CHTN Supports Paradigm Changes in Research

Submitted by melkonya on Wed, 09/26/2018 - 13:13
William Grizzle

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The CHTN provided human tissue samples to one of three related manuscripts that were published in the September 2017 issue of Nature Medicine (1). These 3 articles were accompanied by a News and Views article (4); all were focused on the speckle-type POZ (pox virus and zinc finger protein) or SPOP (1-4). Of note, mutations in SPOP occur in over 10% of prostate cancers and endometrial cancers (4). Such mutations are associated with two specific areas of the MATH domain (about 140 residues such as amino acids) of SPOP which facilitates the degradation of proteins; thus, mutations anywhere in the SPOP gene might expect to result in inefficient degradation of some oncoproteins. Previously, it had been assumed that mutations in a small domain of genes such as in SPOP would have similar functional effects even in similar cancers (e.g., adenocarcinomas) in different organs. Another common feature of these journal articles is a focus on another specific domain, “bromodomain and extraterminal (BET) proteins.” The BET family of proteins is degraded via SPOP associated processes. These three manuscripts indicate the effects of mutations in SPOP may have opposite effects on prostate adenocarcinomas (reduced degradation of BET proteins) than in endometrial adenocarcinomas (increased degradation of MET proteins). This could change therapeutic decisions using BET inhibitors. Importantly, these results indicate that mutations affecting different amino acids in different areas of a relatively small bromodomain (e.g., frequently an area in a protein composed of about 110 amino acids) may have very different biological results. Of concern, such differences due to mutations may occur in domains of other genes in different organs suggesting that there may need to be biological characterizations of some mutations in order to demonstrate their exact biological consequences. Thus, this group of three manuscripts introduces a new approach in characterizing some mutations and in selecting targeted therapies. The major goal of the CHTN is to facilitate such important research via its provision of human tissues to support research.

1)   Janouskova H, El Tekle G, Bellini E, et al. Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors. Nature Medicine. 2017;23(9): 1046-1054.

2)   Dai X, Gan W, Li X, et al. Prostate cancer-associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4. Nature Medicine. 2017;23(9): 1063-1071.

3)   Zhang P, Wang D, Zhao Y, et al. Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT-mTORC1 activation. Nature Medicine. 2017;23(9):1055-1062.

4)   Fennell KA, Dawson MA. SPOP tips the balance of BETs in cancer. Nature Medicine 2017;23(9):1014-1015.

Dr. William Grizzle