title: A Pan-Cancer Review of ALK Mutations: Implications for Carcinogenesis and Therapy.
abstract: The anaplastic lymphoma kinase (ALK) is a druggable target for cancer therapy. By and large, the oncogenic activation of ALK in human tumors is known to occur by gene rearrangement (e.g. EML4-ALK, NMP-ALK, etc.). Clinical use of ALK inhibitors for "ALK-rearranged" lung cancers has remarkably improved patient survival. To date, much has been known about ALK gene rearrangement in human carcinogenesis and its drug sensitivity relationship. However, emerging genomic data from the Cancer Genome Atlas (TCGA, USA) are now revealing common ALK point mutations (~3.06%) in various cancer types other than lung cancer. Importantly, several recent studies have demonstrated that ALK point mutations, independent of ALK-gene rearrangement, can be oncogenic. Thus, ALK mutations can be pathogenically and perhaps therapeutically important for various cancer types. Here, we summarized the latest ALK mutation frequencies and mutation patterns across 17 human cancer types stemming from TCGA. Unlike many other oncogenes with high frequency of hotspot mutations, ALK point mutations tend to span along the entire gene. Up till now, several recurrent mutations (G263, R401, R551, P968 and E1242) and mutation-rich cluster regions have been identified, but their functional effects remain unknown. We also conducted a comprehensive review of all ALK-mutated human cancer cell lines (from the Cell Line Encyclopedia (CCLE) and the NCI-60 panel), which can be used as model systems for ALK mutation biology and drug screening studies. Lastly, we summarized both the preclinical and clinical findings of ALK mutations on carcinogenesis and drug sensitivity, which may provide important insight into new treatment strategies and prompt future ALK mutation studies in various cancer types.
authors.forename: Nick Ka Ming
authors.initials: NK
authors.lastname: Yau
authors.forename: Andrew Yuon
authors.initials: AY
authors.lastname: Fong
authors.forename: Hiu Fung
authors.initials: HF
authors.lastname: Leung
authors.forename: Krista Roberta
authors.initials: KR
authors.lastname: Verhoeft
authors.forename: Qin Ying
authors.initials: QY
authors.lastname: Lim
authors.forename: Wai Yip
authors.initials: WY
authors.lastname: Lam
authors.forename: Ian Chi Kei
authors.initials: IC
authors.lastname: Wong
authors.affiliation: Department of Pharmacology and Pharmacy, L2-54, Laboratory Block, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong. vlui002@hku.hk.
authors.forename: Vivian Wai Yan
authors.initials: VW
authors.lastname: Lui
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D063646:Carcinogenesis / Q000235:genetics; D005784:Gene Amplification; D015321:Gene Rearrangement; D055106:Genome-Wide Association Study; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009154:Mutation; D009369:Neoplasms / Q000145:classification / Q000235:genetics / Q000628:therapy; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases