Genetics of Melanoma

8/14/2019 Genetics of Melanoma

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Melanoma Pathology,

Treatment and Genetics


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Key Issues

Incidence

What is melanoma?

Pathology

Pathology/Aetiology of Skin cancer.

Causes

Who gets it

Location of melanomas (what part of body) Role of UV radiation

Treatment of Melanoma

Melanoma Associated genes

Tumour suppressor genes Oncogenes

Antigenicity of Melanomas.

A genetic model of melanoma.


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Incidence of Melanoma

Skin cancer is the second most common cancer in theUK.

About 50,000 cases per year in the UK (includes SCC& BCC)

5-6000 are melanoma

1 in 80 people in the US/Australia get CMM

1 in 200-250 in the UK get CMM

CMM is responsible for 90% of skin cancer associateddeaths


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Cutaneous MalignantMelanoma

CMMs are derived from the melanocytes located inthe basal layer of the epidermis.

Very aggressive tumour and metastasise to a varietyof organs

Bone

Brain

Juxtaposed lymph nodes

Two modes of growth Radial growth phase over surface of skin

Vertical growth phase into lower layers prior tometastasis


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Skin Anatomy


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Melanoma Types

Lentigo MM Superficial Spreading MM

Acral MM Nodular MM


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Melanoma Pathology


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Cutaneous MalignantMelanoma

If tumour resected before a vertical invasion of lessthan 3mm - associated with a cure.

Greater than 3mm metastatic disease likely.

80% of CMM patients get metastatic disease.

Metastatic lesions associated with about 6 months

survival following diagnosis.


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Local Spreading of Melanoma

Point of origin: Acquired/dysplastic neavus (mole)

Radial Growth Phase

Vertical g

rowthphase

Malignant


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What Causes Melanoma

Strong evidence that melanoma occurs on sundamaged skin.

High risk associated with short bursts of intense UVexposure. Intermittent exposure during childhood - important factor.

Who gets it

Those with high number of naevae (moles).

Type 1 skin blue eyes, blond, burn easily, thosewith a family history of melanoma.

Age group: 40 60 year olds, but can occur at any age(rarely in children)

More women than men get melanoma.


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Pathology/Aetiology ofSkin Cancer

SCC BCC CMM

Sun Sensitive skin Total Sun Exposure Childhood Sun

Exposure

Intermittent Over

Exposure

P53 Mutation


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Location

Affect most parts of the body.

Women legs.

Men trunk especially the back.

Role of Sunlight (UV irradiation)

UVA: 320 400nm

UVB: 280 320nm

UVC: 100 280nm

All UVC and some UVB is blocked by atmospheric ozone.

UVB causes the erythemal response reddening associated with sunburn.

UVA: Skin ageing


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If melanoma is detected early:

Surgical resection of primary tumour followed bycareful monitoring.

Advanced Disease Resection of Primary tumour

Lymph node excision and surgical removal ofmetastases where possible

High dose interferon to treat disseminated

disease (boost immune system) Melphalan + Interferon

Prognosis is poor with advanced disease


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Experimental Models

Xiphophorus fish: Irradiation with single dose UVBinduces melanoma in fish (Setlow). Spectral regions contributing to melanoma: a personal view.

Setlow RB, J Investig Dermatol Symp Proc. 1999 Sep;4(1):46-9

XPA transgenic mice: Knockout mice (excision repairgene XPA) are susceptible to melanoma induction byUVB irradiation

Photocarcinogenesis: UVA vs UVB.de Gruijl FR.Methods Enzymol. 2000;319:359-66.

Aim is to produce anAction Spectrum in humansDetermination of what UV wavelength is responsiblefor CMM induction.


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Molecular Genetics of

Melanoma

A number of chromosomal aberrations are knownto accumulate during CMM development.

Principally non-random Losses of Heterozygosity(LOH) (remember Knudsons two hit hypothesis ofretinoblastoma)


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LOH in Melanoma

Chromosome Frequency of LOH

1p36 25%

6q22-24 30-35%

9p21 (p16) 50-60%

10q22-25 30%

11q23-ter 25%


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Tumour Suppressor Genes

No evidence of P53 involvement in melanoma development.

CDKN2A/INK4A/P16: Cyclin dependent kinase 4 inhibitor.

Causes a G1 arrest by inhibiting the phosphorylation of RB.Inhibits the action of cyclin dependent kinases 4 and 6.

