Dataset Information

Transcriptomic heterogeneity in multifocal prostate cancer.

ABSTRACT:

Background

Commercial gene expression assays are guiding clinical decision making in patients with prostate cancer, particularly when considering active surveillance. Given heterogeneity and multifocality of primary prostate cancer, such assays should ideally be robust to the coexistence of unsampled higher grade disease elsewhere in the prostate in order to have clinical utility. Herein, we comprehensively evaluated transcriptomic profiles of primary multifocal prostate cancer to assess robustness to clinically relevant multifocality.

Methods

We designed a comprehensive, multiplexed targeted RNA-sequencing assay capable of assessing multiple transcriptional classes and deriving commercially available prognostic signatures, including the Myriad Prolaris Cell Cycle Progression score, the Oncotype DX Genomic Prostate Score, and the GenomeDX Decipher Genomic Classifier. We applied this assay to a retrospective, multi-institutional cohort of 156 prostate cancer samples. Derived commercial biomarker scores for 120 informative primary prostate cancer samples from 44 cases were determined and compared.

Results

Derived expression scores were positively correlated with tumor grade (rS = 0.53-0.73; all P < 0.001), both within the same case and across the entire cohort. In cases of extreme grade-discordant multifocality (co-occurrence of grade group 1 [GG1] and ?GG4 foci], gene expression scores were significantly lower in low- (GG1) versus high-grade (?GG4) foci (all P < 0.001). No significant differences in expression scores, however, were observed between GG1 foci from prostates with and without coexisting higher grade cancer (all P > 0.05).

Conclusions

Multifocal, low-grade and high-grade prostate cancer foci exhibit distinct prognostic expression signatures. These findings demonstrate that prognostic RNA expression assays performed on low-grade prostate cancer biopsy tissue may not provide meaningful information on the presence of coexisting unsampled aggressive disease.

Funding

Prostate Cancer Foundation, National Institutes of Health (U01 CA214170, R01 CA183857, University of Michigan Prostate Specialized Program of Research Excellence [S.P.O.R.E.] P50 CA186786-05, Weill Cornell Medicine S.P.O.R.E. P50 CA211024-01A1), Men of Michigan Prostate Cancer Research Fund, University of Michigan Comprehensive Cancer Center core grant (2-P30-CA-046592-24), A. Alfred Taubman Biomedical Research Institute, and Department of Defense.

SUBMITTER: Salami SS

PROVIDER: S-EPMC6238741 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Transcriptomic heterogeneity in multifocal prostate cancer.

Salami Simpa S SS Hovelson Daniel H DH Kaplan Jeremy B JB Mathieu Romain R Udager Aaron M AM Curci Nicole E NE Lee Matthew M Plouffe Komal R KR de la Vega Lorena Lazo LL Susani Martin M Rioux-Leclercq Nathalie N Spratt Daniel E DE Morgan Todd M TM Davenport Matthew S MS Chinnaiyan Arul M AM Cyrta Joanna J Rubin Mark A MA Shariat Shahrokh F SF Tomlins Scott A SA Palapattu Ganesh S GS

JCI insight 20181102 21

<h4>Background</h4>Commercial gene expression assays are guiding clinical decision making in patients with prostate cancer, particularly when considering active surveillance. Given heterogeneity and multifocality of primary prostate cancer, such assays should ideally be robust to the coexistence of unsampled higher grade disease elsewhere in the prostate in order to have clinical utility. Herein, we comprehensively evaluated transcriptomic profiles of primary multifocal prostate cancer to assess ...[more]

PMID: 30385730

Similar Datasets

Project description:BackgroundNext-generation sequencing is revealing genomic heterogeneity in localized prostate cancer (CaP). Incomplete sampling of CaP multiclonality has limited the implications for molecular subtyping, stratification, and systemic treatment.ObjectiveTo determine the impact of genomic and transcriptomic diversity within and among intraprostatic CaP foci on CaP molecular taxonomy, predictors of progression, and actionable therapeutic targets.Design, setting, and participantsFour consecutive patients with clinically localized National Comprehensive Cancer Network intermediate- or high-risk CaP who did not receive neoadjuvant therapy underwent radical prostatectomy at Roswell Park Cancer Institute in June-July 2014. Presurgical information on CaP content and a customized tissue procurement procedure were used to isolate nonmicroscopic and noncontiguous CaP foci in radical prostatectomy specimens. Three cores were obtained from the index lesion and one core from smaller lesions. RNA and DNA were extracted simultaneously from 26 cores with ≥90% CaP content and analyzed using whole-exome sequencing, single-nucleotide polymorphism arrays, and RNA sequencing.Outcome measurements and statistical analysisSomatic mutations, copy number alternations, gene expression, gene fusions, and phylogeny were defined. The impact of genomic alterations on CaP molecular classification, gene sets measured in Oncotype DX, Prolaris, and Decipher assays, and androgen receptor activity among CaP cores was determined.Results and limitationsThere was considerable variability in genomic alterations among CaP cores, and between RNA- and DNA-based platforms. Heterogeneity was found in molecular grouping of individual CaP foci and the activity of gene sets underlying the assays for risk stratification and androgen receptor activity, and was validated in independent genomic data sets. Determination of the implications for clinical decision-making requires follow-up studies.ConclusionsGenomic make-up varies widely among CaP foci, so care should be taken when making treatment decisions based on a single biopsy or index lesions.Patient summaryWe examined the molecular composition of individual cancers in a patient's prostate. We found a lot of genetic diversity among these cancers, and concluded that information from a single cancer biopsy is not sufficient to guide treatment decisions.

