Zodiac (case 10): PTEN and MYC — Is there a middle man?

This is the 10th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here

There has been a lot of recent work discussing the association of pTEN deletion and MYC amplification with progression of prostate cancer. Led by my colleagues at NorthShore University HealthSystem, Dr. Wennuan Liu, some pioneering work has shown the association between pTEN deletion and c-MYC amplification, and its effect on the progression of prostate cancer. In addition, other work has shown that over-expression in c-MYC is also associated with bad prognosis of prostate cancer.

I started a search of “PTEN” in Zodiac and looked for CN-CN (copy number-copy number) associations between other human gens and PTEN. Almost all the top genes reside on the same chromosome 10 of pTEN, implying  the reason that these genes are co-deleted or co-amplified with pTEN is due to segmental changes on the chromosome spanning a large region. Zodiac successfully identified these genes as the top ranked ones in the genome. Among the list of genes that have high associations with pTEN, one gene, MXI1, stood out.

MXI1 Expression of the c-myc gene, which produces an oncogenic transcription factor, is tightly regulated in normal cells but is frequently deregulated in human cancers. The protein encoded by this gene is a transcriptional repressor thought to negatively regulate MYC function, and is therefore a potential tumor suppressor. This protein inhibits the transcriptional activity of MYC by competing for MAX, another basic helix-loop-helix protein that binds to MYC and is required for its function. Defects in this gene are frequently found in patients with prostate tumors.

MXI1 ranks as the 17th gene that has the highest copy number co-change pattern in the genome (about 20,000 genes) according to Zodiac. It spans about 104K base pairs on Chromosome 10q24-q25 (note pTEN resides at Chromosome 10q23.3). So when pTEN is deleted in tumors, very likely MXI1 will also be deleted. Since MXI1 copy number positively affects MXI1 gene expression (see Zodiac Figure here), MXI1 deletion will down regulate MXI1 gene expression, which in turn will reduce the repressing effects on MYC expression (i.e., upregulate MYC expression). In other words, a hypothesis can be generated in prostate where

pTEN (deletion) —-> MXI1 (deletion) —-> MXI1 (expression down) —-> MYC (expression up)

pTEN deletion is associated with MXI1 deletion due to their proximity on the genome. MXI1 deletion leads to down regulation of MXI1 expression which then leads to up regulation of MYC expression.

Our team is currently working on a full analysis of pTEN, MXI1, and MYC in prostate cancer data of TCGA. This new hypothesis could potentially explain the association between pTEN deletion and MYC over expression. However, it does not explain the association between pTEN deletion and MYC amplification. Reasons for joint copy number changes are still mostly unknown to humans. Zodiac has all the copy number co-changes for pairs of genes and could be queried to reveal any potential patterns.

Lastly, MXI1 might be an important gene for prostate cancer progression, especially metastasis to bone. Below are a couple of genes among the top ones that have positive GE-GE association with MXI1. They are known prognosis markers for prostate cancer.

BMP6 The bone morphogenetic proteins (BMPs) are a family of secreted signaling molecules that can induce ectopic bone growth. Many BMPs are part of the transforming growth factor-beta (TGFB) superfamily. BMPs were originally identified by an ability of demineralized bone extract to induce endochondral osteogenesis in vivo in an extraskeletal site. Based on its expression early in embryogenesis, the BMP encoded by this gene has a proposed role in early development. In addition, the fact that this BMP is closely related to BMP5 and BMP7 has lead to speculation of possible bone inductive activity.
TNFRSF11B The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification.
Unfortunately, the top gene C11ORF88 that is associated with MXI1 in terms of GE is an open read frame. This gene has much stronger association with MXI1 than any other genes, but humans know nothing about it!
I hope this blog could generate some new research direction for prostate cancer, especially its mechanism of progression and metastasis.
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