Renal Cell Cancer: Chromosome 3 Translocations as Risk Factors

Renal cell cancer (RCC) is relatively rare, with overall incidence rates of approximately five per 100 000 ( 1 ). The disease can be cured only by surgery if detected early and clinically restricted to the organ, that is, without metastasis. Usually, RCCs occur as sporadic tumors, but hereditary RCCs have also been reported in particular as a consequence of von Hippel-Lindau (VHL) disease ( 2 ). Until recently, two families with RCC and with balanced chromosomal translocations were reported. In the first family, a constitutional translocation t(3;8)(p14;q24) (i.e., a genetic exchange between position p14 of chromosome 3 and position q24 of chromosome 8) was found in several family members, including 10 patients with RCC ( 3 ). In the second family, a constitutional t(3;6)(p13;q25) was found in three consecutive generations. As yet, only the oldest member of this family developed bilateral RCC ( 4 ). In addition, a single sporadic case of RCC has been reported carrying a constitutional t(3;12)(q13;q24) ( 5 ). Recently, we added another hereditary case to this list, a t(2;3)(q35;q21) in several family members over three generations, including four patients with RCC ( 6 ). Via allele-segregation and loss-of-heterozygosity analyses in this family, a modification of the standard two-step model of tumorigenesis was proposed in which the initial event, loss of the translocation-derivative chromosome 3 through nondisjunction, was predicted to lead to chromosomal mosaicism ( 7 ). Subsequently, cells lacking this chromosome might have a second hit in the form of a random somatic mutation that initiates tumorigenesis. In support of this model, it was found that the VHL gene, which maps to this chromosome, carried different mutations in different RCCs, even in tumors from the same individual. In addition, it was hypothesized that the risk of developing RCC could be associated with the extent of somatic (kidney) mosaicism resulting from the initial chromosomal loss ( 7 ).