Human Papillomavirus And The Inactivation Of Expression Of Multiple Large Common Fragile Site Genes In Oropharyngeal Squamous Cell Carcinoma

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Human papillomavirus (HPV) appears to be responsible for dramatic increases in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the United States in the last two decades, in spite of decreases in the incidence of smoking. It is generally assumed that the role of HPV in the development of OPSCC is identical to the one that it plays in cervical cancer where HPV infection followed by integration into the host genome and the subsequent increased expression of the E6 and E7 oncoproteins leads to increased genomic instability. The common fragile sites (CFSs) are highly unstable chromosomal regions that will be particularly sensitive to increased genomic instability and they are also hot-spots for viral integrations in cervical cancer. The CFS regions span many megabases and many of them also span extremely large genes, a number of which have been demonstrated to function as important tumor suppressors. We therefore examined the expression of very large genes in OPSCC. An analysis of RNAseq data generated on 11 OPSCCs and matched normal oropharyngeal tissue from the same patients revealed that some of the tumors had greatly decreased expression for many of the largest genes. The two genes with the greatest decreases in expression in the tumors as compared to matched normal were the known tumor suppressor PARK2 and the putative tumor suppressor DLG2, but three other large CFS genes: CTNNA3, LRP1B and DMD, and one large gene not yet precisely localized within a CFS region: PDE4D, also had much more decreased expression than any of the other large genes. Real-time RT-PCR was used to measure the expression of these six genes in a much larger number of OPSCC tumor-normal pairs. The expression of these six genes was concordant in most OPSCCs. An individual tumor generally had either decreased expression of these six genes, no changes in the expression of these genes or increased expression of all six genes. When the tumors were grouped with respect to which ones were HPV-positive or HPV-negative we observed that 40% of the HPV-positive OPSCCs had greatly decreased expression (more than 100-fold) for all six genes. Half of the HPV-negative tumors had decreased expression of these six genes, but the amount of decreased expression was much more modest (4-16 fold). Most exciting, however was that 7 of the 12 HPV-positive tumors, and three of the four of the HPV-negative patients that had decreased expression of these genes were from patients who had tumor recurrence. In contrast only one of 18 patients whose tumors did not have decreased expression of the large genes had tumor recurrence. The loss of expression of multiple large genes, many of which are derived from CFS regions, could thus be a powerful predictor for which patients will have tumor recurrence. These results also suggest a linkage between HPV-induced chromosomal instability and dramatic decreases in the expression of multiple CFS genes in some OPSCCs. Citation Format: David I. Smith, Ge Gao, Nicole Tombers, Jan Kasperbauer, Vivian Wang. Human papillomavirus and the inactivation of expression of multiple large common fragile site genes in oropharyngeal squamous cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 582. doi:10.1158/1538-7445.AM2014-582