Melanoma epidemiology, etiopathogenesis and prevention - Professor Torello Lotti, MD - University G.Marconi, Rome, Italy - and Linda Tognetti, MD - Department of Dermatologic Sciences

The International School of Vitiligo & Pigmentary Disorders

Barcelona, 2-5 November 2011

Edizioni Fernando Folini, Alessandria 2008

Torello LottiDepartment of Dermatologic

SciencesUniversity of Florence, Italy

Melanomaepidemiology,

etiopathogenesis and prevention

Melanoma

EPIDEMIOLOGY

Melanoma

EPIDEMIOLOGY

Epidemiologic data

Although malignant melanoma comprises less than 5%

of malignant skin tumors, it is responsible for almost

60% of lethal skin neoplasia.

Radović-Kovacević V, Pekmezović T, Adanja B, et al. Survival analysis in patients with cutaneous malignant melanoma. Srpski Arhiv Za Celokupno Lekarstvo 1997;125(5-6):132–137.

The most common sites,

in decreasing order, are:

- trunk (43.5%)

- extremities (33.9%)

- acral sites (11.9%)

- and head and neck (10.7%)

From: http://esubart.info/diseases-and-conditions/skin-diseases-and-conditions/page/3/

Epidemiologic data

However, increased

incidence of melanoma is

partly due to early

detection, especially thin

melanomas.

MacKie RM. Melanoma and the dermatologist in the third millennium. Arch Dermatol 2000;136(1):71–73.

Melanoma incidence has continued to increase

significantly during the last half of 20th century wherever

available data exist.

Richert SM, D'Amico F, Rhodes AR. Cutaneous melanoma: patient surveillance and tumor progression. JAAD 1998;39(4):571–577.

The highest incidence rates in fair-skinned populations of Australia (especially in

Queensland) and New Zeland (20–50 per 100 000), America (10–20 per 100 000),

and Europe (5–20 per 100 000).

In the United States, the incidence of melanoma has more than tripled in the

white population during the last 20 years, and melanoma currently is the sixth

most common cancer.

Epidemiologic data:

GLOBOCAN 2000 IARC. Cancer incidence, mortality and prevalence worldwide, version 1.0.cancerbase no. 5. Lyon: IARC Press; 2001.

Czarnecki D, Meehan CJ. Is the incidence of malignant melanoma decreasing in young Australians? JAAD 2000; 42(4):672–674.

ethnic group

The incidence of malignant melanoma appears to be lower and stable in dark-

skin individuals (Africans, Native Americans, Asians, and Hispanics).

Decreased incidence reported from some countries is probably partly due to an

influx of low risk immigrants.

Hall HI, Miller DR, Rogers JD et al. Update on the incidence and mortality from melanoma in the United States. JAAD 1999; 40 (1):35–42.

RacLennan R, Green AC, McLeod GR, Martin NG. Increasing incidence of cutaneous melanoma in Queensland, Australia. J Nat Canc Inst 1992; 84(18):1427–1432.

Epidemiologic data: age

Lasithiotakis KG, Petrakis IE, Garbe C. Cutaneous melanoma in the elderly: epidemiology, prognosis and treatment. Mel Res 2010;20:163-170.

Kelly JW. Melanoma in the elderly. A neglected public health challenge. Med J Aust 1998;169(8): 403-4.

With increased life expectancy of the elderly population, melanoma will

be a public health challenge.

The incidence of cutaneous melanoma in patients older than 65 years

is up to 10 times higher than in patients younger than 40 years, reaching

100 cases per 100.000 in high-incidence regions of Australia.

The increase of the incidence rates of melanoma during the last 30

years has been consistently higher for elderly people all over the world.

Jemal A, Devesa SS, Hartge P, Tucker MA. Recent trends in cutaneous melanoma incidence among whites in the United States. J Natl Cancer Inst 2001; 93:678–683.

In Europe, Australia and United States, the highest incidence rates

have been observed in patients older than 60 years old, predominantly

males.

Marrett LD, Nguyen HL, Armstrong BK. Trends in the incidence of cutaneous malignant melanoma in New South Wales, 1983–1996. Int J Cancer 2001; 92:457–462.

