High‐resolution analysis of DNA copy number alterations and gene expression in renal clear cell carcinoma

Abstract

We analysed chromosomal copy number aberrations (CNAs) in renal cell carcinomas by array-based comparative genomic hybridization, using a genome-wide scanning array with 2304 BAC and PAC clones covering the whole human genome at a resolution of roughly 1.3 Mb. A total of 30 samples of renal cell carcinoma were analysed, including 26 cases of clear cell carcinoma (CCC) and four cases of chromophobe renal cell carcinoma (ChCC). In CCCs, gains of chromosomes 5q33.1-qter (58%), 7q11.22-q35 (35%) and 16p12.3-p13.12 (19%), and losses of chromosomes 3p25.1-p25.3 (77%), 3p21.31-p22.3 (81%), 3p14.1-p14.2 (77%), 8p23.3 (31%), 9q21.13-qter (19%) and 14q32.32-qter (38%) were detected. On the other hand, the patterns of CNAs differed markedly between CCCs and ChCCs. Next, we examined the correlation of CNAs with expression profiles in the same tumour samples in 22/26 cases of CCC, using oligonucleotide microarray. We extracted genes that were differentially expressed between cases with and without CNAs, and found that significantly more up-regulated genes were localized on chromosomes 5 and 7, where recurrent genomic gains have been detected. Conversely, significantly more down-regulated genes were localized on chromosomes 14 and 3, where recurrent genomic losses have been detected. These results revealed that CNAs were correlated with deregulation of gene expression in CCCs. Furthermore, we compared the patterns of genomic imbalance with histopathological features, and found that loss of 14q appeared to be a specific and additional genetic abnormality in high-grade CCC. When we compared the expression profiles of low-grade CCCs with those of high-grade CCCs, differentially down-regulated genes tended to be localized on chromosomes 14 and 9. Thus, it is suggested that copy number loss at 14q in high-grade CCC may be involved in the down-regulation of genes located in this region.

Decreased expression of CXXC4 promotes a malignant phenotype in renal cell carcinoma by activating Wnt signaling

“…Loss of 4q was observed in 10-50% of RCCs examined previously by conventional and array comparative genomic hybridization (Moch et al, 1996;Jiang et al, 2000;Yoshimoto et al, 2007). Several additional studies of RCC have also indicated that the loss of 4q is associated with sarcomatoid transformation and high-grade tumors (Jiang et al, 1998;Yoshimoto et al, 2007). In Wilms' tumors, a 2.4-Mb minimal region of loss of heterozygosity has been detected at 4q24-q25 by 10K SNP array, which is a CXXC4 and progression of RCC T Kojima et al region that includes the CXXC4 gene (Yuan et al, 2005).…”

“…Loss of 4q was observed in 10-50% of RCCs examined previously by conventional and array comparative genomic hybridization (Moch et al, 1996;Jiang et al, 2000;Yoshimoto et al, 2007). Several additional studies of RCC have also indicated that the loss of 4q is associated with sarcomatoid transformation and high-grade tumors (Jiang et al, 1998;Yoshimoto et al, 2007).…”

Cysteine-rich intestinal protein 2 ( CRIP2 ) acts as a repressor of NF-κB–mediated proangiogenic cytokine transcription to suppress tumorigenesis and angiogenesis

“…Using a panel of tumor-suppressive chromosome 14 MCH cell lines established in a previous study (1), a novel candidate TSG, cysteine-rich intestinal protein 2 (CRIP2), was identified and shown to induce tumor suppression in nasopharyngeal carcinoma (NPC). CRIP2 is located in the chromosome 14q32.3 region, which often shows high allelic loss in many cancers, including NPC (2, 3) and esophageal, renal, and colon carcinomas (4)(5)(6)(7). In fact, because of its location in a hot spot for chromosome truncation in tumor development, it was reported to be a candidate for leukemic translocation (8).…”

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

“…Among the RCC histotypes, clear cell renal carcinoma (ccRCC) is the most frequent and aggressive subtype and is characterized by a specific pattern of chromosomal alterations (Yoshimoto et al, 2007) that represents a molecular fingerprint potentially useful for diagnostic and prognostic applications (Klatte et al, 2007). Nowadays, the standard clinical treatment comprises surgical resection followed by IFN-and/or IL2-based immunotherapy, although therapy toxicity still represents a major problem (Molina & Motzer, 2011).…”