Biological determinants of health disparities in prostate cancer

Martin, Damali N.; Starks, Adrienne M.; Ambs, Stefan

doi:10.1097/cco.0b013e32835eb5d1

Cited by 66 publications

(51 citation statements)

References 41 publications

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“…Two cancers of the same grade and stage do not necessarily exhibit similar progression characteristics and CaP does not behave equally across age groups or ethnicities (1)(2)(3)(4)(5)18). Molecular alterations are likely involved in the ethnic differences of CaP and we sought to describe the prevalence of ERG in higher-grade disease in AA and CA men with a focus on index tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Almost complete concordance between the detection of ERG gene fusions by fluorescence in situ hybridization and ERG protein detection by immunohistochemistry (IHC), has significantly accelerated the evaluation of the ERG protein as the surrogate of this common CaP genome alteration in pathological specimens (14)(15)(16)(17). Studies from our and other groups indicate that the overall frequency of ERG alterations in CaP varies significantly among different ethnicities: It is highest in CA, intermediate in AA and lowest in Asian CaP patients (4,5). Our recent evaluations of representative whole-mount prostate sections from a matched cohort of 91 CA and 91 AA men demonstrated a significant difference (P<0.0001) in the prevalence of the ERG oncoprotein in index tumors of CA (63%) and AA (29%) men (13).…”

Section: Introductionmentioning

confidence: 89%

“…While socioeconomic factors contribute to CaP outcomes among men of different ethnicities (2), it has also been recognized that AA men have more advanced CaP at diagnosis (3). Although there remains controversy over the role of biological differences between prostate tumors in AA and Caucasian American (CA) men, emerging data suggest the presence of differences in somatic and germline alterations (4,5).…”

Section: Introductionmentioning

confidence: 98%

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Predominance of ERG-negative high-grade prostate cancers in African American men

Farrell

Young

Chen

et al. 2014

Molecular and Clinical Oncology

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Erythroblast transformation-specific-related gene (ERG) fusions, the most common and validated prostate cancer (CaP) genome alteration, result in alterations in the expression of the ERG oncoprotein. Significantly lower frequencies of ERG have been reported in tumors of African American (AA) in comparison to Caucasian American (CA) men. Building on our preliminary observations, this study has focused on the increased association of the ERG-negative status with higher-grade prostate tumors in AA men. Representative whole-mount prostate sections from a matched cohort of 63 AA and 63 CA men with Gleason scores of 4+3 and those with Gleason scores of 8-10 were analyzed for ERG oncoprotein by immunohistochemistry. The striking finding of this study was that ERG expression was 3 times more likely to be present in the higher-grade index tumors of CA men compared to AA men (31 of 63 vs. 10 of 63 patients, respectively; P<0.0001). Although the mechanisms underlying these differences have not been elucidated, the present study along with our previous observations underscores that ERG typing may enhance the understanding of ethnic differences and future targeted therapy of CaP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 98%

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Predominance of ERG-negative high-grade prostate cancers in African American men

Farrell

Young

Chen

et al. 2014

Molecular and Clinical Oncology

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“…Many of these constitutively expressed ISGs have been characterized as antiviral genes (11). Recently, enhanced levels of constitutively expressed ISGs have been reported in advanced cancers and were often associated with a poor prognosis related to aggressive tumor growth, metastatic spread, resistance to IR/chemotherapy, or combinations of these factors (11)(12)(13)(14)(15)(16)(17)(18). The studies presented in this report are based on the hypothesis that a specific set of constitutively expressed ISGs, whose enhanced expression is by cytotoxic stress, confers a selective advantage to individual tumor clones (5,9,10,13,19).…”

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confidence: 99%

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

Widau¹,

Parekh²,

Ranck³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNβ. Specifically (i) suppression of LGP2 leads to enhanced IFNβ, (ii) cytotoxic effects following IR correlated with expression of IFNβ inasmuch as inhibition of IFNβ by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNβ and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNβ.innate immunity | cytoplasmic sensor | interferon beta | DHX58

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“…Some of the tools used to characterize gene alterations and identify potential driver genes include genome-wide association studies, karyotyping of chromosomal copy number, as well as exome and whole-genome sequencing. In addition to the search for underlying genetic events that initiate cancer or distinguish aggressive from indolent tumors, the search for genetic alterations that may explain the ethnic disparities in CaP is currently actively pursued (3,5,6).…”

Section: Introductionmentioning

confidence: 99%

ERG oncoprotein expression in prostate carcinoma patients of different ethnicities

Kelly

Kong

Dobi

et al. 2014

Molecular and Clinical Oncology

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Abstract. Overexpression of the erythroblast transformation-specific-related gene (ERG) oncoprotein due to transmembrane protease, serine 2 (TMPRSS2)-ERG fusion, the most prevalent genomic alteration in prostate cancer (CaP), is more frequently observed among Caucasian patients compared to patients of African or Asian descent. To the best of our knowledge, this is the first study to investigate the prevalence of ERG alterations in a multiethnic cohort of CaP patients. A total of 191 formalin-fixed paraffin-embedded sections of transrectal ultrasound-guided prostate biopsy specimens, collected from 120 patients treated at the Sime Darby Medical Centre, Subang Jaya, Malaysia, were analyzed for ERG protein expression by immunohistochemistry using the anti-ERG monoclonal antibody 9FY as a surrogate for the detection of ERG fusion events. The overall frequency of ERG protein expression in the population evaluated in this study was 39.2%. Although seemingly similar to rates reported in other Asian communities, the expression of ERG was distinct amongst different ethnic groups (P=0.004). Malaysian Indian (MI) patients exhibited exceedingly high expression of ERG in their tumors, almost doubling that of Malaysian Chinese (MC) patients, whereas ERG expression was very low amongst Malay patients (12.5%). When collectively analyzing data, we observed a significant correlation between younger patients and higher ERG expression (P=0.04). The prevalence of ERG expression was significantly different amongst CaP patients of different ethnicities. The higher number of ERG-expressing tumors among MI patients suggested that the TMPRSS2-ERG fusion may be particularly important in the pathogenesis of CaP amongst this group of patients. Furthermore, the more frequent expression of ERG among the younger patients analyzed suggested an involvement of ERG in the early onset of CaP. The results of this study underline the value of using ERG status to better understand the differences in the etiology of CaP initiation and progression between ethnic groups.

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Biological determinants of health disparities in prostate cancer

Cited by 66 publications

References 41 publications

Predominance of ERG-negative high-grade prostate cancers in African American men

Predominance of ERG-negative high-grade prostate cancers in African American men

RIG-I–like receptor LGP2 protects tumor cells from ionizing radiation

ERG oncoprotein expression in prostate carcinoma patients of different ethnicities

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