File Download

There are no files associated with this item.

  Links for fulltext
     (May Require Subscription)
Supplementary

Article: Genomic aberrations of ALK in head and neck squamous cell carcinoma

TitleGenomic aberrations of ALK in head and neck squamous cell carcinoma
Authors
Issue Date1-Jul-2019
PublisherAmerican Association for Cancer Research
Citation
Cancer Research, 2019, v. 79, n. 13 How to Cite?
Abstract

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<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<0.001, 0.0001, respectively), as well as reduced PRAS40(pT246) and VEGFR2 protein expression (P<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.


Persistent Identifierhttp://hdl.handle.net/10722/340800
ISSN
2023 Impact Factor: 12.5
2023 SCImago Journal Rankings: 3.468
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorWang, L-
dc.contributor.authorLiu, YC-
dc.contributor.authorPiao, WY-
dc.contributor.authorPoon, PHY-
dc.contributor.authorYeung, CK-
dc.contributor.authorChan, ABW-
dc.contributor.authorLau, CW-
dc.contributor.authorSu, YX-
dc.contributor.authorChan, JYK-
dc.contributor.authorLui, VWY -
dc.date.accessioned2024-03-11T10:47:20Z-
dc.date.available2024-03-11T10:47:20Z-
dc.date.issued2019-07-01-
dc.identifier.citationCancer Research, 2019, v. 79, n. 13-
dc.identifier.issn0008-5472-
dc.identifier.urihttp://hdl.handle.net/10722/340800-
dc.description.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>-
dc.languageeng-
dc.publisherAmerican Association for Cancer Research-
dc.relation.ispartofCancer Research-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.titleGenomic aberrations of ALK in head and neck squamous cell carcinoma-
dc.typeArticle-
dc.identifier.doi10.1158/1538-7445.AM2019-2527-
dc.identifier.volume79-
dc.identifier.issue13-
dc.identifier.eissn1538-7445-
dc.identifier.isiWOS:000488279400486-
dc.publisher.placePHILADELPHIA-
dc.identifier.issnl0008-5472-

Export via OAI-PMH Interface in XML Formats


OR


Export to Other Non-XML Formats