What is new in genetics of melanoma? How is itchanging my clinical practice?

Susana Puig

• No conflicts of interest in this talk

• Founding:

pag: 207-15.

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Melanoma Risk FactorsRelative Risk* for Developing Melanoma(Relative risk indicates degree of increased risk compared to the general population)

Risk Factor Approximate/Estimated Relative Risk

Skin Type I-III (fair skin) 1.4

Freckling 2.0 - 3.0

Blue Eyes 1.6

Red Hair 2.4 - 4.0

History of blistering sunburn 2.0 - 3.0

≥ 6 atypical naevi 6.3

≥10 dysplastic naevi 12.0

100 or more naevi 3.1 - 16.5

Previous primary cutaneous melanoma 8.5

Gandini S Et al. European Journal of Cancer 2005

Melanoma susceptibility genes

CDKN2A, CDK4, BAP1

MC1R, MITF

ASIP, TYR, TYRP1, MTAP, PLA2G6

MDM2, VDR …

High-risk genes

Intermediate-risk genes

Low-risk genes

ALLELIC FREQUENCY

Very rare Rare Low frequency Common

0.050.0050.001

EFECT / RISC

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

ALLELIC FREQUENCY

Very rare Rare Low frequency Common

0.050.0050.001

EFECT / RISC

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

Four factors associated with increased frequency of CDKN2A mutations

✓ Increased number of CMM patients in a family✓ CMM patients with multiple primary melanoma

tumors (also sporadic) ✓ Early age at melanoma diagnosis✓ Occurrence of pancreatic cancer

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J Am Acad Dermatol. 2014 Nov;71(5):888-95.

566 Pedigrees(702 melanoma patients)

236 pedigrees(236 sporadic MPM

patients)

330 melanoma-prone families

(466 patients)

J Am Acad Dermatol. 2014 Nov;71(5):888-95.

CDKN2A +(n=66)

CDKN2A WT(n=494) Ratio 95% CI Adj p

No. % No. %

Other solid tumours in the

family (All)

Presence 54 88.5 292 69.72.99 1.40 to 6.40 0.012

Absence 7 11.5 127 30.3

Missing data 5 75

Pancreatic cancer

Presence 11 18.0 22 5.32.97 1.72 to 5.15 0.006

Absence 50 82.0 396 94.7

Missing data 5 76

Nephrourologic cancer

Presence 10 16.4 41 9.81.64 0.89 to 3.03 0.738

Absence 51 83.6 376 90.2

Missing data 5 77

Lung cancer Presence 24 39.3 60 14.4

3.04 1.93 to 4.80 <0.001Absence 37 60.7 357 85.6

Missing data 5 77

Breast cancerPresence 20 32.8 67 16.1

2.19 1.36 to 3.55 0.018Absence 41 67.2 349 83.9

Missing data 5 77

Colon cancerPresence 9 14.3 66 15.8

0.90 0.47 to 1.74 1.000Absence 54 85.7 351 84.2

Missing data 3 77

➢Prevalence of other cancers in sporadic melanoma patient relatives and melanoma-prone families

according to CDKN2A status

➢Smoking is a common risk factor between lung, breast and pancreatic cancers

Type of cancer Exposure

(Cigarrette-year)

Number exposed

OR P-value 95%CI

Lung Ever smoker 844 12.1 <0.001 6.6-22.3

1-500 60 44 2.2-8.6

501-1000 209 99 5.3-18.7

1001-1500 248 16.1 8.5-30.8

>1500 327 28.0 14.5-54.0

Skin Melanoma Ever smoker 66 0.5 NS 0.3-0.9

1-500 28 0.7 0.4-1.4

501-1000 21 0.5 0.2-0.9

1001-1500 10 0.4 0.2-1.0

>1500 7 0.4 0.1-0.9

Pancreas Ever smoker 102 1.6 <0.05 0.9-3.0

1-500 16 1.2 0.5-2.6

501-1000 33 1.2 0.9-3.5

1001-1500 29 1.8 0.8-3.7

>1500 24 1.9 0.9-4.1

Adapted from: International Journal of Epidemiology,Vol 24, 1995

J Natl Cancer Inst. 2013 Apr 17;105(8):515-25.

➢ Pancreatic cancer penetrance is higher in smoking CDKN2A mutation carriers than in non-smokers carriers

1.8 lesions excised per patient 12% of patients diagnosed MM

60% MM diagnosed by DD 40% MM diagnosed by TBP

Mean follow up of 96 months

J Am Acad Dermatol. 2012 Jul;67(1):e17-27.

Diagnosis of a new melanoma during follow-up….

TOTAL patients NO previous MM 1 previous MM ≥2 PREVIOUS MM

11.06.1218.12.12

11.06.1218.12.12

Cancer epidemiology biomarkers prevention a publication of the American Association for Cancer Research cosponsored by the American Society of Preventive Oncology, 2007 16(7), 1499–1502.

