Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma

Francesco Massari, Chiara Ciccarese, Emilio Bria, Camillo Porta, Francesca la Russa, Sakari Knuutila, Walter Artibani, Antonio Benito Porcaro, Davide Bimbatti, Alessandra Modena, Teodoro Sava, Giampaolo Tortora, Liang Cheng, Albino Eccher, Luca Cima, Serena Pedron, Claudio Ghimenton, Guido Martignoni, Matteo Brunelli

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents.

Original languageEnglish (US)
JournalApplied Immunohistochemistry and Molecular Morphology
DOIs
StateAccepted/In press - Oct 27 2015

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Renal Cell Carcinoma
Chromosomes
Cytogenetics
Neoplasms
Neoplasm Metastasis
Fluorescence In Situ Hybridization
Vascular Endothelial Growth Factor A
Genes
Therapeutics
Clear-cell metastatic renal cell carcinoma

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Medical Laboratory Technology
  • Histology

Cite this

Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma. / Massari, Francesco; Ciccarese, Chiara; Bria, Emilio; Porta, Camillo; la Russa, Francesca; Knuutila, Sakari; Artibani, Walter; Porcaro, Antonio Benito; Bimbatti, Davide; Modena, Alessandra; Sava, Teodoro; Tortora, Giampaolo; Cheng, Liang; Eccher, Albino; Cima, Luca; Pedron, Serena; Ghimenton, Claudio; Martignoni, Guido; Brunelli, Matteo.

In: Applied Immunohistochemistry and Molecular Morphology, 27.10.2015.

Research output: Contribution to journalArticle

Massari, F, Ciccarese, C, Bria, E, Porta, C, la Russa, F, Knuutila, S, Artibani, W, Porcaro, AB, Bimbatti, D, Modena, A, Sava, T, Tortora, G, Cheng, L, Eccher, A, Cima, L, Pedron, S, Ghimenton, C, Martignoni, G & Brunelli, M 2015, 'Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma', Applied Immunohistochemistry and Molecular Morphology. https://doi.org/10.1097/PAI.0000000000000257
Massari, Francesco ; Ciccarese, Chiara ; Bria, Emilio ; Porta, Camillo ; la Russa, Francesca ; Knuutila, Sakari ; Artibani, Walter ; Porcaro, Antonio Benito ; Bimbatti, Davide ; Modena, Alessandra ; Sava, Teodoro ; Tortora, Giampaolo ; Cheng, Liang ; Eccher, Albino ; Cima, Luca ; Pedron, Serena ; Ghimenton, Claudio ; Martignoni, Guido ; Brunelli, Matteo. / Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma. In: Applied Immunohistochemistry and Molecular Morphology. 2015.
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title = "Reprofiling Metastatic Samples for Chromosome 9p and 14q Aberrations as a Strategy to Overcome Tumor Heterogeneity in Clear-cell Renal Cell Carcinoma",
abstract = "Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85{\%} of both primary clear-cell RCCs and in matched metastases; 14{\%} showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58{\%} of both primary and matched metastases. Only 3/7 (42{\%}) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents.",
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AU - Massari, Francesco

AU - Ciccarese, Chiara

AU - Bria, Emilio

AU - Porta, Camillo

AU - la Russa, Francesca

AU - Knuutila, Sakari

AU - Artibani, Walter

AU - Porcaro, Antonio Benito

AU - Bimbatti, Davide

AU - Modena, Alessandra

AU - Sava, Teodoro

AU - Tortora, Giampaolo

AU - Cheng, Liang

AU - Eccher, Albino

AU - Cima, Luca

AU - Pedron, Serena

AU - Ghimenton, Claudio

AU - Martignoni, Guido

AU - Brunelli, Matteo

PY - 2015/10/27

Y1 - 2015/10/27

N2 - Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents.

AB - Losses of chromosomes 9p and 14q are associated with worse outcomes in patients affected by clear-cell renal cell carcinoma (RCC) and are helpful for prognostic risk stratification. Both chromosomal loci harbor several hot-spot molecular pathways suitable for targeted therapeutic interventions. Intratumor heterogeneity may foster tumor adaptation and therapeutic failure. We sought to investigate the presence of losses of the hot spots of chromosomal loci 9p and 14q in primary clear-cell RCC and matched metastatic tissues. CD10 and CD13 were performed on 7 cases of clear-cell RCC with hematogenous tissue metastases. Cytogenetic fluorescence in situ hybridization analysis was performed on primary and matched metastatic tissues using specific probes mapping the 9p and the 14q loci. The loss of chromosome 9p was observed in 85% of both primary clear-cell RCCs and in matched metastases; 14% showed discordance between primary and matched metastases showing gains. The loss of chromosome 14q was observed in 58% of both primary and matched metastases. Only 3/7 (42%) did show an equal status of loss of chromosome 14q. Heterogeneity of the cytogenetic status between metastatic and primary clear-cell RCCs is observed for the loss of chromosome 14q rather than chromosome 9p. The impact of chromosome 14q cytogenetic status, harboring the HIF1 gene, a major driver for the angiogenenic switch, may drive the efficacy of targeted inhibitors, whereas the loss of chromosome 9p, harboring other hot-spot genes, seems to be related to the metastatic behavior per se, without cytogenetic modulation. Reprofiling the metastatic tissue, as compared with the primary tumor, in patients affected by metastatic RCC could be a novel approach to overcome resistance to VEGF(Rs)-targeting agents.

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