PREX2 and Melanoma

There is an article in Nature today discussing the role of PREX2 in melanoma. PREX2 controls PTEN and it was observed that mutations there inhibited PTEN.

As the review of the article states:

Berger and his colleagues also found potentially damaging PREX2 mutations in 14% of 107 tumours  that were not part of the initial study. And when they transplanted human skin cells containing PREX2 mutations into mice that had been engineered to develop skin cancer, four of the six different PREX2 mutations accelerated development of the tumours in mice. This led the researchers to suggest that PREX2 might have a similar role in human skin cancers.

There is always the risk in murine models that the pathways may be different, controlled by factors such as other ligands and having other variable intercellular dynamics. This has been, I would argue, some of the difficulty in the Goldstein model for PCa.

PREX2 itself is probably not a good drug target, because the mutations found in the gene do not cluster in any single location that might be easily pinpointed by a drug, says cancer researcher Levi Garraway, also at the Broad Institute, who led the study. However, Garraway says, the discovery should help researchers to improve their knowledge of the biological pathways that are disrupted in melanomas. In turn, that could lead scientists to genes and proteins in other parts of those pathways that might be better drug targets.

The pathway issue keeps coming back as a dominant factor. We show BRAF and PTEN above and BRAF is now a partially controllable mutation. Broadly speaking kinase inhibitors are now somewhat well understood. PREX2 however does not fall in that category.

PREX2 also seems to work differently from BRAF and NRAS, which are considered to be 'classic' oncogenes — overactive genes that have the potential to cause cancer and which are often mutated in the same ways. By contrast, the various PREX2 mutations identified by Berger and his colleagues occurred in different places in the protein. All seemed to lead the cell to make more of the protein than usual, rather than making the protein itself overactive.

One of the issues which seems to be coming to the fore in pathways is the details of the pathway dynamics or kinetics. This is an example of a yet to be determined kinetic model.

The summary of the article states:

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on nonultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5–55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). 

Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)—a PTEN-interacting protein and negative regulator of PTEN in breast cancer2—as a significantly mutated gene with a mutation frequency of approximately 14%in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.

Now the PTEN control element is key in many cancers, such as prostate and many others.

As Fine et al state in their discussion of PREX2 and its effect on PTEN:

The P-REX2a gene is located on chromosome 8q13, a region of frequent amplification in breast, prostate, and colorectal cancers which has also been linked to aggressive cancer phenotypes and metastatic progression. We investigated P-REX2a expression by qRTPCR in a breast tumor data set thoroughly annotated for PI3K pathway alterations. P-REX2a showed a significant two-tailed association with PTEN status (p=0.027) and the median PREX2a expression was 3 fold greater in tumors that retained PTEN than in those that did not. 

Additionally, gene expression data sets from other cancer databases demonstrate increased expression of P-REX2a in various tumors including breast and prostate compared to that in normal tissues. Mutations in P-REX2a were not found in a breast tumor mutation survey, however, our analysis of publicly available databases yielded numerous somatic mutations in P-REX2a in other tumors including those of the colon, pancreas and lung, making it one of the most commonly mutated GEF’s in cancer (Fig. S6). We thus suspected that P-REX2a might be a PTEN-regulating factor that is co-opted in tumors to stimulate PI3K signaling.

Thus the PREX2 nexus has been established and was known as early as 2009. The nexus with PTEN control is a major issue. The question may be if PREX2 mutations are stronger influences than say PTEN mutations.

There is also the issue regarding the melanoma cancer stem cell issue as well as we have been discussing elsewhere. Unlike a blood line stem cells or even prostate stem cells, the melanoma stem cell must most likely be a melanocyte, and one of the issues is how many melanocytes are stem in character, or is the stem cell not yet a melanocyte and if so what is it.A recent prior posting on prostate stem cells raises that issue as well.

I found one of the remarks especially compelling when the state:

In particular, we discovered that PREX2 mutations are both recurrent and functionally consequential
in melanoma biology. Although its precise mechanism(s) of action remains to be elucidated in melanoma, PREX2 appears to acquire oncogenic activity through mutations that perturb or inactivate one or more of its cellular functions. This pattern of mutations may exemplify a category of cancer genes that is distinct from ‘classic’ oncogenes (often characterized by highly recurrent gain-of-function mutations) and tumour suppressors (inactivated by simple loss-of-function alterations). Instead, (over)expression of certain cancer genes with distributed mutation patterns may promote tumorigenicity either through dominant negative effects or more subtle dysregulation of normal  protein functions

It will be interest to follow the implications of the last statements as indicated.

One other factor of interest was the calculation of mutation rates. They state:

This corresponded to an average mutation rate of 30 per Mb. However, the mutation rate varied by nearly two orders of magnitude across the 25 tumours . The acral melanomas showed  mutation rates comparable to other solid tumour types (3 and 14 mutations per Mb), whereas melanomas from the trunk harboured substantially more mutations, in agreement with previous  studies. In particular, sample ME009 exhibited a striking rate of 111 somatic mutations per Mb, consistent with a history of chronic sun exposure.

This is an interesting observation since it appears to confirm, albeit on this small sample, the impact of UV radiation, and I could argue radiation in general. Whether this gives additional merit to my prior work on X Ray scanners is still an open issue.

This is an interesting result and most likely will be followed by more detailed studies. There always are the issues regarding the clear causative nature and the details of the pathways.

References

1. Fine, B., et al, Activation of PI3K Pathway in Cancer through Inhibition of PTEN by Exchange Factor P-REX2a, Science, 2009, pp 1261-1265. 
2. Berger, M., et al,  Melanoma Genome Sequencing Reveals Frequent PREX2 Mutations, Nature, May 2012.