Epidemiologic data: sex The incidence of melanoma is similar in men and

women, although there are reports that the incidence

may be higher in women.

The most recent analysis of global cancer statistics for melanoma

demonstrated a prevalence of 37.7 cases per 100,000 men and 29.4

cases per 100,000 women in Australia and New Zealand, compared with

6.4 cases per 100,000 men and 11.7 cases per 100,000 women in North

America.

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. Mar-Apr 2005;55(2):74-108

Sex is an independent prognostic factor in surviving melanoma.

The sex difference in survival with a better outcome for women is confined to

melanoma patients of 60 years and younger. In addition, in younger age groups,

male patients present with prognostically unfavorable features of primary

melanoma.

Mervic L, Leiter U, Meier F, et al.Sex differences in survival of cutaneous melanoma are age dependent: an analysis of 7338 patients. Mel Res 2011; 21(3):244–252.

Radović-Kovacević V, Pekmezović T, Adanja B, et al. Survival analysis in patients with cutaneous malignant melanoma. Srpski Arhiv Za Celokupno Lekarstvo 1997;125(5-6):132–137.

Curado MP, Edwards B, Shin HR, Storm H, Ferlay J, Heanue M, Boyle P, editors. Cancer incidence in five continents. Vol. IX. Lyon: IARC (IARC Scientific Publications No. 160); 2007. http://www-dep.iarc.fr/CI5_IX_frame.htm

Cutaneous melanoma incidence for selected populations of Australia, the US and Europe for the years 1998–2002.

Rates standardized according to the world standard population. Data retrieved from the cancer incidence in five continents vol. IX database

Cutaneous melanoma incidence rates/100.000 person/year (standardized on global population) for sex and

geographical areas.Geographical areas

Incidence ratesMen Women

Australia/New Zeland 29.4 37.7

North America 11.7 11.4

Western Europe 10.3 7.3

Southern Europe 5.5 6.0

South Africa 4.1 5.4

Eastern Europe 3.8 3.3

Melanesia 2.9 4.8

East Africa 2.3 1.2

South America 2.3 2.4

Central Africa 2.2 2.2

Central America 1.7 1.3

Western Asia 1.5 1.6

Caraibi 1.1 1.0

Western Africa 0.9 1.1

Micronesia o.7 1.2

North Africa 0.5 0.7

South-East Asia 0.5 0.5

South-Center Asia 0.4 0.4

Eastern Asia 0.2 0.3

Polinesia 0.0 5.1Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2002 Cancer Incidence, mortality and prevalence woeldwide IARC cancer base No.5, version 2.0. IARC press, Lyon, 2004.

Melanoma

ETIOPATHOGENES

IS

Melanoma

ETIOPATHOGENES

ISRisk factors

Risk factors

Melanoma genesis

Melanoma genesis

Patient-related risk factors

(endogenous)

genetic

phenotypic Environmental factors (exogenous)

Risk factors

Risk factors

Melanoma skin cancer ethiopatogenesis involves:

Genetic risk factors

Genetic susceptibility to melanoma has

been investigated by several epidemiolgic

studies performed on melanoma-prone

families.

8-12% of melanomas occur in a familial setting (familial

melanoma), has an autosomal dominant transmission with incomplete

penetrance.

Newton Bishop JA, Gruis NA. Genetics: what advice for patients with present with a family history of melanoma? Semin Oncol 2007;34:452-59.

One of the most significant risk factors for melanoma is a positive family history. • It is estimated that approximately 10 %of melanoma cases report a first-or second-degree relative with melanoma.

Hayward NK. Genetics Of melanoma predisposition. Oncogene 2003; 22(20):3053-62.

From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm

Familial melanoma is defined by the presence, within the same family, of:• at least 2 cases in first-degree relatives• ≥ 3 cases in the same side of the family, without respect to the degree of relatedness

at least 2 cases in second-

degree relatives, one of those

with multiple melanoma or with

diagnosis received before the

age of 40.


Newton Bishop JA, Gruis NA. Genetics: what advice for patients with present with a family history of melanoma? Semin Oncol 2007;34:452-59.


Mancini C, Fargnoli MC, Suppa M, et al. Aspetti genetico-molecolari. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp 11-14.

melanoma affected woman

melanoma affected man

= dead

Genealogical tree of melanoma-affected family


Fargnoli MC, Argenziano G, Zalaudek I, et al. High-and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev Anticancer Ther 2006; 6:657-70.

Numerous molecular genetic studies have dimonstrated the

important role of some susceptibility genes in the pathogenesis of

melanoma. To date, mutations of three genes have been demonstrated to

predispose to melanoma development:

CDKN2A (cyclin-dependent kinase inhibitor type 2A)

High penetrance gene

CDK4 (cyclin-dependent kinase type 4) High penetrance

gene

MC1R (melanocortin 1 receptor) Low penetrance gene

CDKN2A The CDKN2A gene acts as a tumor suppressor gene and plays a crucial

role in cell cycle regulation and senescence.

It encodes for two proteins, p16INK4A and p14ARF, which control,

respectively, the two important pathways of Rb (Retinoblastoma) and p53

proteins. Germinal mutations of

CDKN2A have been

identified in 20-40% of

melanoma-prone families,

and most part of these

mutations are missense and

localized in the exon 1α and

2.Mancini C, Fargnoli MC, Suppa M, et al. Aspetti genetico-molecolari. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp 11-14.

Goldstein AM, Chan M, Harland M et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMel. Cancer Res 2006;66:9818-28.

In melanoma-affected

families, mutations in CDKN2A

which alterate p16INK4A are

more frequent (about 38%) than

p16INK4A mutations.

Among CDKN2A mutations which have been described until today, 70%

have been reported one time only, while 30% are recurrent in several

melanoma-prone families around the world.

Aplotype analysis of these families indicated that they share a common

progenitor (“foudator effect”).

A significant association between CDKN2A and other tumors,

especially pancreatic cancer.

CDKN2A

From: http://www.gla.ac.uk/schools/medicine/medicalsubjects/medicalgenetics/dretobias/

Goldstein AM, Chan M, Harland M, et al. Features associated with germline CDKN2A mutation: A GenoMel study of melanoma-prone families from three continents. J Med Genet 207;44:99-106.

CDKN2A

Among melanoma-prone families, the probability of finding a

CDKN2A mutation increases with:

o number of affected family member

o younger age at diagnosis

o presence of multiple melanoma

o cases of pancreatic carcinoma

within the family



Mutations of the CDKN2A

gene confer susceptibility to

familial melanoma.

Partial or complete loss of

p16 expression has also been

identified in sporadic

melanomas.

CDKN2A

Bataille V.Genetics of familial and sporadic melanoma. Clinical and Experimental Dermatology 2000; 25(6):464-70.

Nagore E, Climent J, Planelles MD, et al. Analysis of the CDKN2A and CDK4 genes and HLA-DR and HLA-DQ alleles in two Spanish familial melanoma kindreds. Acta Dermato-Venereologica 2000;80(6): 440–442.

CDKN2A

People with CDKN2A

mutation have variable risk

of melanoma developement

according to different areas.

Otherwise, CDKN2A mutations have been

rarely described in non-familiar melanoma:

• in 1,2% of patient with sporadic melanoma

• in 2.9% of patient with multiple melanoma

Bishop DT, Demenais F, Gldstein AM et al. Geographical variations in the penetrance of CDKN2A mutation for melanoma. J

Natl Cancer Inst 2002; 94:894-903.

Berwick M,Orlow I, Hummer AJ et al. The prevalence of CDKN2A germ-line muatins and relative risk for cutaneous malignant melanoma: an international population-based study. Cancer Epidemiol Biomarkers Prev 2006;15:1520-5.

From:http://www.ricercaitaliana.it/prin/dettaglio_completo_prin-2004061840.htm

CDK4

Proto-oncogene CDK4, localized in the 12q13 region, is rarely

responsible of genetic susceptibility to melanoma.

