. 2023 May 24;188(6):770-776.

doi: 10.1093/bjd/ljad041.

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

Courtney K Wallingford¹, Anastassia Demeshko¹, Asha Krishnankutty Krishnakripa¹, Darren J Smit¹, David L Duffy^{1

2}, Brigid Betz-Stablein^{1

2}, Annette Pflugfelder³, Kasturee Jagirdar^{1

4}, Elizabeth Holland⁵, Graham J Mann^{6

7}, Clare A Primiero¹, Tatiane Yanes¹, Josep Malvehy^{8

9}, Cèlia Badenas^{9

10}, Cristina Carrera^{8

9}, Paula Aguilera^{8

9}, Catherine M Olsen^{1

2}, Sarah V Ward¹¹, Nikolas K Haass¹, Richard A Sturm¹, Susana Puig^{8

9}, David C Whiteman², Matthew H Law^{12

13

14}, Anne E Cust^{5

6}, Miriam Potrony^{9

10}, H Peter Soyer^{1

15}, Aideen M McInerney-Leo¹

Affiliations

¹ Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
² QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, Australia.
³ Center of Dermato-Oncology, Department of Dermatology, University of Tübingen, Tübingen, Germany.
⁴ Biochemistry and Molecular Biology Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, Australia.
⁶ The Melanoma Institute Australia, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
⁷ John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
⁸ Dermatology Department, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
⁹ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
¹⁰ Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
¹¹ School of Population and Global Health, The University of Western Australia, Perth, WA, Australia.
¹² Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.
¹³ School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
¹⁴ School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
¹⁵ Dermatology Department, Princess Alexandra Hospital, Brisbane, Australia.

PMID: 36879448
PMCID: PMC10230961
DOI: 10.1093/bjd/ljad041

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

Courtney K Wallingford et al. Br J Dermatol. 2023.

. 2023 May 24;188(6):770-776.

doi: 10.1093/bjd/ljad041.

Authors

Affiliations

¹ Frazer Institute, University of Queensland, Dermatology Research Centre, Brisbane, Australia.
² QIMR Berghofer Medical Research Institute, 300 Herston Road, Herston, Queensland, Australia.
³ Center of Dermato-Oncology, Department of Dermatology, University of Tübingen, Tübingen, Germany.
⁴ Biochemistry and Molecular Biology Department, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵ The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, Australia.
⁶ The Melanoma Institute Australia, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.
⁷ John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.
⁸ Dermatology Department, Hospital Clínic de Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain.
⁹ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
¹⁰ Biochemistry and Molecular Genetics Department, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
¹¹ School of Population and Global Health, The University of Western Australia, Perth, WA, Australia.
¹² Statistical Genetics, QIMR Berghofer Medical Research Institute, 300 Herston Rd, Herston, QLD, 4006, Australia.
¹³ School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
¹⁴ School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
¹⁵ Dermatology Department, Princess Alexandra Hospital, Brisbane, Australia.

PMID: 36879448
PMCID: PMC10230961
DOI: 10.1093/bjd/ljad041

Abstract

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.

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Conflict of interest statement

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.

Comment in

Joint contribution of MC1R and MITF alleles to melanoma risk in the age of polygenic risk scores.
Bruno W. Bruno W. Br J Dermatol. 2023 May 24;188(6):696-697. doi: 10.1093/bjd/ljad097. Br J Dermatol. 2023. PMID: 36975215 No abstract available.
Two melanoma genes (MITF and MC1R) interact to cause different risks.
[No authors listed] [No authors listed] Br J Dermatol. 2023 May 24;188(6):e44. doi: 10.1093/bjd/ljad146. Br J Dermatol. 2023. PMID: 37226391 No abstract available.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical