Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features

478 Background: Sarcomatoid differentiation is an uncommon histological finding in renal cell carcinoma (RCC) that may develop from any RCC subtype and is associated with a very poor prognosis. The identification of genetic alterations that drive this aggressive phenotype could aid in the development of more effective targeted therapies. In this study, we aimed to identify unique copy number alterations (CNAs) in patients with sarcomatoid RCC when compared to those with other RCC subtypes. Methods: Genomic copy number analysis was performed using single nucleotide polymorphism (SNP)-based microarrays on tissue extracted from the tumors of 80 patients (9 with sarcomatoid features (sRCC), 39 clear cell (ccRCC), 26 papillary (pRCC) and 6 chromophobe RCC (chRCC)) who underwent renal mass excision between 2010 - 2014. Statistical analysis was performed using Kaplan Meier (KM) survival analysis, t-tests and Fisher exact tests where appropriate. Results: sRCC tumors exhibited significantly higher numbers of CNAs when compared to ccRCC, pRCC and chRCC (mean 20.1 vs. 6.6 vs. 7.0 vs. 6.3, respectively; p <0.0001). The most common copy number losses occurred in chromosome arms 1p, 3p, 9q, 15q, 18q, 21q, and 22q, with losses of 9q (88%), 15q (77%), 18q (66%), and 22 (77%) being unique among sRCC tumors when compared to the other 3 histologies. The most common copy number gains were in chromosome arms 1q, 8q, 17q, and 20p/q, with 1q (55%) and 8q (66%) gains unique when compared to the other 3 histologies. Of the sRCC tumors, 3 arose from ccRCC, 2 from pRCC and 4 from unclassified RCC. sRCC was associated with worse survival compared to ccRCC, pRCC and chRCC on KM analysis (p=0.0006), and higher rates of lymph node positivity (77% vs. 3% vs. 12% vs. 0%, respectively; p<0.0001) and metastases (100% vs. 13% vs. 4% vs. 0%, respectively; p<0.0001) on presentation were observed with sRCC. Conclusions: Sarcomatoid differentiation in RCC is associated with a high rate of chromosomal changes with unique copy number alterations including losses of 9q, 15q, 18q and 22q and gains of 1q and 8q. Identification and validation of candidate driver genes or tumor suppressor loci within these chromosomal regions may help identify targets for future therapies.

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Distinct Genomic Copy Number Alterations Distinguish Mucinous Tubular and Spindle Cell Carcinoma of the Kidney From Papillary Renal Cell Carcinoma With Overlapping Histologic Features

The American Journal of Surgical Pathology ◽

10.1097/pas.0000000000001038 ◽

2018 ◽

Vol 42 (6) ◽

pp. 767-777 ◽

Cited By ~ 17

Author(s):

Qinghu Ren ◽

Lu Wang ◽

Hikmat A. Al-Ahmadie ◽

Samson W. Fine ◽

Anuradha Gopalan ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Spindle Cell ◽

Papillary Renal Cell Carcinoma ◽

Spindle Cell Carcinoma ◽

Copy Number Alterations ◽

Genomic Copy Number ◽

Genomic Copy

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MP47-04 EXAMINATION OF GENOMIC COPY NUMBER ALTERATIONS IN RENAL CELL CARCINOMA WITH SARCOMATOID FEATURES

The Journal of Urology ◽

10.1016/j.juro.2015.02.1524 ◽

2015 ◽

Vol 193 (4S) ◽

Cited By ~ 2

Author(s):

Timothy Ito ◽

Jianming Pei ◽

Essel Dulaimi ◽

Craig Menges ◽

Philip Abbosh ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Copy Number Alterations ◽

Genomic Copy Number ◽

Genomic Copy

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393 GENOMIC COPY NUMBER LOSS AT 9P IS ASSOCIATED WITH METASTASIS OF RENAL CELL CARCINOMA

The Journal of Urology ◽

10.1016/j.juro.2011.02.481 ◽

2011 ◽

Vol 185 (4S) ◽

Author(s):

