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Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures.

ABSTRACT: Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadiag®) using a step-wise approach with increasing resolution from pseudo-bulk analysis of the whole biopsy, to differentiation by tissue subtype (benign, stroma, tumour), followed by distinct tumour grade and finally clonal resolution. The gene expression profile of virtual tumour biopsies revealed clear differences between grade groups and tumour clones, compared to a benign control, which were not reflected in bulk analyses. This suggests that bulk analyses of whole biopsies or tumour-only areas, as used in clinical practice, may provide an inaccurate assessment of gene profiles. The type of tissue, the grade of the tumour and the clonal composition all influence the gene expression in a biopsy. Clinical decision making based on biopsy genomics should be made with caution while we await more precise targeting and cost-effective spatial analyses.

SUBMITTER: Figiel S

PROVIDER: S-EPMC10546768 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures.

Figiel Sandy S Yin Wencheng W Doultsinos Dimitrios D Erickson Andrew A Poulose Ninu N Singh Reema R Magnussen Anette A Anbarasan Thineskrishna T Teague Renuka R He Mengxiao M Lundeberg Joakim J Loda Massimo M Verrill Clare C Colling Richard R Gill Pelvender S PS Bryant Richard J RJ Hamdy Freddie C FC Woodcock Dan J DJ Mills Ian G IG Cussenot Olivier O Lamb Alastair D AD

Molecular cancer 20231003 1

Genetic signatures have added a molecular dimension to prognostics and therapeutic decision-making. However, tumour heterogeneity in prostate cancer and current sampling methods could confound accurate assessment. Based on previously published spatial transcriptomic data from multifocal prostate cancer, we created virtual biopsy models that mimic conventional biopsy placement and core size. We then analysed the gene expression of different prognostic signatures (OncotypeDx®, Decipher®, Prostadia ...[more]

PMID: 37789377

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Project description: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. 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. 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). 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. 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.

Project description:IntroductionDiffuse intrinsic pontine glioma (DIPG) and midline high-grade glioma (mHGG) are lethal childhood brain tumors. Spatial genomic heterogeneity has been well-described in adult HGG but has not been comprehensively characterized in pediatric HGG. We performed whole exome sequencing on 38-matched primary, contiguous, and metastatic tumor sites from eight children with DIPG (n = 7) or mHGG (n = 1) collected using a unique MRI-guided autopsy protocol. Validation was performed using Sanger sequencing, Droplet Digital polymerase-chain reaction, immunohistochemistry, and fluorescent in-situ hybridization.ResultsMedian age at diagnosis was 6.1 years (range: 2.9-23.3 years). Median overall survival was 13.2 months (range: 11.2-32.2 months). Contiguous tumor infiltration and distant metastases were observed in seven and six patients, respectively, including leptomeningeal dissemination in three DIPGs. Histopathological heterogeneity was evident in seven patients, including intra-pontine heterogeneity in two DIPGs, ranging from World Health Organization grade II to IV astrocytoma. We found conservation of heterozygous K27M mutations in H3F3A (n = 4) or HIST1H3B (n = 3) across all primary, contiguous, and metastatic tumor sites in all DIPGs. ACVR1 (n = 2), PIK3CA (n = 2), FGFR1 (n = 2), and MET (n = 1) were also intra-tumorally conserved. ACVR1 was co-mutated with HIST1H3B (n = 2). In contrast, PDGFRA amplification and mutation were spatially heterogeneous, as were mutations in BCOR (n = 1), ATRX (n = 2), and MYC (n = 1). TP53 aberrations (n = 3 patients) varied by type and location between primary and metastatic tumors sites but were intra-tumorally conserved.ConclusionSpatial conservation of prognostically-relevant and therapeutically-targetable somatic mutations in DIPG and mHGG contrasts the significant heterogeneity of driver mutations seen in adult HGG and supports uniform implementation of diagnostic biopsy in DIPG and mHGG to classify molecular risk groups and guide therapeutic strategy.

Project description:ImportanceComprehensive understanding of the genomic and gene-expression differences between retinoblastoma tumors from patients with bilateral disease may help to characterize risk and optimize treatment according to individual tumor characteristics.ObjectiveTo compare the genomic features between each eye and a specimen from an orbital relapse in patients with bilateral retinoblastoma.Design, setting, and participantsIn this case, 2 patients with retinoblastoma underwent upfront bilateral enucleation. Tumor samples were subjected to genomic and gene-expression analysis. Primary cell cultures were established from both of the tumors of 1 patient and were used for gene-expression studies.Main outcomes and measuresWhole-exome sequencing was performed on an Illumina platform for fresh tumor samples and DNA arrays (CytoScan or OncoScan) were used for paraffin-embedded samples and cell lines. Gene-expression analysis was performed using Agilent microarrays. Germinal and somatic alterations, copy number alterations, and differential gene expression were assessed.ResultsAfter initial bilateral enucleation, patient 1 showed massive choroidal and laminar optic nerve infiltration, while patient 2 showed choroidal and laminar optic nerve invasion. Patient 1 developed left-eye orbital recurrence and bone marrow metastasis less than 1 year after enucleation. Both ocular tumors showed gains on 1q and 6p but presented other distinct genomic alterations, including an additional gain in 2p harboring the N-myc proto-oncogene (MYCN) in the left tumor and orbital recurrence. Similar copy number alterations between the orbital recurrence and the left eye supported the origin of the relapse, with an additional 11q loss only detected in the orbital relapse. Specimens from patient 2 showed common copy number gains and losses, but further evolution rendered a 2p gain spanning MYCN in the left tumor. For this patient, microarray expression analysis showed differential expression of the MYCN and the forkhead box protein G1 (FOXG1) gene pathways between the left and right tumors.Conclusions and relevanceDifferential genomic and gene expression features were observed between tumors in 2 patients with bilateral disease, confirming intereye heterogeneity that might be considered if targeted therapies are used in such patients. Chromosomal alteration profile supported the origin of the orbital recurrence from the homolateral eye in 1 patient. Loss in chromosome 11q may have been associated with extraocular relapse in this patient.

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Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures.

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Spatial transcriptomic analysis of virtual prostate biopsy reveals confounding effect of tissue heterogeneity on genomic signatures.

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