Ocular melanoma and CNAS proteins

Lorenzo Alonso. MD

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.

Iris 3%

Ciliary body 7%

Choroid 90%

GNAS proteins (GNAQ and GNA11).

Blue nevi associated

43% mutation

Sites of ocular melanoma distribution

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%).

Blue nevi: GNAS mutations more than 80%

Ota nevi

GNAS mutation: 6%

Proteínas G

Protein

Kinases

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

WellWrong

.

Krechowec S , Plagge A Physiology 2008;23:221-229

©2008 by American Physiological Society

Proteins GNAS

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

GNAS proteins location at the cellular level

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