GENES IN UVEAL MELANOMA.

This one rings a bell with me because a good friend and respected professor, wife to an intensive care Doctor, died under our care before the discovery of Ipilimumab.  And how well Ipilimumab fares in this particular case of melanoma is still to be closely reviewed (DTIC was not trusted enough).  At the time, the patient who had liver metastasis ended up getting an Abraxane based combination.

Researchers from  Washington University have now published that the SF3B1 gene could predict a better outcome in patients with Uveal Melanoma since it is linked to far lower metastasis rate and young individuals.
3 additional genes were cited also: BAP1, GNAQ, GNA11,

1. SF3B1
=====   Splicing factor 3B subunit 1

Being a splicing factor puts this gene right there in the differentiating gene as we discussed earlier.  Meaning the gene pushes differentiation further up which in cellular biology has been proven to normal life and submission to normal programmed death. The ATRA story used in APL is proof in the pudding.
SB3F1 is a good prognosis gene globally.  In MDS, it is known to be associated with early MDS, particularly the MDS with ring Sideroblast.  This fact is noticeable and warrants a speculative comment.  That is when you talk of Sideroblast, you incriminate disturbances in Iron Metabolism in or around the Mitochondria.  What does create similar iron disturbance? Well, Inflammatory processes do.  This is confirmed by the link of Splicing Factors to production of Inflammatory proteins and therefore participation in connective tissue disease.  Remember, early MDS can respond to Immune based therapeutic interventions.   So, SB3F1 seems to be an Early event.  To affect differentiation, it must lead to proteins that interact with later Splicing factors and impose a trend away from Apoptosis and migration.  The literature suggests that it is an "evolutionary", that it has an impact on cellular evolution.  The SB3F1 has been seen also in Breast cancer with similar prognosis indications.
The notion that one of the proteins resulting from various splicing factors could be Autoantigenic brings another dimension to bear!  That an abnormality at SB3F1 could in effect produce Autoantigen making the cell susceptible to Autoimmune death, another way that would limit its chances of spreading.  Remember, Melanoma is often susceptible to Interferon and now T cell CTLA-4 related agents (such as Ipilimumab). 

SB3F1, an early Mutation, influencing other late splicers and therefore "evolutionary", and rising autoimmunity!

(In MDS, SB3F1 is also associated with high Hb, Platelet counts, all the good stuff of better prognosis). It has been noted in CLL, MDS and Breast cancer, and now Uveal Melanoma.

Presence of TET2, an angel of proliferation, will stop the good prognosis acting of SB3F1.  And so will the presence of Mutations in P53, EZH, ETV6, RUNX-1, and ASXL! (check it out!) it's all in the literature... 

2. BAP-1 
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Members of the polycomb-group proteins (PcG) of highly conserved transcriptional repressors required for long-term silencing of genes that regulate cell fate determination, stem cell pluripotency, and other developmental processes.^{[3]"  (wikepedia}

In cancer, BAP1 can function both as a Tumor suppressor and as a Metastasis suppressor.
BAP1 mutations were identified in a small number of breast and lung cancer cell lines,^[1] but BAP1 was first shown to act as a tumor suppressor in cultured cells, where its deubiquitinase (UCH) domain and Nuclear localization sequences were required for BAP1 to suppress cell growth.^[9] In 2010, Exome sequencing identified inactivating mutations in BAP1 in 47% of Uveal melanomas, and BAP1 mutation was strongly associated with metastasis.^[10] These mutations included multiple Nonsense mutations and splice site mutations throughout the gene. missense mutations were only found within the UCH and ULD domains, further supporting the requirement for BAP1 catalytic function. This study also identified a Germline mutation in one of the uveal melanoma patients, suggesting that, besides being a Metastasis suppressor, BAP1 could predispose certain people to more aggressive uveal melanoma tumors. Shortly thereafter, BAP1 mutations were identified in aggressive Mesotheliomas with similar mutations as seen in melanomas,^[11] and have also been reported in renal cell carcinomas.^[12]
Two studies used Genome sequencing independently to identify Germline mutations in BAP1 in families with Genetic predispositions to mesothelioma^[13] and melanocytic skin tumors^[14] Further studies have identified germline BAP1 mutations associated with other cancers.^[15] These studies suggest that germline mutation of BAP1 results in a Tumor Predisposition Syndrome linking BAP1 to many more cancers. (wikipedia)

In lung cancer^, it is associated with no lymph node involvement and therefore of Good prognosis.

BRCA-1 Associated Protein-1 could be associated with BRAF, and 15% of clear cell Renal cancers.
 

SPLICEOSOME MACHINERY AND MYELOID MALIGNANCIES
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Spliceosome

From Wikipedia,

A spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA (hnRNA) segment. This process is generally referred to as splicing.
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Spliceosome contains 300 different proteins and 5 RNAs (U1-6). making a very large complex.
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In Myeliod Malignancies, Hamilton et al. reported that Spliceosomal Mutations had prognostic implications in patients undergoing Hematopoietic Cell Transplantation.

SF3B1  having the better survival in MDS patients while
Mutants in SRSF and U2AF1 had worse prognosis.  Transplant is more indicated in these!
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WE DISCUSSED HOW SPLICING IS INCLUDED IN DIFFERENTIATION BECAUSE WHERE IT OCCURS DETERMINES THE LENGTH, NATURE AND MORPHOLOGY OF THE RESULTING PROTEINS.