Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential
Abstract Background Metastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates a...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-020-06817-1 |
| _version_ | 1818317427466829824 |
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| author | Eric T. Miller Sungyong You Radu M. Cadaneanu Minhyung Kim Junhee Yoon Sandy T. Liu Xinmin Li Lorna Kwan Jennelle Hodge Michael J. Quist Catherine S. Grasso Michael S. Lewis Beatrice S. Knudsen Michael R. Freeman Isla P. Garraway |
| author_facet | Eric T. Miller Sungyong You Radu M. Cadaneanu Minhyung Kim Junhee Yoon Sandy T. Liu Xinmin Li Lorna Kwan Jennelle Hodge Michael J. Quist Catherine S. Grasso Michael S. Lewis Beatrice S. Knudsen Michael R. Freeman Isla P. Garraway |
| author_sort | Eric T. Miller |
| collection | DOAJ |
| description | Abstract Background Metastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning > 300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome. Methods PNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000 and 2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121). Results The CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene “metastasis” signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression. Conclusions Measuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis. |
| first_indexed | 2024-12-13T09:37:09Z |
| format | Article |
| id | doaj.art-5aa779b2ab7b411bb44bb52788febd77 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-13T09:37:09Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-5aa779b2ab7b411bb44bb52788febd772022-12-21T23:52:19ZengBMCBMC Cancer1471-24072020-05-0120111510.1186/s12885-020-06817-1Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potentialEric T. Miller0Sungyong You1Radu M. Cadaneanu2Minhyung Kim3Junhee Yoon4Sandy T. Liu5Xinmin Li6Lorna Kwan7Jennelle Hodge8Michael J. Quist9Catherine S. Grasso10Michael S. Lewis11Beatrice S. Knudsen12Michael R. Freeman13Isla P. Garraway14Department of Urology, David Geffen School of Medicine at UCLADepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Urology, David Geffen School of Medicine at UCLADepartment of Surgery, Cedars-Sinai Medical CenterDepartment of Surgery, Cedars-Sinai Medical CenterDepartment of Urology, David Geffen School of Medicine at UCLADepartment of Pathology, David Geffen School of Medicine at UCLADepartment of Urology, David Geffen School of Medicine at UCLADepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Medicine, Division of Hematology-Oncology, David Geffen School of Medicine at UCLADepartment of Surgery, Cedars-Sinai Medical CenterDepartment of Pathology, Greater Los Angeles Veterans Affairs Health SystemDepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Urology, David Geffen School of Medicine at UCLAAbstract Background Metastatic prostate cancer (PC) is highly lethal. The ability to identify primary tumors capable of dissemination is an unmet need in the quest to understand lethal biology and improve patient outcomes. Previous studies have linked chromosomal instability (CIN), which generates aneuploidy following chromosomal missegregation during mitosis, to PC progression. Evidence of CIN includes broad copy number alterations (CNAs) spanning > 300 base pairs of DNA, which may also be measured via RNA expression signatures associated with CNA frequency. Signatures of CIN in metastatic PC, however, have not been interrogated or well defined. We examined a published 70-gene CIN signature (CIN70) in untreated and castration-resistant prostate cancer (CRPC) cohorts from The Cancer Genome Atlas (TCGA) and previously published reports. We also performed transcriptome and CNA analysis in a unique cohort of untreated primary tumors collected from diagnostic prostate needle biopsies (PNBX) of localized (M0) and metastatic (M1) cases to determine if CIN was linked to clinical stage and outcome. Methods PNBX were collected from 99 patients treated in the VA Greater Los Angeles (GLA-VA) Healthcare System between 2000 and 2016. Total RNA was extracted from high-grade cancer areas in PNBX cores, followed by RNA sequencing and/or copy number analysis using OncoScan. Multivariate logistic regression analyses permitted calculation of odds ratios for CIN status (high versus low) in an expanded GLA-VA PNBX cohort (n = 121). Results The CIN70 signature was significantly enriched in primary tumors and CRPC metastases from M1 PC cases. An intersection of gene signatures comprised of differentially expressed genes (DEGs) generated through comparison of M1 versus M0 PNBX and primary CRPC tumors versus metastases revealed a 157-gene “metastasis” signature that was further distilled to 7-genes (PC-CIN) regulating centrosomes, chromosomal segregation, and mitotic spindle assembly. High PC-CIN scores correlated with CRPC, PC-death and all-cause mortality in the expanded GLA-VA PNBX cohort. Interestingly, approximately 1/3 of M1 PNBX cases exhibited low CIN, illuminating differential pathways of lethal PC progression. Conclusions Measuring CIN in PNBX by transcriptome profiling is feasible, and the PC-CIN signature may identify patients with a high risk of lethal progression at the time of diagnosis.http://link.springer.com/article/10.1186/s12885-020-06817-1Prostate cancerMetastasesChromosomal instabilityCINProstate needle biopsiesTCGA |
| spellingShingle | Eric T. Miller Sungyong You Radu M. Cadaneanu Minhyung Kim Junhee Yoon Sandy T. Liu Xinmin Li Lorna Kwan Jennelle Hodge Michael J. Quist Catherine S. Grasso Michael S. Lewis Beatrice S. Knudsen Michael R. Freeman Isla P. Garraway Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential BMC Cancer Prostate cancer Metastases Chromosomal instability CIN Prostate needle biopsies TCGA |
| title | Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential |
| title_full | Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential |
| title_fullStr | Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential |
| title_full_unstemmed | Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential |
| title_short | Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential |
| title_sort | chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential |
| topic | Prostate cancer Metastases Chromosomal instability CIN Prostate needle biopsies TCGA |
| url | http://link.springer.com/article/10.1186/s12885-020-06817-1 |
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