1. Ocular melanoma and CNAS
proteins
Lorenzo Alonso. MD

2. Percentages of genetic mutations in
melanoma
• BRAF (40-70%)
• RAS: 20%
• PTEN: 20-40%
• C-Kit: acral(36%), mucoses(39%) and
chronic sun-damaged skin(28%).
• GNAQ y GNA11: more than 50% in ocular
melanoma.

4. Iris 3%
Ciliary body
7%
Choroid 90%
GNAS proteins
(GNAQ and GNA11).
Blue nevi associated
43% mutation
Sites of ocular melanoma distribution

5. The Collaborative Ocular Melanoma Study
• 5 year percentage acumulative
metastases: 25%
• 10 year : 34%
• Median overall survival 5 months
• 1-year overall survival: 10-15%
• Metastases distribution: liver, lung(30%),
bone(23%), skin (17%).

6. Blue nevi: GNAS mutations more
than 80%

7. Ota nevi
GNAS mutation: 6%

8. Proteínas G
Protein
Kinases

9. G, GNAS proteins
Locus GNA: q, 11 (GNAS).
Gen that control alpha subunit
Activation
alpha subunit
incorporate
phosphato
(GDP a GTP) and
Beta y Gamma
subunit independent
Mutation:
Codon 209
alfaq and alfa11
(GNAQ, GNA11)
disfunction
Metabolic process,
growth, intracelular
signal, proliferatión
Normal
Well
Wrong

11. .
Krechowec S , Plagge A Physiology 2008;23:221-229
©2008 by American Physiological Society
Proteins GNAS

12. Diseases associated with alterated G
proteins
Mutations
pseudohypoparathyroidism type 1a,
pseudohypoparathyroidism type 1b,
Albright hereditary osteodystrophy,
pseudopseudohypoparathyroidism,
McCune-Albright syndrome,
progressive osseus heteroplasia,
polyostotic fibrous dysplasia of bone, and
some pituitary tumors.[1]
Deficiencies:
Albright hereditary osteodystrophy
pseudohypoparathyroidism type Ia
pseudopseudohypoparathyroidism
McCune-Albright syndrome

13. GNAS proteins location at the cellular level

14. Disseminated ocular melanoma: rationale
for a therapeutic
• GNAQ and GNA11 stimulate the MAPK pathway.GNAS
proteins are mutated in 80% of ocular melanomas.
• MEK is a key step in the MAPPK pathway.
• MEK inhibitor are the logical drugs to be used and they
have been already tested clinically.
• Selumetinib, a MEK ½ inhibitor, has been compared with
temozolamide with a significant benefit for Selumetinib in
terms of interval free of progression.
• Ipilimumab has shown also activity in metastatic ocular
melanoma