Takahiro Narimatsu ◽

Keiko Matsuura ◽

Chisato Nakada ◽

Toru Inoue ◽

Takeo Nomura ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Copy Number Loss ◽

Genomic Copy Number ◽

Genomic Copy

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Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma

Genes Chromosomes and Cancer ◽

10.1002/gcc.20771 ◽

2010 ◽

pp. NA-NA ◽

Cited By ~ 1

Author(s):

Jianming Pei ◽

Madelyn M. Feder ◽

Tahseen Al-Saleem ◽

Zemin Liu ◽

Angen Liu ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Clear Cell ◽

Copy Number Analysis ◽

Cell Renal Cell Carcinoma ◽

Genomic Copy Number ◽

Genomic Copy ◽

Classical Cytogenetics

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Molecular Portrait of Clear Cell Renal Cell Carcinoma: An Integrative Analysis of Gene Expression and Genomic Copy Number Profiling

Emerging Research and Treatments in Renal Cell Carcinoma ◽

10.5772/27677 ◽

2012 ◽

Author(s):

Cristina Battaglia ◽

Eleonora Mangano ◽

Silvio Bicciato ◽

Fabio Frascati ◽

Simona Nuzzo ◽

...

Keyword(s):

Gene Expression ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Clear Cell ◽

Integrative Analysis ◽

Cell Renal Cell Carcinoma ◽

Genomic Copy Number ◽

Genomic Copy

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Association of genome-wide copy number alterations with metastasis of clear cell renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.428 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 428-428

Author(s):

Banumathy Gowrishankar ◽

Venkata Jaganmohan Thodima ◽

Ana M. Molina ◽

Charles Ma ◽

Asha Guttapalli ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Clear Cell ◽

Rank Statistic ◽

Copy Number Alterations ◽

Cell Renal Cell Carcinoma ◽

Metastatic Lesions ◽

Genome Wide

428 Background: About one-third of patients with clear cell renal cell carcinoma (ccRCC) exhibit metastasis at the time of diagnosis and show poor prognosis. The genetic and epigenetic alterations associated with metastasis in ccRCC have variably been studied, and their role in the metastatic process is unclear. The goals of the current study were to identify genomic copy number alterations (CNAs) associated with ccRCC metastasis and examine their clinical utility. Methods: In this IRB-approved study, genome-wide copy number profiling was performed on DNA from 144 ccRCC (81 primary and 63 metastatic lesions). Differential CNAs between primary and metastatic lesions and between different metastatic sites were identified using Fisher’s exact test. Associations between CNAs and overall survival (OS) were tested using the log rank statistic and Kaplan-Meier method. Genomic profiling data of 437 and 240 primary ccRCC (TCGA and PMID: 23797736, respecitively) were used for verification. Results: Between primary and metastatic lesions, 25 CNAs were significantly different (p<0.05). Of the 11 more frequent in metastatic lesions, nine retained significance when comparing stage IV and stage I TCGA ccRCC. For 368 TCGA locally-invasive tumors (stages I, II, and III), three CNAs (loss of 9p24.3-p13.3, 9p12-q11, and 9q21.12-q21.33) were associated with inferior survival (p=0.002). In the second dataset of 214 locally-invasive lesions, loss of 18q11.2-q23 correlated with shorter OS (p=0.025). Across metastatic lesions, nine CNAs were found to be significantly enriched in lung lesions and three in bone. In a subset of 127 ccRCC with known metastatic status at 5 years after diagnosis, two of these CNAs (gain of 7q36.1-36.3 in lung and loss of 22q13.2 in bone) were significantly enriched in the corresponding primary specimens. Conclusions: This study identified CNAs associated with ccRCC metastasis and common sites of metastasis that have the potential to serve as biomarkers to assist in better risk stratification of patients with this disease. Integrated analyses of genes mapping to the loci of genomic imbalance would further our understanding of the biology of metastasis in renal cancer.

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