Site-Specific Molecular Signatures Predict Aggressive Disease in HNSCC

Abstract

It is known that head and neck squamous cell carcinomas (HNSCC) originating from different anatomic locations can exhibit varying behavior that is not predictable by histopathology of the primary tumor. Using a microarray containing 27,323 cDNA clones, we generated sets of gene expression profiles for 36 HNSCC primary tumors (12 oral cavity, 12 oropharynx, and 12 larynx/ hypopharynx). From these datasets, we ranked genes according to their ability to differentiate between patients whose disease progressed within a 24 month period (aggressive phenotype) and those that did not (nonaggressive phenotype) based on levels of gene expression. A merging of datasets from the three sites revealed that only a fraction of identified genes were shared between any two sites. This contrasted greatly with the significant overlap (approximately 50%) in down-regulated genes identified in tumor/normal comparisons using cases both from oropharynx and larynx/hypopharynx. From these data, we conclude that HNSCC tumors originating from different anatomic sites share consistent changes in gene expression when comparing primary tumors to normal adjacent mucosa; these common changes most likely reflect alterations required for tumor development. In contrast, once a tumor has developed, tumor-host interactions at the different anatomic sites are likely responsible for the site-specific signatures associated with aggressive versus non-aggressive disease. Predictions of outcome based on gene expression profiling are therefore heavily influenced by the anatomic site of the primary tumor.

Identification of site-specific prognostic biomarkers in patients with oral squamous cell carcinoma

“…It seems to grow faster than other sites of the oral cavity and, more frequently metastasize to cervical lymph nodes with a poorer prognosis [10]. Moreover, an analysis of the Surveillance, Epidemiology, and End-Results (SEER) registry data for head and neck squamous cell carcinomas (HNSCC) demonstrated that site-specific differences in this entity may also be seen in the varied treatment approaches [11]. However, the causes for such differences in tumor behavior remain enigmatic.…”

Transcriptome sequencing uncovers novel long noncoding and small nucleolar RNAs dysregulated in head and neck squamous cell carcinoma

“…A number of studies have identified molecular distinctions among HNSCCs of varying anatomic origin (Rodrigo et al 2001;Belbin et al 2008;Kokko et al 2011;Lleras et al 2013). CD44 expression, for instance, was found to be predictive of 5-yr survival in primary pharyngeal and laryngeal tumors, but not in tumors arising in the oral cavity (Kokko et al 2011).…”

Current potential and limitations of molecular diagnostic methods in head and neck cancer

“…Global genomic analyses have identified molecular subsets of HNSCC, which may have prognostic implications [2,33,44,45]. The challenge has been to reproduce prognostic gene signatures.…”

“…In addition, it has been recently shown that differences in gene expression related to aggressiveness of HNSCC disease are highly site specific. Therefore, it is plausible that specific biological mechanisms underlying tumor aggressiveness are heavily influenced by the anatomic site of the primary tumor such that different mechanisms offer advantage only within the specific environment of a single anatomic site [2].…”

“…governing head and neck cancer progression [1,2]. It could be expected that the identification of molecular signatures and understanding mechanisms of tumor progression may facilitate the identification of new predictive and prognostic markers and new therapeutic targets for the treatment of this cancer.…”