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Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma.

ABSTRACT: INTRODUCTION:High Grade Prostatic Intraepithelial Neoplasia (HGPIN) is the putative precursor lesion to prostatic adenocarcinoma (PCa), but the precise relationship between HGPIN and PCa remains unclear. METHODS:We performed a molecular case study in which we studied mutation profiles of six tumor-associated HGPIN lesions in a single case of TMPRSS2:ERG fusion positive Gleason score 7 PCa that we had previously mapped for somatic mutations in adjacent Gleason patterns 3 and 4 foci, using microdissection and targeted deep-sequencing. RESULTS:A total of 32 tumor-specific mutated sites were successfully amplified and sequenced, including 25 truncal mutations and 7 mutations that were specific to either the Gleason pattern 3 or pattern 4 foci. All six HGPIN foci shared the same tumor-specific TMPRSS2:ERG fusion breakpoint, establishing that they were all clonally related to the adjacent invasive tumor. Among the 32 gene targets mutated in the invasive tumor, only mutation of the OR2AP1 gene, a truncal mutation, was found in a single focus of HGPIN. The remaining gene targets that were successfully sequenced were wild-type in all other HGPIN foci. DISCUSSION:This study demonstrates the feasibility of targeted mutation profiling of HGPIN lesions, which will be important to understand PCa tumorigenesis. The results in this case, showing a remarkable absence of truncal mutations in HGPIN lesions bearing the tumor-specific ERG fusion, indicate HGPIN lesions may be relatively stable genetically and argue against a stepwise clonal evolution model of HGPIN to PCa. Prostate 76:1227-1236, 2016. © 2016 Wiley Periodicals, Inc.

SUBMITTER: Gerrin SJ

PROVIDER: S-EPMC5507580 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma.

Gerrin Sean J SJ Sowalsky Adam G AG Balk Steven P SP Ye Huihui H

The Prostate 20160608 13

<h4>Introduction</h4>High Grade Prostatic Intraepithelial Neoplasia (HGPIN) is the putative precursor lesion to prostatic adenocarcinoma (PCa), but the precise relationship between HGPIN and PCa remains unclear.<h4>Methods</h4>We performed a molecular case study in which we studied mutation profiles of six tumor-associated HGPIN lesions in a single case of TMPRSS2:ERG fusion positive Gleason score 7 PCa that we had previously mapped for somatic mutations in adjacent Gleason patterns 3 and 4 foci ...[more]

PMID: 27272561

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Project description:Prostate cancer often manifests as morphologically distinct tumour foci and is frequently found adjacent to presumed precursor lesions such as high-grade prostatic intraepithelial neoplasia (HGPIN). While there is some evidence to suggest that these lesions can be related and exist on a pathological and morphological continuum, the precise clonal and temporal relationships between precursor lesions and invasive cancers within individual tumours remain undefined. Here, we used molecular genetic, cytogenetic, and histological analyses to delineate clonal, temporal, and spatial relationships between HGPIN and cancer lesions with distinct morphological and molecular features. First, while confirming the previous finding that a substantial fraction of HGPIN lesions associated with ERG-positive cancers share rearrangements and overexpression of ERG, we found that a significant subset of such HGPIN glands exhibit only partial positivity for ERG. This suggests that such ERG-positive HGPIN cells either rapidly invade to form adenocarcinoma or represent cancer cells that have partially invaded the ductal and acinar space in a retrograde manner. To clarify these possibilities, we used ERG expression status and TMPRSS2-ERG genomic breakpoints as markers of clonality, and PTEN deletion status to track temporal evolution of clonally related lesions. We confirmed that morphologically distinct HGPIN and nearby invasive cancer lesions are clonally related. Further, we found that a significant fraction of ERG-positive, PTEN-negative HGPIN and intraductal carcinoma (IDC-P) lesions are most likely clonally derived from adjacent PTEN-negative adenocarcinomas, indicating that such PTEN-negative HGPIN and IDC-P lesions arise from, rather than give rise to, the nearby invasive adenocarcinoma. These data suggest that invasive adenocarcinoma can morphologically mimic HGPIN through retrograde colonization of benign glands with cancer cells. Similar clonal relationships were also seen for intraductal carcinoma adjacent to invasive adenocarcinoma. These findings represent a potentially undervalued indicator of pre-existing invasive prostate cancer and have significant implications for prostate cancer diagnosis and risk stratification.

Project description:BackgroundVulval intraepithelial neoplasia (VIN) is a pre-malignant condition of the vulval skin; its incidence is increasing in women under 50 years. VIN is graded histologically as low grade or high grade. High grade VIN is associated with infection with human papilloma virus (HPV) infection and may progress to invasive disease. There is no consensus on the optimal management of high grade VIN. The high morbidity and high relapse rate associated with surgical interventions call for a formal appraisal of the evidence available for less invasive but effective interventions for high grade VIN.ObjectivesTo evaluate the effectiveness and safety of medical interventions for high grade VIN.Search strategyWe searched the Cochrane Gynaecological Cancer Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3), MEDLINE and EMBASE (up to September 2010). We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field.Selection criteriaRandomised controlled trials (RCTs) that assessed medical interventions, in adult women diagnosed with high grade VIN.Data collection and analysisTwo review authors independently abstracted data and assessed risk of bias. Where possible the data were synthesised in a meta-analysis.Main resultsFour trials met our inclusion criteria: three assessed the effectiveness of topical imiquimod versus placebo in women with high grade VIN; one examined low versus high dose indole-3-carbinol in similar women. Meta-analysis of three trials found that the proportion of women who responded to treatment at 5 to 6 months was much higher in the group who received topical imiquimod than in the group who received placebo (relative risk (RR) = 11.95, 95% confidence interval (CI) 3.21 to 44.51). A single trial showed similar results at 12 months in (RR = 9.10, 95% CI 2.38 to 34.77). Only one trial reported adverse events, which were more common in the imiquimod group. One trial found no significant differences in quality of life (QoL) or body image between the imiquimod and placebo groups.Authors' conclusionsImiquimod appears to be effective, but its safety needs further examination. Its use is associated with side effects which are tolerable, but more extensive data on adverse effects are required. Long term follow-up should be mandatory in view of the known progression of high grade VIN to invasive disease. Alternative medical interventions, such as cidofovir, should be explored.

Dataset Information

Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma.

Publications

Mutation Profiling Indicates High Grade Prostatic Intraepithelial Neoplasia as Distant Precursors of Adjacent Invasive Prostatic Adenocarcinoma.

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