This document discusses genetic susceptibility to melanoma. It finds that 20-40% of melanoma risk is genetic. Certain genes are associated with increased risk, including MC1R, which is associated with red hair and freckling. Variants in MC1R, TYR, ASIP, and TYRP1 are associated with increased risk of melanoma and nevus count. Having more than one variant in MC1R is associated with higher risk of second primary melanomas in survivors. Low vitamin D levels are also a risk factor, especially in those with obesity or MC1R variants. Genetic information can help identify high risk groups for targeted prevention strategies.

1. Susceptibilidad genética en el
melanoma esporádico
Eduardo Nagore
Servicio de Dermatología
Fundación IVO

2. Ethiopathogenesis

3. ALLELIC FREQUENCY
Very
rare
Rare Low frequency Common
0.050.0050.001
EFFECT / RISK
Low
Moderate
Medium
High
1.1
1.5
3.0
50.0
Low risk
genes
Medium risk
genes
High risk
genes
Adaptated from Manolio et al. Nature (2009)
Susceptibility to
Melanoma

4. ALLELIC FREQUENCY
Very
rare
Rare Low frequency Common
0.050.0050.001
EFFECT / RISK
Low
Moderate
Medium
High
1.1
1.5
3.0
50.0
Low risk
genes
Medium risk
genes
High risk
genes
Adaptated from Manolio et al. Nature (2009)
Susceptibility to
Melanoma

6. 20-40%

7. Risk factors for melanoma
development

8. Risk factors for melanoma
development
Factor RR (IC 95%)
Atypical melanocytic nevus (5 vs. 0) 10.5 (5.1-21.8)
Common melanocytic nevi (>100 vs. <15) 6.9 (4.6-10.3)
Hair color (red vs. dark) 3.6 (2.6-5.4)
Phototype (I vs. IV) 2.1 (1.7-2.6)
Freckling (many vs. few) 2.1 (1.8-2.5)
Blue eyes 1.5 (1.3-1.7)
Severe sunburns (yes vs. no) 2.0 (1.7-2.4)
Past personal history of melanoma 8.6 (8.3-8.9)

9. Risk factors for melanoma
development
Factor RR (IC 95%)
Atypical melanocytic nevus (5 vs. 0) 10.5 (5.1-21.8)
Common melanocytic nevi (>100 vs. <15) 6.9 (4.6-10.3)
Hair color (red vs. dark) 3.6 (2.6-5.4)
Phototype (I vs. IV) 2.1 (1.7-2.6)
Freckling (many vs. few) 2.1 (1.8-2.5)
Blue eyes 1.5 (1.3-1.7)
Severe sunburns (yes vs. no) 2.0 (1.7-2.4)
Past personal history of melanoma 8.6 (8.3-8.9)
Trend to melanocytic proliferation
(genetically determined)

10. Loci de susceptibilidad

11. Chromosome Postulated gene SNP % P % P
Genome-wide significant
16q24.3 MC1R rs73283859 0.00 0.83 7.01 2.0E-34
11q14-q21 TYR rs1126809 0.03 0.56 1.54 1.5E-08
20q11.2-q12 ASIP rs6059655 0.04 0.46 1.32 1.6E-07
5p13.2 SLC45A2 rs16891982 0.10 0.26 1.24 1.2E-06
15q OCA2 rs4778138 0.03 0.53 1.08 2.2E-06
22q13.1 PLA2G6 rs3891103 0.34 0.031 0.34 7.7E-03
9q31.2 KLF4 rs10816590 1.01 2.1E-04 0.00 0.99
5p15.33 TERT/CLPTM1L rs2447853 0.62 0.0038 0.02 0.48
16q12.2 FTO rs12596638 0.32 0.036 0.01 0.68
2q33-q34 CASP8 rs2349073 0.24 0.068 0.09 0.18
9p21 CDKN2A/MTAP rs869330 0.24 0.071 0.03 0.47
11q22-q23 ATM rs4753835 0.06 0.35 0.00 0.78
1q21.3 ARNT rs3768013 0.06 0.36 0.00 0.98
1q42.12 PARP1 rs1858550 0.05 0.40 0.01 0.63
7p21.1 AGR3 rs76130342 0.05 0.41 0.00 0.94
21q22.3 MX2 rs443099 0.02 0.61 0.03 0.46
11q13 CCND1 rs12422135 0.02 0.63 0.00 0.83
Not Genome-significant to date
6p25-p23 IRF4 rs12203592 0.08 0.31 2.80 2.00E-14
9p23 TYRP1 rs2733832 0.11 0.21 0.09 0.17
TOTAL % OF VARIANCE EXPLAINED 3.33% 15.05%
MC1R R/r genotype 0.39 0.43 25.47 5.1E-76
TOTAL % OF VARIANCE EXPLAINED 4.18% 32.47%
Variation in log
nevus count
explained by SNP
Variation in log
nevus count
explained by SNP
Variation in
pigmentation
explained by SNP

12. Risk factors for melanoma
development
Factor RR (IC 95%)
Atypical melanocytic nevus (5 vs. 0) 10.5 (5.1-21.8)
Common melanocytic nevi (>100 vs. <15) 6.9 (4.6-10.3)
Hair color (red vs. dark) 3.6 (2.6-5.4)
Phototype (I vs. IV) 2.1 (1.7-2.6)
Freckling (many vs. few) 2.1 (1.8-2.5)
Blue eyes 1.5 (1.3-1.7)
Severe sunburns (yes vs. no) 2.0 (1.7-2.4)
Past personal history of melanoma 8.6 (8.3-8.9)
Pigmentary trait
(genetically determined)

