Molecular Pathology of High-Grade Prostatic Intraepithelial Neoplasia: Challenges and Opportunities

Trabzonlu, Levent; Kulaç, İbrahim; Zheng, Qizhi; Hicks, Jessica L.; Haffner, Michael C.; Nelson, William G.; Sfanos, Karen S.; Ertunç, Onur; Lotan, Tamara L.; Heaphy, Christopher M.; Meeker, Alan K.; Yegnasubramanian, Srinivasan; Marzo, Angelo M. De

doi:10.1101/cshperspect.a030403

Cited by 29 publications

(31 citation statements)

References 116 publications

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“…Morphologically, our series of iIDC-P strongly implicates a subset of IDC-P as a distinct in situ lesion and one that may precede the development of high-grade invasive disease. HGPIN is currently the only accepted precursor lesion to invasive PCa, with a preponderance of morphologic and molecular evidence supporting this notion [41][42][43]. However, two of our prior studies and one by Miyai et al reported IDC-P in the absence of, or regionally separate from, high-grade invasive carcinoma (i.e.…”

Section: Discussionmentioning

confidence: 78%

Intraductal carcinoma of the prostate in the absence of high‐grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Khani

Wobker

Hicks

et al. 2019

The Journal of Pathology

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Intraductal carcinoma of the prostate (IDC‐P) most often appears associated with high‐grade invasive prostate carcinoma (PCa), where it is believed to represent retrograde spread. However, IDC‐P rarely occurs as an isolated finding at radical prostatectomy or with concurrent low‐grade (Grade Group 1) invasive carcinoma. We hypothesized that isolated IDC‐P (iIDC‐P) in these unusual cases may represent a distinct in situ lesion and molecularly profiled 15 cases. iIDC‐P was characterized by copy number alteration (CNA) profiling and targeted next generation sequencing in cases with sufficient tissue (n = 7). Immunohistochemistry for PTEN and ERG was performed on the total cohort (n = 15), where areas of iIDC‐P and associated invasive disease were evaluated separately (n = 9). By copy number profiling, iIDC‐P alterations were similar to those previously described in high‐grade invasive PCa (PTEN, RB1, and CHD1 loss; MYC gain). However, in four cases, targeted sequencing revealed a striking number of activating oncogenic driver mutations in MAPK and PI3K pathway genes, which are extraordinarily rare in conventional PCa. In addition, pathogenic mutations in DNA repair genes were found in two cases of iIDC‐P (BRCA2, CHEK2, CDK12) and other known PCa‐associated mutations (FOXA1, SPOP) in two cases. Overall, ERG was expressed in 7% (1/15) of the iIDC‐P lesions and PTEN was lost in 53% (8/15). Discordance for ERG or PTEN status between IDC‐P and the low‐grade PCa was observed in five of nine cases, with intact PTEN in the invasive tumor and PTEN loss in IDC‐P in four. Despite a CNA profile similar to conventional PCa, iIDC‐P is enriched with potentially targetable oncogenic driver mutations in MAPK/PI3K genes. Based on PTEN and ERG status, iIDC‐P is not likely a precursor to the associated low‐grade invasive PCa, but represents a molecularly unique in situ tumor of unclear clinical significance. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 78%

Intraductal carcinoma of the prostate in the absence of high‐grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Khani

Wobker

Hicks

et al. 2019

The Journal of Pathology

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“…These observations suggest that the HGPIN lesion adjacent to invasive carcinoma does not necessarily represent its respective precursor lesion and additional studies based on single-cell molecular analysis and lineage tracing studies are required to define such a relationship [7]. Furthermore, recent studies have suggested that some HGPINs are in fact invasive prostate cancers masquerading as a HGPIN-like condition [19].…”

Section: Tumor Evolution Of Prostate Cancer From Precursor Lesionsmentioning

confidence: 99%

“…In spite all the limitations in the definition and identification of precursor lesions of prostate cancer, the search of prostate cancer precursors lesions is of fundamental importance because offers the unique opportunity for disease prevention and treatment [19].…”

Section: Tumor Evolution Of Prostate Cancer From Precursor Lesionsmentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

2019

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Prostate cancer is the most frequent nonskin cancer and second most common cause of cancer-related deaths in man. Prostate cancer is a clinically heterogeneous disease with many patients exhibiting an aggressive disease with progression, metastasis, and other patients showing an indolent disease with low tendency to progression. Three stages of development of human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, and adenocarcinoma androgen-independent or castration-resistant. Advances in molecular technologies have provided a very rapid progress in our understanding of the genomic events responsible for the initial development and progression of prostate cancer. These studies have shown that prostate cancer genome displays a relatively low mutation rate compared with other cancers and few chromosomal loss or gains. The ensemble of these molecular studies has led to suggest the existence of two main molecular groups of prostate cancers: one characterized by the presence of ERG rearrangements (~50% of prostate cancers harbor recurrent gene fusions involving ETS transcription factors, fusing the 5′ untranslated region of the androgen-regulated gene TMPRSS2 to nearly the coding sequence of the ETS family transcription factor ERG) and features of chemoplexy (complex gene rearrangements developing from a coordinated and simultaneous molecular event), and a second one characterized by the absence of ERG rearrangements and by the frequent mutations in the E3 ubiquitin ligase adapter SPOP and/or deletion of CDH1, a chromatin remodeling factor, and interchromosomal rearrangements and SPOP mutations are early events during prostate cancer development. During disease progression, genomic and epigenomic abnormalities accrued and converged on prostate cancer pathways, leading to a highly heterogeneous transcriptomic landscape, characterized by a hyperactive androgen receptor signaling axis.

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“…We analytically validated an automated IHC assay against human GSTP1 protein using well-known cell lines and controls and human prostate cancer tissues (8) . Cell line FFPE blocks were prepared and utilized as described (29,30) .…”

Section: Ihc Stainingmentioning

confidence: 99%

“…We developed a novel in situ hybridization assay for GSTP1 mRNA using ACD RNAscope, which we analytically validated (Probe-Hs-GSTP1 Cat No. 453221, kit version 2.5 manual assay according to manufacturer's recommendations) using cell lines with known GSTP1 expression status for positive and negative controls as described (8) .…”

Section: In Situ Hybridization For Gstp1 Mrnamentioning

confidence: 99%

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States

Vidal

Zheng

Hicks

et al. 2020

Preprint

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GSTP1 is a member of the Glutathione-S-transferase (GSTS) family silenced by CpG island DNA hypermethylation in 90-95% of prostate cancers. However, prostate cancers expressing GSTP1 have not been well characterized. We used immunohistochemistry against GSTP1 to examine 1673 primary prostatic adenocarcinomas on TMAs with redundant sampling from the index tumor from prostatectomies. GSTP1 protein was positive in at least one TMA core in 7.7% of cases and in all TMA cores in 4.4% of cases. The percentage of adenocarcinomas from Black patients who had any GSTP1 positive TMA cores was 14.9%, which was 2.5 times higher than the percentage from White patients (5.9%; P < 0.001). Further, the percentages of tumors from Black patients who had all TMA spots positive for GSTP1 (9.5%) was 3-fold higher than the percentage from White patients (3.2%; P<0.001). The increased percentage of GSTP1 positive cases in Black men was present only in ERG positive cases. By in situ hybridization, GSTP1 mRNA expression was concordant with protein staining, supporting the lack of silencing of at least some GSTP1 alleles in GSTP1-positive tumor cells. This is the first report revealing that the GSTP1-positive prostate cancer subset is substantially over-represented among prostate cancers from Black compared to White men. This observation should prompt additional studies to determine whether GSTP1 positive cases represent a distinct molecular subtype of prostate cancer and whether GSTP1 expression could provide a biological underpinning for the observed disparate outcomes for Black men.

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Molecular Pathology of High-Grade Prostatic Intraepithelial Neoplasia: Challenges and Opportunities

Cited by 29 publications

References 116 publications

Intraductal carcinoma of the prostate in the absence of high‐grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Intraductal carcinoma of the prostate in the absence of high‐grade invasive carcinoma represents a molecularly distinct type of in situ carcinoma enriched with oncogenic driver mutations

Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

GSTP1 positive prostatic adenocarcinomas are more common in Black than White men in the United States

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