Like CDKN2A, it plays a role in the regulation of the G1/S

checkpoint of the cellular cicle, trough the binding with p16INK4A

protein.

From: http://ghr.nlm.nih.gov/gene/CDK4

Two germinal

mutations of CDK4,

within the same codon of

the exon 2, have been

recently identified in 8

melanoma-prone

families.Majore S, De Simone P, Crisi A et al. CDKN2A/CDK4 molecular study on 155 Italian subjects with familial

and/or primary multiple melanoma. Pigment Cell Melanoma Res 2008;21:209-11.

MC1R

Mancini C, Fargnoli MC, Suppa M, et al. Aspetti genetico-molecolari. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp 11-14.

The Melanocortin-1-receptor

(MC1R) gene plays an

important role in cutaneous

pigmentation

MCR1 gene encods for an

high-affinity receptor for MSH,

the melanocortin whose

binding determines eumelanin

production.

If MCR1 function is altered,

there is maily pheomelanin

synthesis. Rees J. The genetics of sun sensitivity in humans. Am J Hum genet 2004;75:739-51.

MC1R

MCR1 gene is highly polymorphic, with more than 75

allelic variants expressed in different populations.

It is considered a main determinant of the diversity of

human pigmentation, with the wild-type MC1R

predominantly expressed in Africa, where high eumelanin

content in the skin is critical for optimal photoprotection.

Garcia-Borron JC, Sanchez-Laorden BL, Jimenez-Cervantes C.Melanocortin-1 receptor structure and functional regulation. Pigment Cell Res 2005;18:393–410.

Stimulation of eumelanin synthesis by activation of

MC1R confers photoprotection; however, the effect of

MC1R genotype on melanoma risk is independent of the

effect on pigmentation, suggesting that MC1R

determines the risk for melanoma by other

mechanisms.

Stratigos AJ, Dimisianos G, et al. Melanocortin receptor-1 gene polymorphisms and the risk of cutaneousmelanoma in a low-risk southern European population. J Invest Dermatol 2006;126:1842–1849.

MC1R Some MC1R variants, mainly R151C, R160W and

D294H, are strongly associated with red hair color

(RHC) phenotype.

High penetrance “R”.

Three other variants (V60L, V92M and R163Q) have

a low association, so they are defined NRHC Low

penetrance “r”.

Sturm RA, Box NF et al. Genetic association and cellular funcion of MCR1 variant alleles in human pigmentation. Am NY Acad Sci 2003; 994:348-58..

Kadekaro AL, Leachman S, Kavanagh RJ, et al. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J 2010;24:3850–3860.

Expression of any two of the RHC variants

in the homozygous or compound heterozygous

state results in loss of function of the receptor,

disrupting its ability to signal when bound by its

agonists.

From:http://www.thetech.org/genetics/ask.php?id=301

MC1R In sporadic melanoma, the presence of the RCH

variants of MCR1 gene, is associated with poor tanning

ability and increased risk of melanoma development,

with a major effect in patients who has more than one

allelic variant.

In familial melanoma, RCH variants can augment the

penetrance of CDKN2A mutations, reduce the age of

melanoma onset and predispose to multiple melanoma development.

Epidemiological studies from different populations have demonstrated

that RHC variants are also related to non-melanoma skin cancer, which

is independent from skin type and hair color.

Kennedy C, ter Huurne J, Berkhout M, et al.Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color. J Investig Dermatol 2001;117:294–300.


MC1R

It has been also demonstrated that patient

with MC1R gene allelic variants have an

increased risk of developing a melanoma

cancer with somatic mutations of BRAF gene,

and this risk is proportional to the number of

variants existing in genotype.

Moreover, the MCR1/BRAF association seems to be

independent from age, phenotype, location and thickness of

melanoma and nevi’s number.

Fargnoli MC, Pike K, Pfeiffer RM, et al. MC1R variants increase risk of melanomas harboring BRAF mutations. J Invest Dermatol 2008;128(10): 2485–2490.

OTHER GENES

• pigmentation pathway: OCA2

• cellular grow and differentiation:

BRAF, EGF, VDR, EDN

• DNA repair: XCP, XPD, XRCC3

• metal detoxification: GSTM1, GSTT1

Other various low-penetrance genes have

been studied, with conflicting results.