Nature Genetics. Maig. 2014 Science. Febrer.2013

Nonsense Mutations in the Shelterin Complex Genes ACD and TERF2IP in Familial Melanoma.Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M, Choi J, Gartside M, Quesada V, Johansson P, Palmer JM, Ramsay AJ, Zhang X, Jones K, Symmons J, Holland EA, Schmid H, Bonazzi V, Woods S, Dutton-Regester K, Stark MS, Snowden H, van Doorn R, Montgomery GW, Martin NG, Keane TM, López-Otín C, Gerdes AM, Olsson H, Ingvar C, Borg A, Gruis NA, Trent JM, Jönsson G, Bishop DT, Mann GJ, Newton-Bishop JA, Brown KM, Adams DJ, Hayward NK.

The Journal of the National Cancer Institute. 2014 Desembre

• This paper confirms prior observations that TERT promoter mutations are common in melanoma.

• This report is the largest cohort to date. However, the important aspect of this paper is that it is the first to correlate with other prognostic characteristics.

• The novel finding is that TERT promoter mutation is an independent prognostic indicator in non-acral skin melanomas.

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228C>T

242CC>TT

250C>T

Wild-type

Figure 1. Recurrent mutations identified in the TERT promoter

228CC>TT

Figure 2. Associations of selected genetic and clinico-pathological parameters with disease-specific survival in melanomas of non-acral skin

Stage 1

Stage 2

Stage 3Stage 4

Stage at diagnosis

NRAS or BRAF mut

Wild-typeWild-type

TERT mutant

NRAS / BRAF status TERT promoter status

months

Cu

mu

lati

ve s

urv

ival

p<0.001

p=0.003p=0.046

A B C

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TERT gene amplification predicts poor outcome in acral lentiginous melanoma. Alba Diaz1, Joan A. Puig-Butillé2,3, Concha Muñoz1, Dolors Costa1, Anna Díez4, Adriana Garcia-Herrera1, Cristina Carrera5, Celia Badenas2,3, Francesc Solé6, Josep Malvehy3,5, Susana Puig3,5 and Llucia Alos1

J Am Acad Dermatol. 2014 Oct;71(4):839-41.

Test set

Validation set

“melanocytic BAP1-mutated atypical intradermal tumors” (MBAITs)

Nature genetics, 43(10), 1018–21.

Bap 1 tumour

Loss of expression of nuclearBap1

ALLELIC FREQUENCY

Very rare Rare Low frequency Common

0.050.0050.001

EFECT / RISC

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

MC1R Low/Medium Penetrance Genes

✓ Increase the risk to develop melanoma

✓ Decrease in the age of onset

✓ Increased risk for melanoma development

✓ Increased risk for MPM

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MC1R variants, melanoma and red hair color phenotype: a meta-analysis. Raimondi S, Sera F, Gandini S, Iodice S, Caini S, Maisonneuve P, Fargnoli MC. Int J Cancer. 2008 Jun 15;122(12):2753-60.

Pigmentation

52

• Increased nevus count

(OR 2.54, 95% CI 1.42–4.55) combined P = 0.002. Yokoyama et al. Nature. 2011.

(84.2 [95% CI 24.5-143.9] vs 32.6 [95% CI 26.7-38.4] ) P =0.008. Sturm et al. J Invest Dermatol. 2013.

• Reticular nevi pattern (P=0.004). Sturm et al. J Invest Dermatol. 2013.

Total body and dermoscopic images from patient M3879-03 (Barcelona)

Total body and dermoscopic images from patient M3879-01 (Barcelona)

Amelanotic melanoma from patient E318K in MITF & MC1R genotype = R/r afected by previous LMM, Renal Carcinoma and Lung carcinoma

Second nodular melanoma in a ptient with 4 primary melanomas carrier of E318K in MITF. Tumour developed in 1 months, Breslow 1mm MC1R genotype = R/r and p.Gly32Arg in p14arf

Prevalence of MITF p.E318K in melanoma patients independent of the presence of CDNK2A causative mutations Miriam Potrony, MSc,1 Joan Anton Puig-Butille, PhD,2,3 Paula Aguilera, MD,1,2 Celia Badenas, PhD2,3 Gemma Tell-Marti, MSc,1,2 Cristina Carrera, MD, PhD,1,2 Luis Javier del Pozo, MD,4 Julian Conejo-Mir, MD,5 Josep Malvehy, MD, PhD,1,2 Susana Puig, MD, PhD1,2

JAMA Dermatology (in press)

