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Intracrinology-revisited and prostate cancer.

ABSTRACT: The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such as prostate and breast cancer in which the disease can be either castrate resistant or occur post-menopausally, respectively. In these instances, the major precursor steroid of androgens and estrogens is dehydroepiandrosterone (DHEA) and DHEA-SO₄. This article reviews the major pathways by which adrenal steroids are converted to the potent male sex hormones, testosterone (T) and 5?-dihydrotestosterone (5?-DHT) and the discrete enzyme isoforms involved in castration resistant prostate cancer. Previous studies have mainly utilized radiotracers to investigate these pathways but have not used prevailing concentrations of precursors found in castrate male human serum. In addition, the full power of stable-isotope dilution liquid chromatography tandem mass spectrometry has not been applied routinely. Furthermore, it is clear that adaptive responses occur in the transporters and enzyme isoforms involved in response to androgen deprivation therapy that need to be considered.

SUBMITTER: Penning TM

PROVIDER: S-EPMC6954292 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Intracrinology-revisited and prostate cancer.

Penning Trevor M TM Detlefsen Andrea J AJ

The Journal of steroid biochemistry and molecular biology 20191012

The formation of steroid hormones in peripheral target tissues is referred to as their intracrine formation. This process occurs in hormone dependent malignancies such as prostate and breast cancer in which the disease can be either castrate resistant or occur post-menopausally, respectively. In these instances, the major precursor steroid of androgens and estrogens is dehydroepiandrosterone (DHEA) and DHEA-SO<sub>4</sub>. This article reviews the major pathways by which adrenal steroids are con ...[more]

PMID: 31614208

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Project description:BackgroundEmerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.ObjectiveTo characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.Design, setting, and participantsThis was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.Outcome measurements and statistical analysisWe measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).Results and limitationsThe frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p < 0.001) were associated with a higher number of metastases. Mutations in TP53 were also independently associated with shorter rPFS (hazard ratio [HR] 1.59; p = 0.03) and the development of CRPC (HR 1.71; p = 0.01) on multivariable analysis. This study was limited by its retrospective nature, sample size, and the use of commercially available sequencing platforms, resulting in a limited predefined set of genes examined.ConclusionsSomatic mutational profiles reveal a spectrum of metastatic biology that helps in redefining oligometastasis beyond a simple binary state of lesion enumeration.Patient summaryOligometastatic prostate cancer is typically defined as less than three to five metastatic lesions and evidence suggests that using radiation or surgery to treat these sites improves clinical outcomes. As of now, treatment decisions for oligometastasis are solely defined according to the number of lesions. However, this study suggests that tumor mutational profiles can provide a biological definition of oligometastasis and complement currently used numerical definitions.

Project description:BACKGROUND:At the molecular level breast cancer comprises a heterogeneous set of subtypes associated with clear differences in gene expression and clinical outcomes. Single sample predictors (SSPs) are built via a two-stage approach consisting of clustering and subtype predictor construction based on the cluster labels of individual cases. SSPs have been criticized because their subtype assignments for the same samples were only moderately concordant (Cohen's ?<0.6). METHODS:We propose a semi-supervised approach where for five datasets, consensus sets were constructed consisting of those samples that were concordantly subtyped by a number of different predictors. Next, nine subtype predictors - three SSPs, three subtype classification models (SCMs) and three novel rule-based predictors based on the St. Gallen surrogate intrinsic subtype definitions (STGs) - were constructed on the five consensus sets and their associated consensus subtype labels. The predictors were validated on a compendium of over 4,000 uniformly preprocessed Affymetrix microarrays. Concordance between subtype predictors was assessed using Cohen's kappa statistic. RESULTS:In this standardized setup, subtype predictors of the same type (either SCM, SSP, or STG) but with a different gene list and/or consensus training set were associated with almost perfect levels of agreement (median ?>0.8). Interestingly, for a given predictor type a change in consensus set led to higher concordance than a change to another gene list. The more challenging scenario where the predictor type, gene list and training set were all different resulted in predictors with only substantial levels of concordance (median ?=0.74) on independent validation data. CONCLUSIONS:Our results demonstrate that for a given subtype predictor type stringent standardization of the preprocessing stage, combined with carefully devised consensus training sets, leads to predictors that show almost perfect levels of concordance. However, predictors of a different type are only substantially concordant, despite reaching almost perfect levels of concordance on training data.

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Intracrinology-revisited and prostate cancer.

Publications

Intracrinology-revisited and prostate cancer.

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