The investigated genes are involved in:


Although genetic studies have reported a number of loci associated

with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic

association studies and a systematic meta-analysis for all eligible

polymorphisms have been performed only recently by Chatzinasiou et al.

In the main meta-analyses, 4 loci showed genome-wide statistically

significant association with cutaneous melanoma and reached strong

epidemiological credibility: MC1R, TYR, SLC45A2 and

MYH7B/PIGU/ASIP.

In the supplementary meta-analyses, alsoTYRP1

and CDKN2A/MTAPresulted to be associated with an

increased susceptibility to melanoma.

Chatzinasiou F, Lill CM, Kypreou K, et al.Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma. J Natl Cancer Inst 2011;103(16):1227-35.

OTHER GENES


(endogenous)

genetic


Risk factors

Risk factors


Phenotypic risk factors• pale skin

• red or blond hair

• numerous freckles

• tendency to burn and tan poorly

• presence of more than 50 acquired (common, banal) nevi

• more than five dysplastic (atypical, Clark’s) nevi

• large congenital nevi

• nevi larger than 6 mm

• Xeroderma pigmentosum

• older age

• family history of melanoma

• actinic keratosis, non melanoma skin cancers

• scars, Marjolin’s ulcer

• immunosuppression

Bandarchi B, Ma L, Navab R, et al. From melancyte to metastatic malignant melanoma. Dermatology Research and Practice 2010: ID 583748

predominantly skin phototype 1–3

Phenotypic risk factors

Stanganelli I, Palmieri G. Prevenzione primaria e secondaria del melanoma. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp:15-20.

People with red/blond/light brown hair, blu/green eyes and pale skin

have an higher relative risk (RR) than people with dark brown or black

hair/eyes.

In particular:

• RR 3.6 : red hair

• RR 2.5 : freckles

• RR 2.0 : blond hair

• RR 2.1 : phototype I

• RR 1.7-1.8 : phototype II-III

• RR 1.5-1.6 : blue/green eyes


(endogenous)

genetic


Risk factors

Risk factors


Exogenous risk factors

Environmental risk factors include :

• intermittent sun-exposure

• excessive childhood sun exposure

• blistering childhood sunburns

• use of tanning devices (sunbeds)

• PUVA therapy

• chemical exposures

• intermittent sun-exposure

• excessive childhood sun exposure

• blistering childhood sunburns

• use of tanning devices (sunbeds)

• PUVA therapy

• chemical exposures

Bandarchi B, Ma L, Navab R, et al. From melancyte to metastatic malignant melanoma. Dermatology Research and Practice 2010: ID 583748

Whiteman DC, Green AC. Melanoma and sun exposure: where are we now? Int J Dermatol 1999;38(7):481–489.

The role of chronic sun exposure is controversial. Some studies suggested

that total accumulated exposure to sun is a very important factor, whereas long-

term correct exposure actually may be protective .

Ricceri F. De Giorgi V. Lotti . Melanoma:un’ipotesi eretica relativamente alla fotoesposizione cronica. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp:15-20.

Ultraviolet (UV) radiation is the major risk

factor, and up to 65% of melanomas are sun-

related.

Exogenous risk factors

The Earth's ozone layer blocks 97-99% of this UV radiation from

penetrating through the atmosphere. UV radiation is divided into 3

wavelength ranges:

UVA rays (400 nm–315 nm): they represent the 98.7% of the UV

radiation that reaches the Earth's surface. UVA rays cause cells to age

and can cause some damage to cells' DNA. They are linked to long-term

skin damage such as wrinkles, but are also thought to play a role in skin

cancers.

UVB rays (315 nm–280 nm): they can cause direct

damage to the DNA, and are the main rays that cause

sunburns. They are also thought to cause most skin cancers.

UVC rays (280 nm–100 nm): they don't get through our

atmosphere and therefore are not present in sunlight.

