Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk

Jennifer Y. Lin, Mingfeng Zhang, Tobias Schatton, Brian J. Wilson, Allireza Alloo, Jie Ma, Abrar A. Qureshi, Natasha Y. Frank, Jiali Han, Markus H. Frank

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 108.2. kb 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.

Original languageEnglish (US)
Pages (from-to)536-542
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume436
Issue number3
DOIs
StatePublished - Jul 5 2013
Externally publishedYes

Fingerprint

Pigmentation
Polymorphism
Melanoma
Phenotype
Nucleotides
Single Nucleotide Polymorphism
Melanins
Hair Color
Stem cells
Neoplasms
Tumors
Neoplastic Stem Cells
Multiple Drug Resistance
Genes
Adenosine Triphosphate
Cells
Color
Amino Acids
Cell Line
Growth

Keywords

  • ABCB5
  • Cancer
  • Cancer stem cells
  • Case-controlled study
  • Genotype
  • Humans
  • Melanoma
  • Pigmentation
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk. / Lin, Jennifer Y.; Zhang, Mingfeng; Schatton, Tobias; Wilson, Brian J.; Alloo, Allireza; Ma, Jie; Qureshi, Abrar A.; Frank, Natasha Y.; Han, Jiali; Frank, Markus H.

In: Biochemical and Biophysical Research Communications, Vol. 436, No. 3, 05.07.2013, p. 536-542.

Research output: Contribution to journalArticle

Lin, JY, Zhang, M, Schatton, T, Wilson, BJ, Alloo, A, Ma, J, Qureshi, AA, Frank, NY, Han, J & Frank, MH 2013, 'Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk', Biochemical and Biophysical Research Communications, vol. 436, no. 3, pp. 536-542. https://doi.org/10.1016/j.bbrc.2013.06.006
Lin, Jennifer Y. ; Zhang, Mingfeng ; Schatton, Tobias ; Wilson, Brian J. ; Alloo, Allireza ; Ma, Jie ; Qureshi, Abrar A. ; Frank, Natasha Y. ; Han, Jiali ; Frank, Markus H. / Genetically determined ABCB5 functionality correlates with pigmentation phenotype and melanoma risk. In: Biochemical and Biophysical Research Communications. 2013 ; Vol. 436, No. 3. pp. 536-542.
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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 108.2. kb 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.",
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AU - Alloo, Allireza

AU - Ma, Jie

AU - Qureshi, Abrar A.

AU - Frank, Natasha Y.

AU - Han, Jiali

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