The MC1R r allele does not increase melanoma risk in MITF E318K carriers.

Humans Alleles Receptor, Melanocortin, Type 1 / genetics Microphthalmia-Associated Transcription Factor / genetics Australia / epidemiology Melanoma / genetics Genotype Genetic Predisposition to Disease / genetics Skin Neoplasms / genetics

Journal

The British journal of dermatology
ISSN: 1365-2133
Titre abrégé: Br J Dermatol
Pays: England
ID NLM: 0004041

Informations de publication

Date de publication:
24 05 2023
Historique:
received: 15 01 2023
accepted: 18 02 2023
medline: 26 5 2023
pubmed: 8 3 2023
entrez: 7 3 2023
Statut: ppublish

Résumé

Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored. To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals. Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank). The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals. RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.

Sections du résumé

BACKGROUND
Population-wide screening for melanoma is not cost-effective, but genetic characterization could facilitate risk stratification and targeted screening. Common Melanocortin-1 receptor (MC1R) red hair colour (RHC) variants and Microphthalmia-associated transcription factor (MITF) E318K separately confer moderate melanoma susceptibility, but their interactive effects are relatively unexplored.
OBJECTIVES
To evaluate whether MC1R genotypes differentially affect melanoma risk in MITF E318K+ vs. E318K- individuals.
MATERIALS AND METHODS
Melanoma status (affected or unaffected) and genotype data (MC1R and MITF E318K) were collated from research cohorts (five Australian and two European). In addition, RHC genotypes from E318K+ individuals with and without melanoma were extracted from databases (The Cancer Genome Atlas and Medical Genome Research Bank, respectively). χ2 and logistic regression were used to evaluate RHC allele and genotype frequencies within E318K+/- cohorts depending on melanoma status. Replication analysis was conducted on 200 000 general-population exomes (UK Biobank).
RESULTS
The cohort comprised 1165 MITF E318K- and 322 E318K+ individuals. In E318K- cases MC1R R and r alleles increased melanoma risk relative to wild type (wt), P < 0.001 for both. Similarly, each MC1R RHC genotype (R/R, R/r, R/wt, r/r and r/wt) increased melanoma risk relative to wt/wt (P < 0.001 for all). In E318K+ cases, R alleles increased melanoma risk relative to the wt allele [odds ratio (OR) 2.04 (95% confidence interval 1.67-2.49); P = 0.01], while the r allele risk was comparable with the wt allele [OR 0.78 (0.54-1.14) vs. 1.00, respectively]. E318K+ cases with the r/r genotype had a lower but not significant melanoma risk relative to wt/wt [OR 0.52 (0.20-1.38)]. Within the E318K+ cohort, R genotypes (R/R, R/r and R/wt) conferred a significantly higher risk compared with non-R genotypes (r/r, r/wt and wt/wt) (P < 0.001). UK Biobank data supported our findings that r did not increase melanoma risk in E318K+ individuals.
CONCLUSIONS
RHC alleles/genotypes modify melanoma risk differently in MITF E318K- and E318K+ individuals. Specifically, although all RHC alleles increase risk relative to wt in E318K- individuals, only MC1R R increases melanoma risk in E318K+ individuals. Importantly, in the E318K+ cohort the MC1R r allele risk is comparable with wt. These findings could inform counselling and management for MITF E318K+ individuals.

Identifiants

DOI: 10.1093/bjd/ljad041 PMID: 36879448 PMC: PMC10230961
pubmed: 36879448
pii: 7069844
doi: 10.1093/bjd/ljad041
pmc: PMC10230961
doi:

Substances chimiques

Receptor, Melanocortin, Type 1 0
Microphthalmia-Associated Transcription Factor 0
MITF protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

770-776

Subventions

Organisme : NIH HHS
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.

Déclaration de conflit d'intérêts

Conflicts of interest H.P.S. is a shareholder of MoleMap NZ Limited and e-derm consult GmbH, and undertakes regular teledermatological reporting for both companies; he is also a Medical Consultant for Canfield Scientific Inc., Blaze Bioscience Inc., MoleMap Australia Pty Limited, and a Medical Advisor for First Derm and Revenio Research Oy. The other authors state no conflicts of interest.

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Auteurs

Courtney K Wallingford (CK)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
ORCID: 0000-0001-6529-7528

Anastassia Demeshko (A)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.

Asha Krishnankutty Krishnakripa (AK)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.

Darren J Smit (DJ)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
ORCID: 0000-0002-3288-3659

David L Duffy (DL)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, Australia.
ORCID: 0000-0001-7227-632X

Brigid Betz-Stablein (B)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, Australia.

Annette Pflugfelder (A)

Center of Dermato-Oncology, Department of Dermatology, University of Tübingen, Tübingen, Germany.
ORCID: 0000-0001-7858-0453

Kasturee Jagirdar (K)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
Biochemistry and Molecular Biology Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
ORCID: 0000-0001-8761-132X

Elizabeth Holland (E)

The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, Australia.

Graham J Mann (GJ)

The Melanoma Institute Australia, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.

Clare A Primiero (CA)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.

Tatiane Yanes (T)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
ORCID: 0000-0002-3905-3025

Josep Malvehy (J)

Dermatology Department, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.

Cèlia Badenas (C)

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.

Cristina Carrera (C)

Dermatology Department, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.

Paula Aguilera (P)

Dermatology Department, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.

Catherine M Olsen (CM)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, Australia.
ORCID: 0000-0003-4483-1888

Sarah V Ward (SV)

School of Population and Global Health, The University of Western Australia, Perth, WA, Australia.

Nikolas K Haass (NK)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
ORCID: 0000-0002-3928-5360

Richard A Sturm (RA)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
ORCID: 0000-0003-1301-0294

Susana Puig (S)

Dermatology Department, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.

David C Whiteman (DC)

QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, Australia.
ORCID: 0000-0003-2563-9559

Matthew H Law (MH)

Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.
School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
ORCID: 0000-0002-4303-8821

Anne E Cust (AE)

The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, Australia.
The Melanoma Institute Australia, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
ORCID: 0000-0002-5331-6370

Miriam Potrony (M)

Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.

H Peter Soyer (HP)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
Dermatology Department, Princess Alexandra Hospital, Brisbane, Australia.
ORCID: 0000-0002-4770-561X

Aideen M McInerney-Leo (AM)

Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
ORCID: 0000-0002-0059-5732

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Classifications MeSH

Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Phénomènes génétiques › Structures génétiques › Génome › Composants de génome › Gènes › Allèles › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur hormone hypophysaire › Récepteur corticotrophine › Récepteurs à la mélanocortine › Récepteur de la mélanocortine de type 1 › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription à motif basique et à glissière à leucines › Facteurs de transcription à motifs basiques hélice-boucle-hélice et à glissière à leucines › Facteur de transcription associé à la microphtalmie › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Régions géographiques › Océanie › Australasie › Australie › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Tumeurs › Tumeurs par type histologique › Naevus et mélanomes › Mélanome › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Phénomènes génétiques › Génotype › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › The MC1R r allele does not increase melanoma...
Recherchemedicale.com › Maladies de la peau et du tissu conjonctif › Maladies de la peau › Tumeurs cutanées › The MC1R r allele does not increase melanoma...