They are not normally a cause of skin cancer.Hockberger, PE. A history of ultraviolet photobiology for humans, animals and microorganisms. Photochem. Photobiol. 2002;76 (6): 561–579. From: http://www.anthelios.com/anthelios-

uvraydamage.html

UVA rays

Use of artificial UV tanning devices

(sunbeds) consists mainly of repeated

exposure to high UVA doses.

Epidemiological studies published over the

last years confirmed the association between

sunbed use and melanoma.

A recent study of Autier et al. has demonstrated that UVA could be

involved in the occurrence of nonlife-threatening melanoma.

The authors also suggest that the increasing use of sunbeds and of

sunscreens may partly explain why melanoma incidence increases in

most light-skinned populations without concomitant increase in

mortality.Autier P, Doré JF, Eggermont AM, Coebergh JW. Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma.Curr Opin Oncol 2011;23(2):189-96.

Absorption of UVB by DNA causes damage that, if not repaired, can

become initiating mutations in skin cancer. UVB rays cause two types of

DNA lesions:

o the 6–4 photoproducts, generated between adjacent pyrimidine

residues.

o pyrimidine dimers, formed specifically between adjacent thymine or

cytosine residues.

UVB rays

Matsumura Y, Ananthaswamy HN. Front Biosci.2002;7:d765–d783.You YH, Lee DH, Yoon JH, Nakajima S. J Biol Chem 2001;276:4688–94.

Pyrimidine dimers are considered to be

more carcinogenic than the 6–4

photoproducts, forming almost three times

as often and being repaired less efficiently.

Melanoma genesis

Melanoma genesis

Nearly 30% of cases

derives from

melanocytic nevi

(ie, common, congenital,

and atypical/dysplastic

types)

Nearly 30% of cases

derives from

melanocytic nevi

(ie, common, congenital,

and atypical/dysplastic

types)

The sequence of events in which normal melanocytes transform into

melanoma cells, referred to as melanomagenesis, is still poorly

understood.

Melanomagenesis

Primary cutaneous melanoma

about 70% of cases

arise de novo

(ie, not from a

preexisting

pigmented lesion).

about 70% of cases

arise de novo

(ie, not from a

preexisting

pigmented lesion).

Palmieri G, Capone M, Capone M, Main roads to melanoma Journal of Translational Medicine 2009;7:art86.

Melanomagenesis is likely to involve a combination

of up- or downregulation of various effectors acting on

different molecular pathways, along with a multistep

process of

progressive genetic mutations that:

alter cell proliferation, differentiation, and

death

impact susceptibility to the carcinogenic

effects of UV ray.

Demierre MF, Nathanson L. Chemoprevention of melanoma: an unexplored strategy. J Clin Oncol 2003;21(1):158-65.

From melanocytes to melanoma

Alteration of cell cycle proteins (e.g., cyclin D1, pRb, and p16) has a

role in transformation and progression in melanocytic tumors.

Progressive increase in expression of cyclin D1 and pRb is associated

with progression to melanoma cells.

Karim RZ, Li W, Sanki A, et al. Reduced p16 and increased cyclin D1 and pRb expression are correlated with progression in cutaneous.International Journal of Surgical Pathology 2009; 17(5):361–367.

During the early stages of melanomagenesis, melanocytes

acquire the ability to proliferate and escape from cell cycle

regulation by uncoupling from keratinocytes.

This is achieved by downregulating the expression of the adhesion

molecules E-cadherin, P-cadherin, and desmoglein in response to the

paracrine factor HGF via

binding to c-Met and activation of ERK1/2 and IP3 kinase.


Mutations which disrupt MAP kinase ERK1/2 and IP3 kinase pathways of

melanocyte homeostasis are common in melanoma: e,g, BRAFV900E

mutation causes constitutive activation of BRAF and upstream of ERK1/2,

thus increased proliferation and survival.

Jamal S, Schneider RJ. UV-induction of keratinocyte endothelin-1 downregulates E-cadherin in melanocytes and melanoma cells. J Clin Investig 2002;110:443–452. Sosman JA, Margolin KA. Inside life of melanoma cell signaling, molecular insights, and therapeutic targets. Curr Oncol Rep 2009;11:405–411.


