Specific genomic aberrations predict survival, but low mutation rate in cancer hot spots, in clear cell renal cell carcinoma

Abstract

Detailed genetic profiling of clear cell renal cell carcinoma (ccRCC) has revealed genomic regions commonly affected by structural changes and a general genetic heterogeneity. VHL and PBRM1, both located at chromosome 3p, are 2 major genes mutated at high frequency but apart from these aberrations, the mutational landscape in ccRCC is largely undefined. Potential prognostic information given by the genomic changes appears to depend on the particular cohort studied. We analyzed a Swedish ccRCC cohort of 74 patients and found common changes (loss or gain occurring in >20% of the tumors) in 12 chromosomal regions (1p, 3p, 3q, 5q, 6q, 7p, 7q 8p, 9p, 9q, 10q, and 14q). A poor outcome was associated with gain of 7q and losses on 9p, 9q, and 14q. These aberrations were more frequent in metastasized tumors, suggesting alterations of genes important for tumor progression. Sequencing of 48 genes implicated in cancer revealed that only VHL, TP53, and PTEN were mutated at a noticeable frequency (51%, 9%, and 9%, respectively). Shorter relative telomere length (RTL) has been associated with loss of specific chromosomal regions in ccRCC tumors, but we could not verify this finding. However, a significantly lower tumor/nontumor (T/N) RTL ratio was detected for tumors with losses in 4q or 9p. In conclusion, poor outcome in ccRCC was associated with gain of 7q and loss on 9p, 9q, and 14q, whereas the mutation rate overall was low in a screen of cancer-associated genes.

FIGURE 1

Heat map of tumors showing chromosomes affected by a genetic change. M0 (nonmetastatic) tumors are shown in the left pane and M1 (metastatic) in the right. The color gradients going from light green/red to dark green/red represents the extent of loss/gain on each chromosome. The darkest shading equals whole chromosome loss/gain and the palest shading represent more loss than gain/more gain than loss. Black color indicates undefined change. Arrows denote 3 tumors that showed no genomic alteration.

FIGURE 2

The Kaplan-Meier analysis with disease-specific survival as endpoint in relation to genomic alterations in the 7q, 9p, 9q, and 14q regions. Survival time is shown in months and log-rank P-values are presented. A–D, Tumors containing the given genomic alteration showed a significantly decreased survival time.

FIGURE 3

Nonsynonymous and frame-shift mutations found in 48 sequenced genes. M0 (nonmetastatic) tumors are shown in the left panel and M1 (metastatic) in the right. Black squares represent a detected mutation. Arrows denote the 3 tumors that showed no genomic alteration in the single-nucleotide polymorphism (SNP) array.