Genomic aberrations of ALK in head and neck squamous cell carcinoma

Abstract

<p>Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the gene <em>ALK</em>, which belongs to a subfamily of the insulin receptor superfamily. ALK signaling has been shown to be involved in cell proliferation, differentiation, and development, etc. Thus far, <em>ALK</em> aberrations are known to be involved in the oncogenesis of non-small cell lung cancer and glioblastoma. Head and neck cancer squamous cell carcinoma (HNSCC) is an aggressive cancer with genomic heterogeneity as revealed by recent whole-exome studies.</p><p>Though <em>ALK</em> aberrations are found in a notable subset of HNSCC, their biological importance is largely unknown. Comprehensive pan-cancer analysis of 33 cancer types (TCGA, Pan-cancer, Provisional, N=11617, www.cbioportal.org) showed that <em>ALK</em> aberrations (mutations, amplification and gene copy gain) are commonly noted in 27 cancers, with HNSCC ranking 9th having ~22% cases of primary tumors harboring these <em>ALK</em> genomic aberrations. Within the US TCGA HNSCC dataset (Provisional; N=510), 3.5% of HNSCC patient tumors harbor somatic <em>ALK</em> mutations, 0.4% cases with <em>ALK</em> amplification, and 17.4% cases with <em>ALK</em> gain. Further, RNA-seq analysis revealed tumor specific <em>ALK</em> mRNA upregulation in 43 pairs of normal-tumor tissues (~2-fold, P=0.001***), and 457 HNSCC tumors (~1.5-fold, P=0.039*). There are currently 172261 single-nucleotide polymorphism (SNP) on <em>ALK</em> exons in human reported in the dbSNP database. We noted 18.9% of Asian HNSCC patients (N=53) bearing <em>ALK</em> germline variants (N=10) with unknown clinical significance.</p><p>Interestingly, <em>ALK</em> aberrations (mutations, amplification, gene copy gain) are noted to be significantly associated with <em>TP53</em> mutations (P<0.0001), HPV-negativity (P=0.0094) and the male gender (P=0.0041; Fisher’s Exact test), but not associated with HNSCC patient survival (P=0.734). Further, patients with <em>ALK</em> mutation and amplification are largely advanced cases (93.33%, Stage III and Stage IV). Gene Set Enrichment Analysis (GSEA) of mRNA expression shows that <em>ALK</em>-altered HNSCC tumors (vs unaltered tumors) appear to have significantly downregulation of immune response gene set [NES (normalized enrichment score)=-6.773, P=0.0026] and inflammatory response gene set (NES=-5.54, P= 0.0022), while nervous system development and cell development signaling gene sets are significantly upregulated (P=0.0015, 0.0016, respectively). Proteomic analysis (TCPA, N=209) showed that <em>ALK</em>-altered HNSCC (vs. -unaltered tumors) have increased PIK3CA and CHEK2 protein expression (P<0.001, 0.0001, respectively), as well as reduced PRAS40(pT246) and VEGFR2 protein expression (P<0.001, 0.001, respectively). In conclusion, <em>ALK</em> aberrations may contribute to HNSCC aggressiveness, potentially via reduction of immune response and activation of PI3K signaling pathway. Future investigations studying the biological effects of <em>ALK</em> aberrations on HNSCC oncogenesis are warranted.</p>