Further studies showed that overexpression of basic fibroblast grow

factor (bFGF) in a human xenograft model followed by UVB irradiation

gave rise to hyperplastic melanocytic cells with high-grade atypia,

reminiscent of lentiginous melanoma.

Berking C, Takemoto R, Satyamoorthy K, et al. Basic fibroblast growth factor and ultraviolet B transform melanocytes in human skin. Am J Pathol 2001;158:943–953.

Overexpression of bFGF concomitantly with

endotelin-3 (ET-3) and stem cell factor

(SCF) followed by UVB exposure, led to the

formation of nests of atypical melanocytes

representing melanoma in situ.

Berking C, Takemoto R, Satyamoorthy K, et al. Induction of melanoma phenotypes in human skin by growth factors and ultraviolet B. Cancer Res 2004;64:807–811.

Both types of lesions

induced by UVB rays,

i.e., 6–4

photoproducts (6-4-

PP) and pyrimidine

dimers (PD), can

lead to genetic

mutations such as

the CT or CC TT

transitions (the latter

mutation being the

hallmark of UV-

induced

mutagenesis).

Molecular and carcinogenic responses of melanocytes to UV radiation

Jhappan C, Noonan FP, Merlino G. Ultraviolet radiation and cutaneous malignant melanoma. Oncogene 2003;22.

From nevi to melanoma

Although nevi and melanomas share initiating genetic

alterations such as oncogenic mutations in BRAF and

NRAS, melanomas often show recurrent patterns of

chromosomal aberrations such as losses of chromosomes 6q, 8p, 9p,

and 10q along with gains of chromosomes 1q, 6p, 7, 8q, 17q, and 20q.

Differences in frequency of BRAF or NRAS mutations are also related

to patterns of sun exposure:

- BRAF mutations are more common in intermittently UV-exposed skin

- KIT mutations are common in chronically sun exposed skin or relatively

unexposed skin.

Palmieri G, Capone M, Capone M, Main roads to melanoma Journal of Translational Medicine 2009;7:art86. Maldonado JL, Fridlyand J, Patel H, et al. Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst. 2003;95(24):1878-90.

Otherwise, benign nevi tend to have no detectable chromosomal

aberrations by comparative genomic hybridization or karyotyping.

Transmission electron micrograph (TEM) of a melanocyte from human malignant melanoma.

From: http://www.sciencephoto.com/media/253749/enlarge

An overproduction of melanin is indicated by the small black areas around the periphery of the cell.

The cell nucleus has the appearance of a fried egg, with a central dark nucleolus.

Transmission electron micrograph (TEM) of melanosomes within a malignant melanocyte.

From: http://www.sciencephoto.com/media/253750/enlarge

Melanoma

PREVENTION

Melanoma

PREVENTIONPrimary

preventionphotoprotection

Primary prevention

photoprotection Secondary prevention

early diagnosis

Secondary prevention

early diagnosis

Photoprotection

Photoprotection

Behavioral norms

Sunscreen use

Melanocortin analog administration

Behavioral norms

The intensity of UV radiations varies with the

season, the altitude and latitude, and the time

of day.

In this range of hours, people with phenotypic risk factors should

wear hat and protective clothes, and, in summer months, avoiding

sun exposition.

Stanganelli I, Palmieri G. Prevenzione primaria e secondaria del melanoma. In: De Giorgi V, Aricò M, Lotti T, eds. Il melanoma.Prevenzione, diagnosi e terapia. Tortona: Fernando Folini; 2008. pp:15-20.

In our latitudes, the 60% of UV radiation that reaches the

Earth’s surface is concentrated in 4 hours, from 11.00 to

15.00, with maximum incidence in summer months.

Sunscreen use

Is now generally accepted that regular

sunscreen use prevents cutaneous squamous

cell carcinoma long term, but their effect on

melanoma arouses contrasting opinions.

Some authors reasoned that sunscreen use may extend sun

exposure intended for getting a tan, while it does not necessarily

decrease sunburn occurrence. Indeed, nearly 99% of UV radiation

that reaches the Earth’s surface is UVA, whereas sunscreen creams

are more effective in blocking UVB rays.

