Chromosomal imbalances in papillary renal cell carcinoma: genetic differences between histological subtypes

Abstract

Papillary renal-cell carcinoma (RCC) is a renal carcinoma variant with distinct gross, microscopic, and cytogenetic features. Recently, a type 1 (pale cytoplasm, small-cell) and a type 2 (eosinophilic cytoplasm, large-cell) subtype of papillary RCC have been described. Chromosomal alterations associated with these tumor types were examined in 25 papillary RCCs by comparative genomic hybridization. Relative copy number gains were frequently detected at chromosomes 7p (56%), 7q (44%), 12q (28%), 16q (32%), 17p (56%), 17q (76%), and 20q (32%). Chromosomal regions that were most often lost included 1p (24%), 4q (36%), 6q (40%), 9p (36%), 13q (36%), Xp (28%), Xq (36%), and Y (73%). There were clinical and genetic differences between the subtypes of papillary RCC. Type 2 tumors were of higher nuclear grade (P = 0.0012) and higher stage (P = 0.01) and had a worse prognosis (P = 0.03) than type 1 tumors. The number of DNA gains per tumor, especially gains of 7p and 17p, was significantly higher in type 1 than in type 2 tumors (P < 0.01). These data suggest the existence of two distinct morphological and genetic subgroups of papillary RCC. Losses of chromosome Xp were associated with short patient survival (P < 0.01). Despite the small number of cases, this finding suggests that a gene on chromosome Xp may contribute to papillary RCC progression.

Figure 1.

A: Type 1 papillary renal cell carcinoma. The papillae are covered by a single layer of small cells with small nuclei. Foamy macrophages are seen in the papillary cores. B: Type 2 papillary renal cell carcinoma. The papillae are covered by a pseudostratified layer of large cells. Nuclei with prominent nucleoli. H&E; magnification, ×280.

Figure 2.

An example of a digital image of a CGH experiment illustrating chromosome 7 and 17 gains and chromosome 4 and 13q losses in a papillary renal cell carcinoma. DNA extracted from the tumor tissue (labeled in green) were hybridized simultaneously to a normal metaphase spread. Chromosomal regions that are overrepresented in the tumor are visualized in a predominantly greenish color, whereas regions that were lost are highlighted in a red color (relative lack of green). Also shown are the green-to-red ratio profiles generated by the image analysis program of all aberrant chromosomes of the same sample. Thin lines indicate normal range of the green-to-red ratios (0.8 to 1.2). Deletions are marked by bars to the right of the chromosome, and gains are marked by bars to the left of the chromosome.

Figure 3.

Summary of all relative DNA sequence copy number changes detected by CGH in 25 papillary renal cell carcinomas. The vertical lines on the right of the chromosome ideograms indicate gains; those on the left indicate losses. Solid bars indicate a gene amplification. *1p31-term, 16p, 19, and 22 were not analyzed.

Figure 4.

A: Overall survival analysis for patients with and without chromosome Xp losses (log-rank test). B: Overall survival analysis for patients with and without chromosome Xq losses (log-rank test).