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Integrative analysis of transcriptomics and clinical data uncovers the tumor-suppressive activity of MITF in prostate cancer.

ABSTRACT: The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor-suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.

SUBMITTER: Valcarcel-Jimenez L

PROVIDER: S-EPMC6181952 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Integrative analysis of transcriptomics and clinical data uncovers the tumor-suppressive activity of MITF in prostate cancer.

Valcarcel-Jimenez Lorea L Macchia Alice A Martín-Martín Natalia N Cortazar Ana Rosa AR Schaub-Clerigué Ariane A Pujana-Vaquerizo Mikel M Fernández-Ruiz Sonia S Lacasa-Viscasillas Isabel I Santos-Martin Aida A Loizaga-Iriarte Ana A Unda-Urzaiz Miguel M Hermanova Ivana I Astobiza Ianire I Graupera Mariona M Starkova Julia J Sutherland James J Barrio Rosa R Aransay Ana M AM Carracedo Arkaitz A Torrano Verónica V

Cell death & disease 20181011 10

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription ...[more]

PMID: 30310055

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Project description:BackgroundImmunotherapy has demonstrated limited activity in prostate cancer to date. This likely reflects an immune suppressive tumor microenvironment (TME), with previous studies suggesting low PD-L1 expression and a sparse immune cell infiltrate. We aimed to further characterise the immune TME in primary prostate cancer and correlate immune subset densities with clinical outcomes.MethodsTwo distinct cohorts of patients treated with radical prostatectomy were identified, based on the development of biochemical recurrence (BCR), one subgroup with high International Society of Urological Pathologists (ISUP) grade group, recurrent disease and a second with low grade, non-recurrent disease. A prostate immunohistochemical (IHC) antibody cocktail was used to differentiate tumor and peritumoral benign tissue. Specific CD8+, CD4+, FoxP3+, CD20+ and CD68+ cell subsets were identified using IHC staining of consecutive slides. PD-L1 and CD8/PD-L1 dual staining were also performed. Cell subset densities were quantified within tumor and peritumoral regions. We used descriptive statistics to report cell subset densities and T-tests to compare groups by age, grade and the development of BCR. Univariable and multivariable logistic regression were used to analyse risk factors for BCR and the development of metastatic disease.ResultsA total of 175 patients were included, with a median age of 63 years and median pre-operative PSA of 8.2ng/ml. BCR occurred in 115 patients (66%) and 56 (32%) developed metastatic disease. CD68+ cells were the most abundant (median 648.8/mm2 intratumoral, 247.6/mm2 peritumoral), while PD-L1+ and PD-L1/CD8+ cell density was low overall (PD-L1+ median 162.4/mm2 intratumoral, 141.7/mm2 peritumoral; PD-L1/CD8+ (median 5.52/mm2 intratumoral, 3.41/mm2 peritumoral). Overall, grade group and T-stage were independently associated with BCR and metastatic disease. Higher density of peritumoral PD-L1+ cells was an independent risk factor for BCR (OR 5.33, 95%CI 1.31-21.61, p = 0.019).Although higher densities of CD8+ and CD4+ cells were observed in higher grade group 3-5 tumors, these were not associated with the development of BCR or metastasis.ConclusionsIn our cohort of prostate cancer patients who underwent radical prostatectomy, higher grade group and T-stage were independent predictors of BCR and metastasis. Despite higher grade group being associated with higher CD8+ cell density, PD-L1+ and PD-L1/CD8+ cell densities were low overall, suggesting lower T cell receptor recognition of tumor antigens. Further understanding of this phenomenon would influence development of future immunotherapeutic strategies in prostate cancer.

Dataset Information

Integrative analysis of transcriptomics and clinical data uncovers the tumor-suppressive activity of MITF in prostate cancer.

Publications

Integrative analysis of transcriptomics and clinical data uncovers the tumor-suppressive activity of MITF in prostate cancer.

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