Upload
vr-foundation
View
1.336
Download
0
Embed Size (px)
DESCRIPTION
Melanoma incidence has continued to increase significantly during the last half of 20th century wherever available data exist. 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.
Citation preview
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.
From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm
Newton Bishop JA, Gruis NA. Genetics: what advice for patients with present with a family history of melanoma? Semin Oncol 2007;34:452-59.
Genetic risk factors
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
Genetic risk factors
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
From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm
From: http://63.126.107.29/SOTS/Meetings/Melanoma/05-05-2003/transcripts/03/transcript.htm
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.
Fargnoli MC, Argenziano G, Zalaudek I, et al. High-and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev Anticancer Ther 2006; 6:657-70.
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:
Fargnoli MC, Argenziano G, Zalaudek I, et al. High-and low-penetrance cutaneous melanoma susceptibility genes. Expert Rev Anticancer Ther 2006; 6:657-70.
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
Patient-related risk factors
(endogenous)
genetic
phenotypic Environmental factors (exogenous)
Risk factors
Risk factors
Melanoma skin cancer ethiopatogenesis involves:
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
Patient-related risk factors
(endogenous)
genetic
phenotypic Environmental factors (exogenous)
Risk factors
Risk factors
Melanoma skin cancer ethiopatogenesis involves:
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.
From melanocytes to melanoma
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.
From melanocytes to melanoma
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.