Structural Protein Analysis of Driver Gene Mutations in Conjunctival Melanoma.

Mak B Djulbegovic,Vladimir N Uversky,Carol L Karp,Anat Galor,J William Harbour

doi:10.3390/genes12101625

Abstract

In recent years, there has been tremendous enthusiasm with respect to detailing the genetic basis of many neoplasms, including conjunctival melanoma (CM). We aim to analyze five proteins associated with CM, namely BRAF, NRAS, c-KIT, NF1, and PTEN. We evaluated each protein for its intrinsically disordered protein regions (IDPRs) and its protein-protein interactions (PPI) with the Predictor of Natural Disordered Protein Regions (PONDR®) and the Search Tool for the Retrieval of Interacting Genes (STRING®). Our PONDR® analysis found high levels of IDPRs in all five proteins with mutations linked to CM. The highest levels of IDPRs were in BRAF (45.95%), followed by PTEN (31.76%), NF1 (22.19%), c-KIT (21.82%), and NRAS (14.81%). Our STRING analysis found that each of these five proteins had more predicted interactions then expected (p-value < 1.0 × 10−16). Our analysis demonstrates that the mutations linked to CM likely affected IDPRs and possibly altered their highly complex PPIs. Quantifying IDPRs in BRAF, NRAS, c-KIT, NF1, and PTEN and understanding these protein regions are important processes as IDPRs can be possible drug targets for novel targeted therapies for treating CM.

Highlights

Conjunctival melanoma (CM) is an aggressive neoplasm of the ocular surface
Our analysis identified and intrinsically characterized disordered protein regions (IDPRs) and protein-protein interaction (PPI) networks of BRAF, NRAS, c-KIT, NF1, and PTEN
An intrinsically disordered proteins (IDPs), nuclear protein 1 (NUPR1), has been successfully targeted in vivo to completely arrest development of the cancer in mice [44]. These advances in IDP-based drug discovery methods may provide a viable target for future campaigns targeting molecular features of CM, which include the high level of intrinsically disordered protein regions (IDPRs) in BRAF, NRAS, c-KIT, NF1, and PTEN

Summary

Introduction

Conjunctival melanoma (CM) is an aggressive neoplasm of the ocular surface. While it is rare, the incidence of this neoplasm is on the rise [1,2]. Wide excision with a “no touch technique” in combination with cryotherapy is the modern approach for managing CM [1,6,7,8,9,10,11]. Limitations of this technique include the concern for extensive insult to the ocular surface with excisional biopsy and the potential for residual neoplastic cells. De novo mutations have the highest chance of metastasizing with 35% at 5 years and 49% at 10 years These cases are associated with lower survivability as compared to the lesions that arise from PAM or nevus [18]. The burden of CM is evident as it has high rates of recurrence and mortality

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