Melanoma

Question 1

Genes involved in melanoma pathogenesis

Answer 1

• Mitogen-activated protein kinase: MAPK and phosphoinositide 3-kinase (PI3K) signaling pathways: BRAF, NRAS, KIT
• Secondary genetic alterations: amplification of CCND1 (encodes cyclin D1), deletion or mutation of CDKN2A (encodes p16 and p14) and/or mutation of TP53 (encodes P53)
• early on in development the genetic instability predominates, but with time melanomas regain telomerase expression
• When they arise in intermittently sun-exposed site they are more likely to have BRAF mutation, carry a lower mutation burden
• Chronic sun exposed sites: less likely to have BRAF mutation

Question 2

Where can you get melanoma

Answer 2

cutaneous, mucosal, uveal tract of the eye, leptomeninges

Question 3

MAPK signaling in melanoma

Answer 3

• Regulates cellular proliferation, growth and migration
• This pathway results in interactions between growth factors (mitogens) and receptor tyrosine kinases - such as KIT receptor on the cell surface eventually leading to changes in activity of transcription factors and gene expression within the nucleus
• Lots of phosphorylation etc goes on in this pathway
• Important tumour suppressor is p16: encoded by CDKN2A –> this can be inherited and result in familial melanoma
• Key role of MAPK: lots of mutations in genes that encode it such as BRAF and NRAS
• Acral and mucosal melanomas and chronically sun exposed - 30-40% KIT mutation

Question 4

PI3K signaling in melanoma

Answer 4

• These regulate cell growth, proliferation, differentiation, motility and survival
• Activated by RTKs and phosphorylate PIP2 to PIP3, which then acts as a second messenger and AKT is activated via phosphorylation
• PTEN can inhibit AKT activation
• PI3K signalling is activated in a high % of melanomas via:
  
  • inactivation of PTEN
  • activating mutations of NRAS
  • overexpression of AKT

Question 5

WNT signaling in melanoma

Answer 5

• can promote tumour growth by activating proliferation and cell migration
• can also inhibit tumour growth by activating proliferation and cell migration
• tightly regulated but occasionally implicated in melanoma

Question 6

MC1R-MITF signaling in melanoma

Answer 6

• MC1R activated by melanocortins, and is a G-protein coupled receptor –> regulates skin and hair colour
• MITF - microphthalmia associated transcription factor - regulates expression of melanocyte lineage specific genes that encode enzymes of the melanin biosynthetic pathway
• MC1R have been associated with red hair/fair skin phenotype, and an additional risk factor for melanoma, but can also be an antiproliferative transcription factor

Question 7

Host immune response to melanoma

Answer 7

• Melanoma antigens have been recognised on surface as MHC/peptide complexes - p16/CDKN2A, tumour specific antigens, and then the type-specific differentiation antigens - MART-1/Melan-A
• When CD8 recognise these antigens, they are able to kill tumour cells
• Important cells to know about:
  
  • CTLA-4 - cytotoxic T lymphocyte assoicated antigen-3: inhibitory homolog of CD28
  • Programmed cell death protein 1 - PD-1: immunoinhibitory receptor in the CD28 family –> when interacts with ligands (PD-L1 and 2) it promotes apoptosis of tumour antigen specific T cells and reduces apoptosis in regulatory T cells

Question 8

Melanoma epidemiology

Answer 8

• Caucasian
• Annual increase - estimated to be between 3 and 7% –> doubling of rates every 10-20 years
• Highest incidence rates in Australia and New Zealand - 39/100 000 women, 60/100 000 men, and highest in QLD
• Mortality rates peaked in the 90s
• Local prognostic factor: Breslow - most important

Question 9

Genetic defects that put those at risk of melanoma

Answer 9

• CDKN2A - familial melanoma, 2% of melanomas attributed to this
  
  • Locus ends in p16 and p14 –> exert regulatory effects on cell cycle progression through retinoblastoma protein and p53 respectively
  • Germline mutations observed in ~20% of familial melanoma
  • In some families, also increased risk of developing pancreatic cancer
  • currently recommendation is to only test as part of a research protocol, but others recommend if have had: 3 or more primary invasive melanomas or families with at least one invasive melanoma, and 2 or more other diagnoses or invasive melanoma or pancreatic cancer in a first or second degree relative –> test
• MC1R: strong association between MC1R and risk of developing BRAF-mutant melanomas has been observed
  
  • Risk of developing melanoma 1.5-3 fold increased risk for those with MC1R variation
  • If have 2 MC1R germline variants - risk of developing BRAF-mutant melanoma as high as 17 fold
• Others: tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1) and the SLC45A2 gene