the lowest risk group after 40 months. The presence of either of the two alterations formed an intermediate risk group with approximately 60% patient survival after 40 months.