Novel Biomarker Signature That May Predict Aggressive Disease in African American Men With Prostate Cancer

Yamoah, Kosj; Johnson, Michael H.; Choeurng, Voleak; Faisal, Farzana A.; Yousefi, Kasra; Haddad, Zaid; Ross, Ashley E.; Alshalafa, Mohammed; Den, Robert B.; Lal, Priti; Feldman, Michael; Dicker, Adam P.; Klein, Eric A.; Davicioni, Elai; Rebbeck, Timothy R.; Schaeffer, Edward M.

doi:10.1200/jco.2014.59.8912

Cited by 122 publications

(115 citation statements)

References 46 publications

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“…These studies will inform whether alterations in these genes may be enriched in certain ancestral groups. Recent studies have implicated prostate tumor location, differential gene expression, and somatic genomic events such as LSAMP deletions in prostate cancers in AA men (2–4,42–44). Our study suggests that there are still unexplained reasons for the aggressive nature of prostate cancer in AA men that is only partially explained by the genomic studies to date.…”

Section: Discussionmentioning

confidence: 99%

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

et al. 2017

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African-American men have the highest incidence and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (n=102) and targeted validation (n = 90) of localized primary hormone-naïve prostate cancer in African-American men identified several gene mutations not previously observed in this context, including recurrent loss-of-function mutations in ERF, an ETS transcriptional repressor, in 5% of cases. Analysis of existing prostate cancer cohorts revealed ERF deletions in 3% of primary prostate cancers and mutations or deletions in ERF in 3–5% of lethal castration-resistant prostate cancers. Knockdown of ERF confers increased anchorage-independent growth and generates a gene expression signature associated with oncogenic ETS activation and androgen signaling. Together, these results suggest that ERF is a prostate cancer tumor suppressor gene. More generally, our findings support the application of systematic cancer genomic characterization in settings of broader ancestral diversity to enhance discovery and, eventually, therapeutic applications.

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Section: Discussionmentioning

confidence: 99%

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

et al. 2017

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“…There is significant evidence that AA PCa may have higher AR signaling (7,10,12). Thus at least some of the increase in MNX1 in AA PCa may reflect higher activity of AR signaling in AA PCa.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have evaluated differential expression of specific proteins among AA and EA cohorts including epidermal growth factor receptor, the androgen receptor (AR), PGEM1, MDM2 and caveolin-1(5–8). More recently, the TMPRSS2/ERG fusion gene has been shown to occur at lower rate in AA PCa (9–12). Several studies have compared gene expression in AA and EA PCa using expression microarrays.…”

Section: Introductionmentioning

confidence: 99%

MNX1 Is Oncogenically Upregulated in African-American Prostate Cancer

Zhang

Wang

et al. 2016

Cancer Research

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Incidence and mortality rates for prostate cancer (PCa) are higher in African-American (AA) men than European American (EA) men, but the biological basis for this disparity is unclear. We carried out a detailed analysis of gene expression changes in PCa compared to their matched benign tissues in a cohort of AA men and compared them to existing data from EA men. In this manner, we identified MNX1 as a novel oncogene upregulated to a relatively greater degree in PCa from AA men. Androgen and AKT signaling play a central role in the pathogenesis of PCa and we found that both of these signaling pathways increased MNX1 expression. MNX1 in turn upregulated lipid synthesis by stimulating expression of SREBP1 and fatty acid synthetase. Our results define MNX1 as a novel targetable oncogene increased in AA PCa that is associated with aggressive disease.

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“…Many PCa-associated genes are differentially expressed between AA and Caucasian-American (CA) men [2,3], and prior genome-wide studies have identified common molecular subtypes based on gene fusions [4]. …”

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confidence: 99%

Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location

et al. 2016

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Prostate cancer (PCa) subtypes based on ETS gene expression have been described. Recent studies suggest there are racial differences in tumor location, with PCa located anteriorly more often among African-American (AA) compared to Caucasian-American (CA) men. In this retrospective analysis of a multi-institutional cohort treated by radical prostatectomy (179 CA, 121 AA), we evaluated associations among molecular subtype, race, anatomic tumor location, and androgen receptor (AR) signaling. Subtype (m-ERG+, m-ETS+, m-SPINK1+, or triple-negative) was determined using distribution-based outlier analysis. AR signaling was investigated using gene expression profiling of canonical AR targets. m-ERG+ was more common in CA than AA men (47% vs 22%, p < 0.001). AA men were more likely to be m-SPINK1+ (13% vs 7%; p = 0.069) and triple-negative (50% vs 37%; p = 0.043). Racial differences in molecular subtypes did not persist when tumors were analyzed by location, suggesting a biologically important relationship between tumor location and subtype. Accordingly, anterior tumor location was associated with higher Decipher scores and lower global AR signaling. Patient summary This study demonstrates associations among patient race, prostate cancer molecular subtypes, and tumor location. Location-specific differences in androgen regulation may further underlie these relationships.

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Novel Biomarker Signature That May Predict Aggressive Disease in African American Men With Prostate Cancer

Cited by 122 publications

References 46 publications

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function ERF Mutations

MNX1 Is Oncogenically Upregulated in African-American Prostate Cancer

Racial Variations in Prostate Cancer Molecular Subtypes and Androgen Receptor Signaling Reflect Anatomic Tumor Location

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