Project description:Multifocal breast cancer (MFBC), defined as multiple synchronous unilateral lesions of invasive breast cancer, is relatively frequent and has been associated with more aggressive features than unifocal cancer. Here, we aimed to investigate the genomic heterogeneity between MFBC lesions sharing similar histopathological parameters. Characterization of different lesions from 36 patients with ductal MFBC involved the identification of non-silent coding mutations in 360 protein-coding genes (171 tumour and 36 matched normal samples). We selected only patients with lesions presenting the same grade, ER, and HER2 status. Mutations were classified as 'oncogenic' in the case of recurrent substitutions reported in COSMIC or truncating mutations affecting tumour suppressor genes. All mutations identified in a given patient were further interrogated in all samples from that patient through deep resequencing using an orthogonal platform. Whole-genome rearrangement screen was further conducted in 8/36 patients. Twenty-four patients (67%) had substitutions/indels shared by all their lesions, of which 11 carried the same mutations in all lesions, and 13 had lesions with both common and private mutations. Three-quarters of those 24 patients shared oncogenic variants. The remaining 12 patients (33%) did not share any substitution/indels, with inter-lesion heterogeneity observed for oncogenic mutation(s) in genes such as PIK3CA, TP53, GATA3, and PTEN. Genomically heterogeneous lesions tended to be further apart in the mammary gland than homogeneous lesions. Genome-wide analyses of a limited number of patients identified a common somatic background in all studied MFBCs, including those with no mutation in common between the lesions. To conclude, as the number of molecular targeted therapies increases and trials driven by genomic screening are ongoing, our findings highlight the presence of genomic inter-lesion heterogeneity in one-third, despite similar pathological features. This implies that deeper molecular characterization of all MFBC lesions is warranted for the adequate management of those cancers.

Project description:A significant proportion of breast cancer patients develop multiple synchronous unilateral breast tumors, also referred to as multifocal tumors, which represent a diagnostic and therapeutic challenge. Multifocality has been associated with a possible adverse patient outcome, propensity for axillary nodal involvement, and increased risk of local recurrence following breast conserving surgery when compared to unifocal tumors. Previous studies indicate that most lesions from multifocal tumors are concordant with regard to the currently used pathological parameters (histological subtype and grade, hormonal receptors and HER2 status). However, to our knowledge, no study has yet provided a detailed molecular analysis of multifocal breast cancer. Here, we aimed to better define the incidence of multifocal breast cancer using a systematic analysis of pathology reports of primary breast cancers and to compare different foci from 5 multifocal breast cancers in a global analysis using genomic, transcriptomic and epigenomic data. We demonstrate that multifocality is a frequent finding since it concerns 22% (945/4340) of breast cancer patients with primary ductal breast cancer. We find that different lesions from multifocal breast cancer can differ at the (epi)genomic and transcriptomic level even when the foci present similar histology, grading, hormonal and HER2 status despite having a common genetic background. Since the number of (epi)genetic alterations with potential clinical utility is rapidly growing due to increasing numbers of targeted therapies, these findings suggest that it might be necessary to interrogate the different lesions of multifocal breast cancers for adequate treatment management of these tumors. The biological characterization of multifocal breast cancer here is focused on 5 cancers for which the foci did not differ in terms of histological grade, hormonal receptors and HER2 status. The characterization of multifocal tumors involved the identification of somatic rearrangements in 2 foci from each patient via low-coverage whole genome sequencing. Putative rearrangements were amplified by polymerase chain reaction (PCR) and capillary sequenced in tumor and matching blood-derived germline DNA to validate the somatic rearrangements. For all patients, the presence of a number of validated rearrangements was assessed in different paraffin blocks of tumor-adjacent histologically normal tissue by nested PCR. We also performed transcriptomic and epigenomic profiling in 4 and 5 patients respectively using the HG-U133 Plus 2.0 Chips and Infinium Methylation 450K arrays (RNA was not available for patient E).

Dataset Information

Transcriptomic heterogeneity in multifocal prostate cancer.

Background

Methods

Results

Conclusions

Funding

Publications

Transcriptomic heterogeneity in multifocal prostate cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets