title: Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk.
abstract: ABCB5 is a multidrug resistance (MDR) member of the ATP-binding cassette (ABC) superfamily of active transporters and represents a marker for chemoresistant malignant melanoma-initiating cells. ABCB5 expression is closely linked to tumorigenicity and progression of diverse human malignancies, including melanoma, and is functionally required for tumor growth. Here, we genotyped 585 melanoma cases and 605 age-matched controls for 44 ABCB5 tagging single nucleotide polymorphisms (SNPs) to span a region covering 108.2kb of the gene on the 7p21.1 locus. We identified three SNPs that were associated with decreased melanoma risk in additive models: rs10231520 (OR: 0.83, 95% CI: 0.70-0.98), rs17817117 (OR: 0.82, 95% CI: 0.68-0.98), and rs2301641 (OR: 0.83, 95% CI: 0.69-0.98). Additionally, the rs2301641 SNP was associated with non-red compared to red hair color (OR: 0.38, 95% CI: 0.14-1.03) in controls. Twelve human melanoma cell lines were genotyped for the rs2301641 SNP, which encodes a non-synonymous ABCB5 amino acid change (K115E). Functional studies revealed that the E form associated with lower melanoma risk correlated significantly with decreased ABCB5 transport capacity (P<0.01) and increased melanin production (P<0.05). Our results identify novel associations of the ABCB5 K115E polymorphism with human pigmentation phenotype and melanoma risk and point to potential functional roles of ABCB5 in melanomagenesis. Moreover, they provide a first example that functional variation in a prospective cancer stem cell marker can be associated with disease risk for the corresponding malignancy.
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jennifer Y
authors.initials: JY
authors.lastname: Lin
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Zhang
authors.forename: Tobias
authors.initials: T
authors.lastname: Schatton
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wilson
authors.forename: Allireza
authors.initials: A
authors.lastname: Alloo
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.forename: Abrar A
authors.initials: AA
authors.lastname: Qureshi
authors.forename: Natasha Y
authors.initials: NY
authors.lastname: Frank
authors.forename: Jiali
authors.initials: J
authors.lastname: Han
authors.forename: Markus H
authors.initials: MH
authors.lastname: Frank
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D056426:Genetic Loci; D006200:Hair Color / Q000235:genetics; D006801:Humans; D008297:Male; D008543:Melanins / Q000235:genetics / Q000378:metabolism*; D008545:Melanoma / Q000473:pathology*; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D010858:Pigmentation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008543:Melanins
keywords: ABCB5; Cancer; Cancer stem cells; Case-controlled study; Genotype; Humans; Melanoma; Pigmentation; Single nucleotide polymorphism