A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma

Abstract

Molecular methods for predicting prognosis in patients with oral cavity squamous cell carcinoma (OSCC) are urgently needed, considering its high recurrence rate and tendency for metastasis. The present study investigated the genetic basis of variations in gene expression associated with poor prognosis in OSCC using Affymetrix SNP 6.0 and Affymetrix GeneChip Human Gene 1.0 ST arrays. We identified recurrent DNA amplifications scattered from 8q22.2 to 8q24.3 in 112 OSCC specimens. These amplicons demonstrated significant associations with increased incidence of extracapsular spread, development of second primary malignancies, and poor survival. Fluorescence in situ hybridization, in a validation panel consisting of 295 cases, confirmed these associations. Assessment of the effects of copy number variations (CNVs) on genome-wide variations in gene expression identified a total of 85 CNV-associated transcripts enriched in the MYC-centered regulatory network. Twenty-four transcripts associated with increased risk of second primary malignancies, tumor relapse, and poor survival. Besides MYC itself, a novel dysregulated MYC module plays a key role in OSCC carcinogenesis. This study identified a candidate molecular signature associated with poor prognosis in OSCC patients, which may ultimately facilitate patient-tailored selection of therapeutic strategies.

Figure 1. Genomic loci of the common CNVs occurred in at least 40 OSCC samples.

The copy number state of each patient is reported as a column placed to both sides of each chromosome. In the right side of each chromosome, red lines denote amplifications while blue lines on the left indicate deletions. The empty columns indicate the patients with unchanged copy number of these loci.

Figure 2. Kaplan-Meier estimates for the development of second primary tumors according to the presence or absence of 8q22.2∼24.3 amplifications (log-rank test, p = 0.036).

Figure 3. Expression patterns of genes located within and outside the amplified regions.

The negative log10 p values derived from t-tests were plotted against the average intensity levels for (A) genes located within and (B) outside the amplified regions. The spline curves were fit to extract the main trend of the data.

Figure 4. MYC-centered regulatory network for the CNV-associated genes in OSCC.

The green nodes indicate the top five influential transcriptional factors. The MYC regulates the other four transcription factors (blue arrows). Yellow nodes denote cis-control genes while red nodes represent trans-control genes (only the top five transcriptional modules were plotted).