Deletion lengthening at chromosomes 6q and 16q targets multiple tumor suppressor genes and is associated with an increasingly poor prognosis in prostate cancer

Kluth, Martina; Jung, Simon; Habib, Omar; Eshagzaiy, Mina; Heinl, Anna; Amschler, Nina; Masser, Sawinee; Mäder, Malte; Runte, Frederic; Barow, Philipp; Frogh, Sohall; Omari, Jazan; Möller‐Koop, Christina; Hube‐Magg, Claudia; Weischenfeldt, Joachim; Korbel, Jan O.; Steurer, Stefan; Krech, Till; Huland, Hartwig; Graefen, Markus; Minner, Sarah; Sauter, Guido; Schlomm, Thorsten; Simon, Ronald

doi:10.18632/oncotarget.22408

Cited by 27 publications

(35 citation statements)

References 38 publications

(47 reference statements)

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“…This raises the possibility that one of these deletions facilitates the development of the other through a yet unknown mechanism. Our data enabled us to interrogate this question, because data on 6q15 deletion data were available for this TMA from an earlier study . Similarly as seen for 5q21 ( CHD1 ), we had earlier found in a FISH analysis that 6q15 deletions hampered the development of ERG fusions while the presence of ERG fusions had no impact on the likelihood of 6q deletions to occur .…”

Section: Discussionmentioning

confidence: 65%

“…The molecular database attached to the TMA contained immunohistochemical results on ERG-expression and 6q copy number data analyzed by fluorescence in situ hybridization (FISH) from previous studies. 22,26 The usage of archived diagnostic left-over tissues for manufacturing of TMAs and their analysis for research purposes as well as patient data analysis has been approved by local laws (HmbKHG, §12,1) and by the local ethics committee (Ethics commission Hamburg, WF-049/09 and PV3652). All work has been carried out in compliance with the Helsinki Declaration.…”

Section: Patient Samples and Tma Constructionmentioning

confidence: 99%

“…Depending on the sequel of development of two molecular alterations, one can expect a small area of cancer having both alterations within a larger area having only one (the earlier) of these changes. To study heterogeneity, we have previously developed a prostate cancer heterogeneity TMA platform . This TMA contains multiple samples from the same prostate cancer, thus enabling a high‐throughput mapping of molecular features across the entire tumors.…”

Section: Introductionmentioning

confidence: 99%

“…To study heterogeneity, we have previously developed a prostate cancer heterogeneity TMA platform. 22,23 This TMA contains multiple samples from the same prostate cancer, thus enabling a high-throughput mapping of molecular features across the entire tumors. We have earlier used this approach to dissect the chronology of key molecular alterations of prostate cancers, including activation of the ETS-transcription factor ERG and deletions of the phosphatase and tensin homolog (PTEN) tumor suppressor or deletions at chromosome 6q15 and 3p13.…”

Section: Introductionmentioning

confidence: 99%

“…We have earlier used this approach to dissect the chronology of key molecular alterations of prostate cancers, including activation of the ETS-transcription factor ERG and deletions of the phosphatase and tensin homolog (PTEN) tumor suppressor or deletions at chromosome 6q15 and 3p13. [22][23][24][25][26] In the present study, we used this heterogeneity TMA approach in order to evaluate the degree of heterogeneity of 5q21 deletions in 317 prostate cancers and to study the evolution of 5q21 deletion and its relationship with 6q15 deletion and TMPRSS2:ERG fusions.…”

Section: Introductionmentioning

confidence: 99%

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5q21 deletion is often heterogeneous in prostate cancer