17. MC1R structure

18. MC1R structure
Gran número de variantes
R: asociación fuerte con pelirrojo
r: asociación débil con pelirrojo

22. ASIP AH haplotype CM OR 1.45
TYR rs1126809(R402Q) CM OR 1.21
TYRP1 rs1408799 CM OR 1.15

26. Chromosome Postulated gene SNP % P % P
Genome-wide significant
16q24.3 MC1R rs73283859 0.00 0.83 7.01 2.0E-34
11q14-q21 TYR rs1126809 0.03 0.56 1.54 1.5E-08
20q11.2-q12 ASIP rs6059655 0.04 0.46 1.32 1.6E-07
5p13.2 SLC45A2 rs16891982 0.10 0.26 1.24 1.2E-06
15q OCA2 rs4778138 0.03 0.53 1.08 2.2E-06
22q13.1 PLA2G6 rs3891103 0.34 0.031 0.34 7.7E-03
9q31.2 KLF4 rs10816590 1.01 2.1E-04 0.00 0.99
5p15.33 TERT/CLPTM1L rs2447853 0.62 0.0038 0.02 0.48
16q12.2 FTO rs12596638 0.32 0.036 0.01 0.68
2q33-q34 CASP8 rs2349073 0.24 0.068 0.09 0.18
9p21 CDKN2A/MTAP rs869330 0.24 0.071 0.03 0.47
11q22-q23 ATM rs4753835 0.06 0.35 0.00 0.78
1q21.3 ARNT rs3768013 0.06 0.36 0.00 0.98
1q42.12 PARP1 rs1858550 0.05 0.40 0.01 0.63
7p21.1 AGR3 rs76130342 0.05 0.41 0.00 0.94
21q22.3 MX2 rs443099 0.02 0.61 0.03 0.46
11q13 CCND1 rs12422135 0.02 0.63 0.00 0.83
Not Genome-significant to date
6p25-p23 IRF4 rs12203592 0.08 0.31 2.80 2.00E-14
9p23 TYRP1 rs2733832 0.11 0.21 0.09 0.17
TOTAL % OF VARIANCE EXPLAINED 3.33% 15.05%
MC1R R/r genotype 0.39 0.43 25.47 5.1E-76
TOTAL % OF VARIANCE EXPLAINED 4.18% 32.47%
Variation in log
nevus count
explained by SNP
Variation in log
nevus count
explained by SNP
Variation in
pigmentation
explained by SNP

28. 42% increase for C>T mut in ≥1 R allele
1.7% increase for extra year

29. Clinical impact of low penetrance
genes

32. Location of primary melanoma differs
by phenotype
Nevus prone patient Sun sensitive patient

35. MC1R as a risk factor for second cutaneous
melanomas in melanoma survivors
• 1257 melanomas:
– 989 genotypes for
MC1R
– 40 patients with 2nd
MM
• OR: 2.25 (IC 95% 1,03-
4,93) for the presence of
any non-synonymous
variant.
(adjusted for age, sex, number of
common and atypical nevi)
P=0.041

37. MC1R as a risk factor for NMSC development in melanoma survivors
Pablo Espinosa et al. EJC 2015

38. Regulation of genes involved in response to hypoxia, proliferation and
inflammation

42. Vitamin D sources
o DIET (10%) o SUN (90%)

43. Niveles
vitamina
D
Latitud y
estación del
año
Edad
FototipoFotoprotección
Obesidad

44. Variable dependiente: vitamina D
Deficientes
< 10ng/ml
Insuficientes
10-30 ng/ml
Adecuados
> 30 ng/ml
• Recogida mediante
análisis de sangre
• Se generaron 2 nuevas
variables a partir de
esta clasificación:
Déficit vs
adecuados
Inadecuados
(déficit +
insuficiencia) vs
adecuados

45. Niveles Vitamina D.
Deficiencia vs. Normal
VARIABLE UNIVARIADO
OR IC 95%
EDAD
< 70 años 1 1
> 70 años 6,25 1,93-20,20
IMC
Normal 1 1
Sobrepeso 1,38 0,34-5,52
Obesidad 10,06 1,98-51,04
EFÉLIDES
No 4,46 1,15-17,25
Sí 1 1
MESES PARA EXTRACCIÓN
DE SANGRE
Octubre/Marzo 9,52 2-45,36
Abril/Septiembre 1 1
MC1R
0-1 variante 5,25 1,08-25,42
>1 variante 1 1
VARIABLE MULTIVARIADO
OR IC 95%
IMC
Normal 1 1
Sobrepeso 1,44 0,28-7,33
Obesidad 7,11 1,08-46,94
MC1R
0-1 variante 4,95 0,85-28,88
>1 variante 1 1
ESTACIÓN DE EXTRACCIÓN
DE SANGRE
Octubre/Marzo 6,81 1,24-37,27
Abril/Septiembre 1 1
N=215 pacientes

47. Telomere-maintaining genes
• TERT (rs2853676, rs2242652)
• TRF1 (rs2981096)
• TERT-CLPTM1L (rs401681) : inverse

48. Conclusion: How relevant is this
genetic information?
• Pigmentation: susceptibility to sun damage
– Rise the need of being more thourough with primary
prevention (sun protection)
– Etiopathogenesis
– Secondary prevention for other cutaneous neoplasias
• Nevus proneness:
– Specific secondary prevention measures (digital
dermoscopy)
– Melanoma profile (ethiopathogenesis)