Gene Structure:

3 exons

Exon 1: 150bp (50aa)

Exon 2: 307bp (101aa)

Exon 3:12bp (3 aa)


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Cell Cycle Control(abbrev.)

G1 S G2 M

G0

CyclinD1

CyclinD2

CyclinD3

CDK4

CDK6

p15,p16, p18, p19

pRB

CDK2 CDK2 CDK1

Cyclin BCyclin E Cyclin A


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Exon 1 Exon 2 Exon 1 Exon 1 Exon 2 Exon 3

Exon 1 Exon 2

Exon 1 Exon 2 Exon 3

Exon 1 Exon 2 Exon 3

The INK4 locus of chromosome 9p21

p15

p16

p14 ARF


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Inactivation of P16

Deletion: About 50-60% of melanomas display LOH atchromosome 9p21 (location of P16).

P16 loss is thought to be a critical event in

melanogenesis.

Methylation: CpG islands in the promoter region ofP16. Causes functional silencing of the gene.

Occurs frequently in head and neck (SCC), breast,prostate, bladder cancers.

Probably a significant event in melanoma development

Point mutation: Observed in many cancers includingmelanomas


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Point mutations in P16

Inactivation of P16 by point mutations nota resultof prior exposure to UV irradiation.

UV exposure = pyrimidine dimers in DNA.

Mutation by UV = CCTT tandem base substitution. Never observed in any known melanoma tumour

suppressor gene.

Despite the obvious role of UV in melanogenesis.

Mutation of P16 in the germline of melanomakindreds establishes P16 as a familial TSG.


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Pyrimidine Dimer


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Other Melanoma Tumour SuppressorGenes

PTEN: Phosphatase and Tensin homologue.

also called

MMAC1: Mutated in Multiple Advanced Cancers.

Encodes a tyrosine phosphatase with extensive homology

to the cytoskeletal proteins auxillin and tensin. Suppresses Akt signalling

PTEN/MMAC1 maps to chromosome 10q23.3

9 exons

ORF: 1212nt

403 amino acids 47kDa

Functions as a negative regulator of signal transduction


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Any Other Melanoma TumourSuppressors?

KiSS1 Tumour suppressor Gene Chromosome 1p32

Regulates an antimetastasis gene onchromosome 6.

Associated with LOH on chromosome 6q16

LOH also demonstrated on

chromosomes 11

chromosome 10 (not PTEN)

As yet most of the tumour suppressor genes havenot been fully identified.


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Oncogene Activation and Melanoma

N-RAS mutational activation at codon 61

CAAAAA Destroys natural ATPase activity of Ras protein.

Observed in

Congenital naevi

Dysplastic naevi


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Oncogenes

B-Rafoncogenes: Ras-Raf MAP kinase signaltransduction pathway.

A serine threonine kinase leading to

upregulation of BRN-2 transcription factor

Mutations in 60% of primary melanomas

Elevated kinase activity Capable of transforming NIH3T3 cells in

culture.


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Other Potential Melanoma AssociatedGenes

Integrins

A diverse family of receptors that mediate adhesionbetween the cell membrane and the extracellular matrix.

Composed of and subunits. Combinations of 14 and 8 subunits comprise a

family of over 20 integrin types.

Certain classes of integrin expression has been shown tobe upregulated during transition from radial to verticalgrowth phase.

Integrin v


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Antigenicity of Melanomas

Melanomas are thought to have an antigenic

component Photo-immunological aspects of melanoma.J.Investigative Dermatology. 24: 153-165(1995) Kripke ML et al.

May render them sensitive to immunologicalmethods of treatment.

High molecular weight melanoma associatedantigen: associated with many melanomas

Possible exploitation for immunotherapy.


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A Genetic Model

Normal melanocyte Dysplastic or

acquired naevus

Radial

growth phase

Vertical

growth phase

Metastatic

Melanoma

N-Ras Chromosome 9

P16/other TSGs

Chromosomes 6

and 11

Integrins? Chromosome 1(KiSS 1)

and 10 (PTEN/MMAC1)

B-Raf

Chromosome 7q34


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Summary

Incidence

What is melanoma?

Pathology

Pathology/Aetiology of Skin cancer.

Causes

Who gets it

Location of melanomas (what part of body) Role of UV radiation


Melanoma Associated genes

Tumour suppressor genes Oncogenes

Antigenicity of Melanomas.

A genetic model of melanoma.

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Genetics of Melanoma

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