Kluth

Kilani

Özden

et al. 2019

Genes Chromosomes & Cancer

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Cancer heterogeneity represents a challenge for the analysis of prognostic molecular markers but can be used to study the evolution of molecular events in tumors. To assess the degree of heterogeneity of 5q21 deletions and their relationship with TMPRSS2:ERG status and 6q15 deletions in prostate cancer, a heterogeneity tissue microarray including 10 tissue spots from 10 different areas of 317 cancers was analyzed by fluorescence in situ hybridization for 5q21 deletion. Data on 6q and ERG were available from earlier studies. Deletions of 5q21 were found in 23% of 265 interpretable cancers and showed marked intratumoral heterogeneity. In the subset of 246 cancers with at least 3 interpretable spots, 23% had a 5q21 deletion. Heterogeneous 5q21 deletions were found in 71% and homogeneous in 29% of these cancers. The likelihood of 5q21 deletion was twice as high in ERG‐negative (28%) than in ERG‐positive cancers (16%, P = .024). In all 21 cases harboring both alterations, the tumor area containing a 5q21 deletion was smaller or equally large than the ERG‐positive area but never larger. Deletions of 5q and 6q were significantly linked. However, the analysis of 32 tumors harboring both deletions did not suggest a specific order of appearance of these deletions. The 5q21 deletion preceded 6q15 in 10 tumors and 6q15 preceded 5q21 in 14 tumors. In summary, our study identifies 5q21 deletion as a highly heterogeneous aberration in prostate cancer that usually occurs late during cancer progression. This is a severe limitation for using 5q21 testing as a prognostic tool.

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Section: Discussionmentioning

confidence: 65%

Section: Patient Samples and Tma Constructionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

5q21 deletion is often heterogeneous in prostate cancer

Kluth

Kilani

Özden

et al. 2019

Genes Chromosomes & Cancer

Self Cite

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Deletions of DNA in cancer and their possible uses for therapy

2023

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Despite advances in treatments over the last decades, a uniformly reliable and free of side effects therapy of human cancers remains to be achieved. During chromosome replication, a premature halt of two converging DNA replication forks would cause incomplete replication and a cytotoxic chromosome nondisjunction during mitosis. In contrast to normal cells, most cancer cells bear numerous DNA deletions. A homozygous deletion permanently marks a cell and its descendants. Here, we propose an approach to cancer therapy in which a pair of sequence‐specific roadblocks is placed solely at two cancer‐confined deletion sites that are located ahead of two converging replication forks. We describe this method, termed “replication blocks specific for deletions” (RBSD), and another deletions‐based approach as well. RBSD can be expanded by placing pairs of replication roadblocks on several different chromosomes. The resulting simultaneous nondisjunctions of these chromosomes in cancer cells would further increase the cancer‐specific toxicity of RBSD.

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Prognostic significance of an invasive leader cell–derived mutation cluster on chromosome 16q

Pedro

Rupji

Dwivedi

et al. 2020

Cancer

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Background Intratumoral heterogeneity is defined by subpopulations with varying genotypes and phenotypes. Specialized, highly invasive leader cells and less invasive follower cells are phenotypically distinct subpopulations that cooperate during collective cancer invasion. Because leader cells are a rare subpopulation that would be missed by bulk sequencing, a novel image‐guided genomics platform was used to precisely select this subpopulation. This study identified a novel leader cell mutation signature and tested its ability to predict prognosis in non–small cell lung cancer (NSCLC) patient cohorts. Methods Spatiotemporal genomic and cellular analysis was used to isolate and perform RNA sequencing on leader and follower populations from the H1299 NSCLC cell line, and it revealed a leader‐specific mutation cluster on chromosome 16q. Genomic data from patients with lung squamous cell carcinoma (LUSC; n = 475) and lung adenocarcinoma (LUAD; n = 501) from The Cancer Genome Atlas were stratified by 16q mutation cluster (16qMC) status (16qMC+ vs 16qMC−) and compared for overall survival (OS), progression‐free survival (PFS), and gene set enrichment analysis (GSEA). Results Poorer OS, poorer PFS, or both were found across all stages and among early‐stage patients with 16qMC+ tumors within the LUSC and LUAD cohorts. GSEA revealed 16qMC+ tumors to be enriched for the expression of metastasis‐ and survival‐associated gene sets. Conclusions This represents the first leader cell mutation signature identified in patients and has the potential to better stratify high‐risk NSCLC and ultimately improve patient outcomes.

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Deletion lengthening at chromosomes 6q and 16q targets multiple tumor suppressor genes and is associated with an increasingly poor prognosis in prostate cancer

Cited by 27 publications

References 38 publications

5q21 deletion is often heterogeneous in prostate cancer

5q21 deletion is often heterogeneous in prostate cancer

Deletions of DNA in cancer and their possible uses for therapy

Prognostic significance of an invasive leader cell–derived mutation cluster on chromosome 16q

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