A Molecular Classification of Papillary Renal Cell Carcinoma

Abstract

Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G 1 -S and G 2 -M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIA in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting. (Cancer Res 2005; 65(13): 5628-37)

MMSET is overexpressed in cancers: Link with tumor aggressiveness

“…Thus, we looked for whether MMSET expression could be associated with tumor progression and prognosis. MMSET was significantly overexpressed in oligodendroglioma grade III compared to grade II (P = .009) [11] ( Figure 1) in agreement with previous data [9]; in patients presenting advanced bladder carcinoma (grade II and III) compared to grade I in four independent studies (P = 4E-6, P = .0001, P = .004, P = .008) [19; 43; 44; 45]; in breast carcinoma grades II and III compared to grade I in four independent studies (P = 2.2E-6, P = 9.1E-4, P = .014, P = .017) [46; 47; 48; 49]; in advanced prostate carcinoma grades VII, VIII and IX compared to grade VI (P = 1.4E-4 [50]; in no differentiated hepatocellular carcinoma compared to differentiated hepatocellular carcinoma (P = 7.2E-5) [15]; in undifferentiated compared to differentiated head and neck cancer (P = .002) [17]; in undifferentiated compared to differentiated cervical carcinoma [51]; in advanced papillary renal cell carcinoma stages III and IV compared to stages I and II (P = .0039) [52] (Figure 1). Furthermore, as it has been demonstrated in MM, MMSET expression is associated with bad prognostic in others cancers (Figure 2).…”

“…The identification of the targets of MMSET and their role in cell growth and survival will be key to understanding how MMSET is associated with tumor development. MMSET gene expression in oligodendroglioma [9], bladder [19; 43; 44; 45], breast carcinoma [46; 47; 48; 49], prostate carcinoma [50], in hepatocellular carcinoma [15], head and neck cancer [17], cervical carcinoma [51], papillary renal cell carcinoma [52]. MMSET expression in alive patients with head and neck carcinoma, in dead patients with head and neck carcinoma [53], in MM patients with no relapse, in MM patients with relapse [54], in alive and dead patients with MM [54], in prostate carcinoma patients with no recurrence, prostate carcinoma patients with recurrence [50], in alive and dead patients with glioma [55].…”

Activation of Wnt/β-catenin signalling pathway induces chemoresistance to interferon-α/5-fluorouracil combination therapy for hepatocellular carcinoma

“…Development of microarray technology has facilitated analysis of genome-wide expression profiles (Zembutsu et al, 2002;Yang et al, 2005). It can generate a large body of information concerning genetic networks related to pathological subtype, prognosis and resistance to anticancer drugs of neoplasm.…”

Chromosomal amplification of leucine-rich repeat kinase-2 (LRRK2) is required for oncogenic MET signaling in papillary renal and thyroid carcinomas

“…1D) (18)(19)(20). To confirm that LRRK2 and MET are coordinately amplified in papillary RCC tumors, we performed dual-color FISH on renal tumors with probes targeted to LRRK2 (12q12) and MET (7q31) (Fig.…”