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

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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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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Genomic Copy Number Alterations in Renal Cell Carcinoma with Sarcomatoid Features

The Journal of Urology ◽

10.1016/j.juro.2015.10.180 ◽

2016 ◽

Vol 195 (4 Part 1) ◽

pp. 852-858 ◽

Cited By ~ 10

Author(s):

Timothy Ito ◽

Jianming Pei ◽

Essel Dulaimi ◽

Craig Menges ◽

Philip H. 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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Comprehensive analysis of somatic copy number alterations in clear cell renal cell carcinoma

Molecular Carcinogenesis ◽

10.1002/mc.23164 ◽

2020 ◽

Vol 59 (4) ◽

pp. 412-424 ◽

Cited By ~ 1

Author(s):

Takashi Tsuyukubo ◽

Kazuyuki Ishida ◽

Mitsumasa Osakabe ◽

Ei Shiomi ◽

Renpei Kato ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Clear Cell ◽

Comprehensive Analysis ◽

Copy Number Alterations ◽

Cell Renal Cell Carcinoma ◽

Somatic Copy Number Alterations

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Copy number variations and expression of MPDZ are prognostic biomarkers for clear cell renal cell carcinoma

Oncotarget ◽

10.18632/oncotarget.20220 ◽

2017 ◽

Vol 8 (45) ◽

pp. 78713-78725 ◽

Cited By ~ 3

Author(s):

Yong-Sheng Huang ◽

Wen-Bin Liu ◽

Fei Han ◽

Jun-Tang Yang ◽

Xiang-Lin Hao ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Clear Cell ◽

Copy Number Variations ◽

Prognostic Biomarkers ◽

Cell Renal Cell Carcinoma

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Copy Number Alterations with Prognostic Potential in Clear Cell Renal Cell Carcinoma

Urologia Internationalis ◽

10.1159/000493149 ◽

2018 ◽

Vol 101 (4) ◽

pp. 417-424 ◽

Cited By ~ 2

Author(s):

Matthias Maruschke ◽

Dirk Koczan ◽

Björn Ziems ◽

Oliver W. Hakenberg

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Clear Cell ◽

Copy Number Alterations ◽

Cell Renal Cell Carcinoma

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Impact of chromosomal copy number variation on outcome in metastatic clear cell renal cell carcinoma patients treated with antiangiogenic agents.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.393 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 393-393

Author(s):

Eric Jonasch ◽

Suresh Thakur ◽

Kanishka Sircar ◽

Pheroze Tamboli ◽

Nizar M. Tannir ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Copy Number Variation ◽

Cell Carcinoma ◽

Renal Cell ◽

Copy Number ◽

Clear Cell ◽

Response To Therapy ◽

Antiangiogenic Agents ◽

Cell Renal Cell Carcinoma ◽

Number Variation

393 Background: Antiangiogenic agents (AA) are used to treat metastatic clear cell renal cell carcinoma (ccRCC). Currently there are no biomarkers of therapeutic efficacy with these agents. We have previously shown that chromosome copy number variation (CNV) is associated with poor (14q loss) or more favorable outcomes (5q31-ter gain) in nonmetastatic patients. The purpose of the current study was the impact of CNV on response, progression free survival (PFS) and on overall survival (OS) after AA in patients with metastatic ccRCC. Methods: We obtained archival FFPE or frozen tumor specimens from patients with mRCC treated with sorafenib (after tumor removal), bevacizumab or sunitinib (neoadjuvant treatment). DNA was analyzed with Affymetrix 250K Nsp SNP microarrays. We identified the presence of genomic imbalances and loss of heterozygosity (LOH) to obtain “virtual karyotypes”. We then compared CNV to outcome using Wilcoxon-Gehan statistical analysis. Results: A total of 83 patients were used to analyze CNV after treatment with AA: 22 sorafenib, 29 sunitinib, 31 bevacizumab. Gain of 8q (p = 0.036) and loss of 16q (p = 0.0031), 20p (p = 0.038) or 20q (p = 0.022) were associated with a shorter OS, whereas gain of 1q (p = 0.037) and 5q (p = 0.019) were associated with longer OS in this patient cohort. When 14q loss was combined with 8q gain, median OS was further decreased (p 0.01). Surprisingly, when assessed as a group, no specific CNV was associated with PFS. However, when compared separately, 5q gain was predictive for better PFS in sorafenib or bevacizumab treated patients (p = 0.006), but no such effect was seen in the sunitinib treated cohort. Conclusions: Our results show that chromosomal imbalances are associated with divergent clinical outcome in metastatic ccRCC patients treated with AA, and are predominantly prognostic. Dissecting out driver tumor suppressor or tumor activating genes within these chromosomal regions will guide our understanding of what defines a particularly lethal phenotype. The possibility exists that specific CNV profiles predict for response to therapy, but a larger sample size is required to validate this possibility.

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