Abstract 2527: Genomic aberrations of ALK in head and neck squamous cell carcinoma
Authors: Wang Lan , Liu Yuchen , Piao Wenying , Poon Peony Hiu Yan , Yeung Chun Kit , Chan Amy Bik Wan , Lau Chin Wang , Su Yuxiong , Chan Jason Ying Kuen , Lui Vivian Wai Yan 
Published: August 2019

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the gene ALK, 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, ALK 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.

Though ALK 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 ALK 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 ALK genomic aberrations. Within the US TCGA HNSCC dataset (Provisional; N=510), 3.5% of HNSCC patient tumors harbor somatic ALK mutations, 0.4% cases with ALK amplification, and 17.4% cases with ALK gain. Further, RNA-seq analysis revealed tumor specific ALK 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 ALK exons in human reported in the dbSNP database. We noted 18.9% of Asian HNSCC patients (N=53) bearing ALK germline variants (N=10) with unknown clinical significance.

Interestingly, ALK aberrations (mutations, amplification, gene copy gain) are noted to be significantly associated with TP53 mutations (P&lt;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 ALK mutation and amplification are largely advanced cases (93.33%, Stage III and Stage IV). Gene Set Enrichment Analysis (GSEA) of mRNA expression shows that ALK-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 ALK-altered HNSCC (vs. -unaltered tumors) have increased PIK3CA and CHEK2 protein expression (P&lt;0.001, 0.0001, respectively), as well as reduced PRAS40(pT246) and VEGFR2 protein expression (P&lt;0.001, 0.001, respectively). In conclusion, ALK 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 ALK aberrations on HNSCC oncogenesis are warranted.

Citation Format: Lan Wang, Yuchen Liu, Wenying Piao, Peony Hiu Yan Poon, Chun Kit Yeung, Amy Bik Wan Chan, Chin Wang Lau, Yuxiong Su, Jason Ying Kuen Chan, Vivian Wai Yan Lui. Genomic aberrations of ALK in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2527.