Abstract B1-62: Bumphunting analysis identifies PAX5 promoter methylation and p53 somatic mutations in genomic instability pathways linked to very poor survival in head and neck cancer

Abstract

Abstract For years studies have attempted to come up with measures and markers that predict and are linked to cancer survival. Alterations in a subgroup of genes, tumor suppressor genes (TSG), have recently emerged as important in linkage to cancer survival, particularly the silencing that can occur by somatic mutations and promoter DNA methylation. However, the link between TSG silencing and cancer survival is not well understood. If we can understand how TSG silencing is molecularly linked to cancer survival we can improve clinical management and pave the wave for personalized treatment solutions. Head and neck squamous cell carcinoma (HNSCC) is one of the first tumors in which independent somatic mutations and promoter DNA methylation events were shown to inactivate the same gene, CDKN2a, a well-known TSG. HNSCC is also a tumor in which the linkage between causative agents, molecular alterations, and signaling pathways has been studied. We performed an integrated molecular analysis using methylation sequencing, exome sequencing, mRNA expression, and qMSP platforms in 250 HNSCC samples. Our findings were subsequently validated in 517 samples from The Cancer Genome Atlas (TCGA) project. We uncovered differentially methylated regions and somatic mutations in differentiation and proliferation pathways linked to genomic instability. We uncovered downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified tumor suppressor genes in differentiation and proliferation pathways (HOXC12, CDKN2A, PAX1, PIK3AP1, and HOXC6) inactivated by both promoter methylation and/or somatic mutation in HNSCC. We also found evidence of interplay between mutations in the TP53 and NOTCH1 pathways with gene downregulation associated to PAX5 and PAX1 promoter methylation in HNSCC. Survival analyses revealed that patients with PAX5 (p= 0.001) or NID2 (p=0.05) promoter methylation had a worse outcome than those without it. In subsequent analyses of TCGA data we confirmed that patients with PAX5 methylation had worse survival than those without it (p=0.02). We also found that combined somatic TP53 mutations and PAX5 promoter methylation are linked to worse outcomes when compared to patients with either alteration alone (p<0.012). The next step is to examine the association between survival and combined somatic TP53 mutations and PAX5 promoter methylation in the major HNSCC anatomic subsites: oral cavity, oropharynx and pharynx. This research will be followed by systematic functional studies in short term cultures from patient derived tumorgrafts to obtain a better understanding of sub-site specific molecular and pathways alterations in HNSCC. Genomic and post-genomic research has shifted to focus on biomarker discovery for diagnosis, prognosis and prediction of treatment response, alongside the development of targeted therapies, with the ultimate goal of creating early detection and personalized therapy for HNSCC. Genetic, epigenetic and molecular advances are revealing new links between TSG silencing and survival in pathways involved in the development and progression of HNSCC. These advances are creating new opportunities to enable increased treatment choices and reduce survival disparities in HNSCC. Similar approaches are being implemented in other tumors. Citation Format: Christina Michailidi, Maartje Noordhuis, Tal Hadar, Luigi Marchioni, Elana Fertig, Nishant Agrawal, William Westra, Wayne Koch, Joseph Califano, Victor Velculescu, David Sidransky, Rafael Guerrero-Preston. Bumphunting analysis identifies PAX5 promoter methylation and p53 somatic mutations in genomic instability pathways linked to very poor survival in head and neck cancer. [abstract]. In: Proceedings of the AACR Special Conference on Computational and Systems Biology of Cancer; Feb 8-11 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 2):Abstract nr B1-62.