title: Integrin genes and susceptibility to human melanoma.
abstract: Integrins are transmembrane adhesion molecules that mediate cell-cell and cell-extracellular matrix attachment. Integrins regulate cell growth, proliferation, migration and apoptosis and as a consequence, can have a potential role in tumour progression and metastasis. In this study, we investigated 19 non-synonymous variants in the coding region of the human integrin genes representing 3 beta subunits and 13 alpha subunits, for their potential role in melanoma susceptibility and survival. The variants were selected on the basis of probable functional relevance and theoretical predictions. Our data showed that no genetic variant was significantly associated with survival. However, the variants in ITGA10 and ITGA6 genes showed association with decreased risk, and variants in ITGA2, ITGAE and ITGAM were associated with increased risk of melanoma. The haplotype analysis revealed association of CA haplotype of ITGAE and TAC haplotype of ITGAX with the risk modulation. A prediction analysis of functional effect, homology modelling and multiple sequence alignments of integrin sequences from different species supported our data for linkage of variants in the ITGA2 and ITGAE genes with susceptibility. The amino acid changes in each of these integrin proteins could affect intramolecularly and/or the interaction of the heterodimers. Our experimental data indicated a possible role for some of the variant alleles and/or haplotypes of the integrin genes in melanoma susceptibility, which is augmented by the theoretical analysis performed.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany. r.lenci@dkfz-heidelberg.de
authors.forename: Romina E
authors.initials: RE
authors.lastname: Lenci
authors.forename: P Sivaramakrishna
authors.initials: PS
authors.lastname: Rachakonda
authors.forename: Andriy V
authors.initials: AV
authors.lastname: Kubarenko
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
authors.forename: Andreas
authors.initials: A
authors.lastname: Brandt
authors.forename: Andreas
authors.initials: A
authors.lastname: Gast
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D016023:Integrins / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D017422:Sequence Analysis, DNA; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality; D040681:Structural Homology, Protein; D016019:Survival Analysis; D055815:Young Adult
chemical_list: D016023:Integrins