Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

Thai H Ho, D. J. Serie, M. Parasramka, J. C. Cheville, B. M. Bot, Winston Tan, Liewei M Wang, Richard W Joseph, T. Hilton, B. C. Leibovich, Alexander Parker, Jeanette E Eckel-Passow

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.

Original languageEnglish (US)
Pages (from-to)604-610
Number of pages7
JournalAnnals of Oncology
Volume28
Issue number3
DOIs
StatePublished - 2017

Fingerprint

Gene Expression Profiling
Renal Cell Carcinoma
Extracellular Matrix
Up-Regulation
Neoplasm Metastasis
Genes
Neoplasms
Transcriptome
Survival
Atlases
Linear Models
Clear-cell metastatic renal cell carcinoma
Genome
Gene Expression
Bone and Bones
Lung

Keywords

  • Extracellular matrix
  • Metastases
  • Renal cell carcinoma

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes. / Ho, Thai H; Serie, D. J.; Parasramka, M.; Cheville, J. C.; Bot, B. M.; Tan, Winston; Wang, Liewei M; Joseph, Richard W; Hilton, T.; Leibovich, B. C.; Parker, Alexander; Eckel-Passow, Jeanette E.

In: Annals of Oncology, Vol. 28, No. 3, 2017, p. 604-610.

Research output: Contribution to journalArticle

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title = "Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes",
abstract = "Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.",
keywords = "Extracellular matrix, Metastases, Renal cell carcinoma",
author = "Ho, {Thai H} and Serie, {D. J.} and M. Parasramka and Cheville, {J. C.} and Bot, {B. M.} and Winston Tan and Wang, {Liewei M} and Joseph, {Richard W} and T. Hilton and Leibovich, {B. C.} and Alexander Parker and Eckel-Passow, {Jeanette E}",
year = "2017",
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T1 - Differential gene expression profiling of matched primary renal cell carcinoma and metastases reveals upregulation of extracellular matrix genes

AU - Ho, Thai H

AU - Serie, D. J.

AU - Parasramka, M.

AU - Cheville, J. C.

AU - Bot, B. M.

AU - Tan, Winston

AU - Wang, Liewei M

AU - Joseph, Richard W

AU - Hilton, T.

AU - Leibovich, B. C.

AU - Parker, Alexander

AU - Eckel-Passow, Jeanette E

PY - 2017

Y1 - 2017

N2 - Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.

AB - Background: The majority of renal cell carcinoma (RCC) studies analyze primary tumors, and the corresponding results are extrapolated to metastatic RCC tumors. However, it is unknown if gene expression profiles from primary RCC tumors differs from patient-matched metastatic tumors. Thus, we sought to identify differentially expressed genes between patient-matched primary and metastatic RCC tumors in order to understand the molecular mechanisms underlying the development of RCC metastases. Patients and methods: We compared gene expression profiles between patient-matched primary and metastatic RCC tumors using a two-stage design. First, we used Affymetrix microarrays on 15 pairs of primary RCC [14 clear cell RCC (ccRCC), 1 papillary] tumors and patient-matched pulmonary metastases. Second, we used a custom NanoString panel to validate seven candidate genes in an independent cohort of 114 ccRCC patients. Differential gene expression was evaluated using a mixed effect linear model; a random effect denoting patient was included to account for the paired data. Third, The Cancer Genome Atlas (TCGA) data were used to evaluate associations with metastasis-free and overall survival in primary ccRCC tumors. Results: We identified and validated up regulation of seven genes functionally involved in the formation of the extracellular matrix (ECM): DCN, SLIT2, LUM, LAMA2, ADAMTS12, CEACAM6 and LMO3. In primary ccRCC, CEACAM6 and LUM were significantly associated with metastasis-free and overall survival (P < 0.01). Conclusions: We evaluated gene expression profiles using the largest set to date, to our knowledge, of patient-matched primary and metastatic ccRCC tumors and identified up regulation of ECM genes in metastases. Our study implicates up regulation of ECM genes as a critical molecular event leading to visceral, bone and soft tissue metastases in ccRCC.

KW - Extracellular matrix

KW - Metastases

KW - Renal cell carcinoma

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U2 - 10.1093/annonc/mdw652

DO - 10.1093/annonc/mdw652

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