Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities

Grönroos, Eva; López‐García, Carlos

doi:10.1158/0008-5472.can-18-1958

“…3) [16]. In order for tumor cells to tolerate CIN, inactivation of the TP53 gene or its associated pathway is often required [39]. Interrogation of genes linked to the hallmark p53 pathway activation signature demonstrated downregulated in M1 relative to M0-NM tumors (p = 0.031).…”

Section: Pnbx M1 Cases Represent High Cin Without Deregulated Ddrmentioning

confidence: 99%

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

Miller

¹

,

You

²

,

Cadaneanu

³

et al. 2020

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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).

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“…1). This hallmark of cancer is suggested as a major modulator of tumor adaptation and evolution in response to challenges arising from the tumor microenvironment such as metastasis or therapeutic resistance (2). CIN, one of the major forms of genomic instability in various human cancers, is typically associated with structural and numerical chromosomal changes over time in tumor tissues (3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

Chromosomal Instability in Tumor Initiation and Development

Bach

¹

,

Zhang

²

,

Sood

³

2019

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Chromosomal instability (CIN) is one of the major forms of genomic instability in various human cancers and is recognized as a common hallmark of tumorigenesis and heterogeneity. However, some malignant tumors show a paucity of chromosomal alterations, suggesting that tumor progression and evolution can occur in the absence of CIN. It is unclear whether CIN is stable between precursor lesions, primary tumor, and metastases or if it evolves during these steps. In this review, we describe the influence of CIN on the various steps in tumor initiation and development. Given the recognized significant effects of CIN in cancer, CIN-targeted therapeutics could have a major impact on improving clinical outcomes.

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“…3) [16]. In order for tumor cells to tolerate CIN, inactivation of the TP53 gene or its associated pathway is often required [39]. Interrogation of genes linked to the hallmark p53 pathway activation signature demonstrated down-regulated in M1 relative to M0-NM tumors (p = 0.031).…”

Section: Resultsmentioning

confidence: 99%

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

Miller

¹

,

You

²

,

Cadaneanu

³

et al. 2020

Preprint

0

View full text Add to dashboard Cite

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 2000-2016. 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.

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Tolerance of Chromosomal Instability in Cancer: Mechanisms and Therapeutic Opportunities

Cited by 37 publications

References 70 publications

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

Chromosomal Instability in Tumor Initiation and Development

Chromosomal instability in untreated primary prostate cancer as an indicator of metastatic potential

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