Wild-type cell

Wild-type cell

Mutated cell

Mutated cellAPO

PTO

SIS

SEN

ESCE

NCE

p16INK4a

p14ARF

CDK4

p53

CDK4

Cyclin D1

pRb

E2F

E2F

pRb

P

P

MDM2

p53

-UUU

Proteasomal degradation

Epigenetic regulation

BAP1

BRCA1

BARD1

YY1

HCF1

OGT

HAT1

ASXL1ASX

L2

FOXK1

FOXK2

KDM1B

Telomere maintenancePOT1

ACD

TINF2

TERF2TERF2I

P

TERF1

Proliferation control

TERF2

TERF1

TINF2

TERF2IP

ACD

Telomere enlargement

TERT

A

B C

POT1

Familial melanoma meta-analisis

Familial Melanoma

Fair Skin

DNA repair

Multiple nevi

MC1RTYRASIPTYRP1OCA2

PAX3, MTAP, PLA2G6, TERT, POT1

ERCC1, ERCC2, ERCC3, XPF,

Familial Melanoma

Fair Skin

DNA repair

Multiple nevi

Familial Melanoma

Fair Skin

DNA repairMultiple

nevi

Australia

Familial Melanoma

Fair Skin

DNA repair

Multiple nevi

Spain

Characterization of individuals at high risk of developing melanoma in Latin America: Bases for genetic counseling in melanoma Genetics in Medicine (in press)Susana Puig, MD, PhD1,2,3, Miriam Potrony, MSc1, Francisco Cuellar, MD1,4, Joan Anton Puig-Butille, PhD2,5, Cristina Carrera, MD, PhD1,2, Paula Aguilera, MD1,2, et al

Sporadic MPM patients

All melanoma-prone families

Families with 2 cases

Families with 3 cases

Families with 4 or more cases

All pedigree

s included TOTAL

CDKN2A

mutation P TOTAL

CDKN2A

mutation P TOTAL

CDKN2A

mutation TOTAL

CDKN2A

mutation TOTAL

CDKN2A

mutation PCountry (Region) N N % N % N % N % N % N % N % N % N % N % Argentina 10 5 50.0 1 20.0 5 50.0 0 0 4 80.0 0 0 1 20.0 0 0 0 0 0 0Brazil (Porto Alegre) 50 13 26.0 0 0 37 74.0 3 8.1 27 73.0 1 3.7 7 18.9 1 14.3 3 8.1 1 33.3Brazil (Sao Paulo) 57 22 38.6 1 3.6 35 61.4 8 22.4 21 60.0 1 4.8 13 37.1 7 53.8 1 2.9 0 0Chile 27 12 44.4 3 25.0 15 55.6 7 46.7 12 80.0 5 41.7 1 6.7 0 0 2 13.3 2 100Mexico 5 3 60.0 0 0 2 40.0 1 50.0 2 100 1 50.0 0 0 0 0 0 0 0 0Uruguay 20 5 25.0 1 20.0 15 75.0 8 40.0 11 73.3 4 36.4 4 26.7 3 75.0 0 0 0 0Spain (Barcelona) 564 234 41.5 20 8.5 330 58.5 47 14.2 269 81.5 30 11.2 47 14.2 11 23.4 14 4.2 6 42.9Spain (Valencia) 147 38 25.9 3 7.9 109 74.1 15 13.8 79 72.5 8 10.1 22 20.2 5 22.7 8 7.3 2 25.0

LATIN AMERICA 169 60 35.5 6 10.00.62

3

109 64.5 26 23.90.01

9

77 70.6 12 15.6 26 23.9 11 42.3 6 5.5 3 50.00.00

7

SPAIN 711 272 38.3 23 8.5 439 61.7 62 14.1 348 79.3 38 10.9 69 15.7 16 23.2 22 5.0 8 36.4<0.001

TOTAL 880 332 37.7 29 8.9 548 62.3 88 16.1 425 77.6 50 11.8 95 17.3 27 28.4 28 5.1 11 39.3<0.001

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Practical case

• Genetic counselling

LMM 72 y.o.

Q50R in CDKN2AMC1R wild type

Q50R in CDKN2AV60L in MC1R

Q50R in CDKN2AMC1R wild type

Q50R in CDKN2A

26 y.o. Grand mother melanoma. Phototype IV.

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Practical case

• Genetic counselling

LMM 72 y.o.

Q50R in CDKN2AMC1R wild type

Q50R in CDKN2AV60L in MC1R

Q50R in CDKN2AMC1R wild type

Q50R in CDKN2A

Genetic profiles will be used to:– Identify patients at risk:

• Primary and secondary prevention are important for melanoma and non-melanoma tumours (sun/smoking/other?)

– Identify suspicious tumours according to genetic background

– Better characterization of prognosis

– Target Therapies

Conclusion

Celia BadenasJoan A Puig-ButilleMiriam PotronyGemma Tell

Josep MalvehyCristina CarreraPaula Aguilera

Llucia AlosM Alba Díaz

Gabriel SalerniLouisa Lovatto