From risk to survival: chromosome 3p aberrations in renal cell carcinoma Free

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Purpose: Chromosome 3p aberration is the most frequently mutated genetic region in clear cell renal cell carcinoma (RCC). Recent studies suggested that, besides the VHL gene, loss of heterozygosity (LOH) at 3p14.2-3p21 that may harbor other potential tumor suppressor genes might be an early event in RCC carcinogenesis. However, the tumorigenic significance of these genetic changes in RCC remains unknown. Benzo[a]pyrene diol expoxide (BPDE), a main metabolic product of the tobacco constituent bezo[a]pyrene, may induce chromosomal aberrations in genetic loci including 3p. We hypothesized that BPDE-induced lymphocytic 3p aberrations are biomarkers of genetic susceptibility to RCC and such aberrations in tumor tissues may also predict clinical outcome of RCC therapeutic interventions. Methods: Peripheral blood lymphocyte (PBL) cultures from 107 RCC patients and 108 matched healthy controls were treated with 2 μM BPDE for 24 hours. The 3p25, 3p21.3, 3p14.2 and 3q13 (a control locus) aberrations were assessed by fluorescence in situ hybridization (FISH). One thousand lymphocyte interphases were scored for each sample. In addition, we analyzed 67 tumor tissues using 12 microsatellite markers spanning 3p12-3p25. These data were evaluated for associations with clinicopathological features and prognosis of RCC. Results: RCC patients exhibited significantly higher number of 3p aberrations than controls in 3p25 (cases vs. controls [mean±standard deviation]: 43.7±1.2 vs. 36.7±1.4, P=0.0005), 3p21.3 (case vs. control: 43.5±8.4 vs. 38.3±7.1, P<0.0001) and 3p14.3 (34.1±10.8 vs. 30.6±7.7, P=0.0081). No significant difference was observed for 3q13. Using the 75^th percentile value of the aberrations at each locus in the controls as the cutoff point to dichotomize the subjects into high and low BPDE sensitivity, high sensitivity individuals exhibited a significantly increased risk of RCC at 3p25 (odds ratio [OR]=2.34, 95% confidence interval [CI] 1.25-4.39) and 3p21.3 (OR=3.43, 95% CI 1.83-6.45). Microsatellite analyses identified 59 (88.1%) RCC tissues exhibiting 3p LOH in at least one locus. The LOH frequency was 68.8% at 3p25, 77.3% at 3p21, 68.5% at 3p14 and 45.6% at 3p12. Additionally, low grade tumors exhibited significantly higher frequency of 3p25 LOH than high grade tumors (P=0.04), whereas no association was noted between LOH at other regions and RCC clinicopathological status. Moreover, it was observed that 3p alterations were not associated with cause-specific survival. However, the presence of 3p25 LOH was associated with a significantly longer recurrence-free survival in patients without distant metastasis (three year recurrence-free survival percentage: 95% vs. 64%, for patients with 3p25 LOH vs. patients without 3p25 LOH, long rank P=0.014). Conclusions: Chromosome 3p aberration may be a valuable biomarker to determine both the genetic susceptibility and clinical outcome of RCC. Supported by NCI grant CA98897.