According to Autier et al., sunscreen use for tan acquisition would

thus lead to similar exposure to UVB and greater exposure to UVA,

which could explain the slightly higher melanoma risk often found

among sunscreen users.

Autier P, Doré JF, Eggermont AM, Coebergh JW. Epidemiological evidence that UVA radiation is involved in the genesis of cutaneous melanoma. Curr Opin Oncol. 2011;23(2):189-96.

Recently, Green et al. published the results of a

complex trial, that has demonstrated for the first time a

strong evidence for a reduction in the incidence of

invasive melanoma after regular application of broad-

spectrum sunscreen in adults.

Long-term follow-up of this randomized trial showed that, among adults

age 25 to 75 years, regular application of SPF 15+ sunscreen in a 5-year

period appeared to reduce the incidence of new primary melanomas for up

to 10 years after trial cessation.

A protective effect was also evident for invasive melanoma, which

showed a 73% decrease in those randomly assigned to daily sunscreen

after approximately 15 years of follow-up.

The trial was conducted in Queensland, the region with

the highest rate of skin cancer in the world and achieved

relatively high rates of compliance among the participants

assigned to the group using sunscreen.

Green AC, Williams GM, Logan V and Strutton GM. Reduced Melanoma After Regular Sunscreen Use: Randomized Trial Follow-Up. J Clin Oncol 2011;29(3):257-63.

Gimotty PA, Glanz K. Sunscreen and Melanoma: What Is the Evidence? JCO , 2011;29(3):249-250.

Highly exposed and at-risk individuals should consider making regular

sunscreen use a habit, much like other health routines; in addition,

parents should apply sunscreen to their children's skin and should

model the practice of sunscreen use.

Sunscreen use

Clinicians should advise patients at high risk for

skin cancer because of phenotypic characteristics,

who live in or visit sunny climates, and/or who

have a family history of melanoma, to routinely

and thoroughly apply sunscreen before going

outside, and provide them clear instructions

regarding the use and re-application of sunscreen.

Since decades, there has been interest in targeting the MC1R in a

strategy to prevent melanoma.

The injective α-MSH analog NDP-MSH was found to reduce the

induction of DNA photoproducts in sunexposed human skin.

Despite its effectiveness, NDP-MSH was not specific to the MC1R.

In the last years, small tetrapeptide analogs of α-MSH

for topical application have been developed.

These mlecules showed to surpass α-MSH

in their potency to stimulate melanogenesis and

to reduce UV-induced DNA damage and apoptosis.

Melanocortin analog

Levine N, Sheftel SN, Eytan T, et al. Induction of skin tanning by the subcutaneous administration of a potent synthetic melanotropin. JAMA 1991;266:2730-36

Abdel-Malek ZA, Kadekaro AL, et al. Melanoma prevention strategy based on using tetrapeptide alpha-MSH analogs that protect human melanocytes from UV-induced damage and cytotoxicity. FASEB J 2006;20:1561–63.

Some of these peptides proved to be highly selective for the

MC1R, which should alleviate any side two that has been tested so

far could permeate human skin, suggesting their possible efficacy in

a topical application.

These analogs are expected to confer photoprotection for

individuals with wild-type MC1R, heterozygous for MC1R

variants reducing receptor function, or mutant for other

melanoma susceptibility genes.

Melanocortin analog

Abdel-Malek ZA, Ruwe A, Kavanagh-Starner R. alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes. Pigment Cell Melanoma Res 2009;22:635–644.

Demenais F, Mohamdi H, Chaudru V, et al. Association of MC1R variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study. J Natl Cancer Inst 2010;102:1568-83.

More recently, tripeptide α-MSH analogs were developed and

shown to be capable of activating the MC1R and reducing UV-

induced DNA damage.

[email protected]

Health & Medicine

Melanoma epidemiology, etiopathogenesis and prevention - Professor Torello Lotti, MD - University G.Marconi, Rome, Italy - and Linda Tognetti, MD - Department of Dermatologic Sciences