Role of Inflammatory Related Gene Expression in Clear Cell Renal Cell Carcinoma Development and Clinical Outcomes

Abstract

Purpose Renal cell carcinoma is the eighth most common cancer in the United States and clear cell renal carcinoma is the most common type. Many signaling pathways are implicated in clear cell renal carcinoma development, including the inflammation pathway. However, less is known about how gene expression variation in this pathway influences clear cell renal carcinoma development and clinical outcomes. Materials and Methods Gene expression in tumor and adjacent normal tissues from 93 patients was detected using a genome-wide expression array. A panel of 661 inflammation related genes was then analyzed. Differential expression patterns between tumor and normal tissues were identified. Association with recurrence or survival was evaluated with genes showing significant association tested further in a validation set of 258 tumors using an independent platform (quantitative real-time polymerase chain reaction). Results We identified 151 genes with at least a two-fold change in gene expression between adjacent normal tissue and tumor, of which most were up-regulated in tumors. A total of 20 genes significantly associated with recurrence and/or overall survival were selected for further validation. In the replication data set high expression of GADD45G was significantly associated with a 2.09-fold (95% CI 1.08 – 6.14, p = 0.034) increased risk of recurrence while high CARD9, NCF2 and CIITA expression was significantly associated with a 2.52-fold (95% CI 1.24 –5.12, p = 0.010), 2.26-fold (95% CI 1.12– 4.58, p = 0.023) and 2.11-fold (95% CI 1.05– 4.27, p = 0.037) increased risk of death, respectively. Conclusions Results suggest that inflammation gene expression may be significant prognostic biomarkers for the risk of recurrence (GADD45G) and death (CARD9, CIITA and NCF2) in patients with clear cell renal carcinoma.

Prognostic significance of visceral obesity in patients with advanced renal cell carcinoma undergoing nephrectomy

“…[10][11][12] Visceral obesity increases cancer risk and promotes tumor progression through its adverse impact on inflammation and metabolism, and upregulation of genes involved in tumor cell invasion and metastasis. 3,6,18 Furthermore, the prevalence of abdominal obesity has recently increased in Asian countries because of a Westernized diet. Therefore, the necessity for precise and clinically expedient measures for quantifying visceral obesity is evident.…”

Integrative Genome-Wide Gene Expression Profiling of Clear Cell Renal Cell Carcinoma in Czech Republic and in the United States

“…In addition, a panel of inflammation related genes has recently been analyzed in ccRCC by Tan and colleagues and related to risk of recurrence ( GADD45G ) and death ( CARD9, CIITA and NCF2 ) [15]. Only one report highlights the role of Toll-like receptors (TLRs) in ccRCC.…”

“…Hypoxia-inducible factors (HIF) pathway and compensatory hyperactivation of angiogenesis through upregulation of VEGFR and PDGFR pathways are thought to be particularly important in ccRCC pathogenesis, given the highly vascularised nature of renal tumours and the specific association with mutations in VHL [9]. In addition, activation of PI3K/AKT/mTOR [10], Wnt/β-catenin [4], [11], epithelial to mesenchymal transition (EMT) [12], [13], HGF/MET [11], [14] as well as inflammatory [15] pathways have all been reported to be implicated in RCC carcinogenesis.…”

Immune Contexture, Immunoscore, and Malignant Cell Molecular Subgroups for Prognostic and Theranostic Classifications of Cancers

“…Indeed, gene expression studies in large cohorts of RCC-bearing patients have suggested that some molecules such as IL-1, IL-6, TNF-α, C1q, and C1r could be implicated in the initiation and promotion of an intratumor inflammatory cascade (Peri, Devarajan, Yang, Knudson, & Balachandran, 2013;Romero et al, 2006;Tan et al, 2011). The RCC tumor cells probably orchestrate this inflammatory environment as suggested by the presence of several cytokines in the supernatant of RCC primary cultures, including IL-8, IL-10, TGF-β, GM-CSF, TNF-α, and VEGF (Gogusev, Augusti, Chrétien, & Droz, 1993;Knoefel et al, 1997;Lahn et al, 1999;Lee, Chun, Nadiminty, Lou, & Gao, 2007;Sievers et al, 2007).…”

“…Thus, the plasma concentration of C-reactive protein in RCC-bearing patients (Hu et al, 2014;Ito et al, 2006;Jagdev et al, 2010;Karakiewicz et al, 2007;Lamb, McMillan, Ramsey, & Aitchison, 2006;Steffens et al, 2012) and the presence of an inflammatory gene signature in RCC (Romero et al, 2006;Tan et al, 2011) are linked to a higher tumor grade and positive metastatic status at diagnosis and poor prognosis. In addition, other inflammatory markers are related to poor survival in RCCbearing patients, including an augmented erythrocyte sedimentation rate, leukocytosis, thrombocytosis, and the increased plasmatic concentrations of IL-6 and TNF-α (Dosquet, Coudert, Lepage, Cabane, & Richard, 1997;Dosquet et al, 1994;Escudier et al, 2014;Fox et al, 2013;Negrier et al, 2004;Pichler et al, 2013;Wu et al, 2011;Yoshida et al, 2002).…”