Renal Cell Cancer: Chromosome 3 Translocations as Risk Factors
Authors: A. G. van Kessel, H. Wijnhoven, D. Bodmer, M. Eleveld, L. Kiemeney, P. Mulders, M. Weterman, M. Ligtenberg, D. Smeets, A. Smits
Journal: JNCI Journal of the National Cancer Institute (1999)

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 posi t ion 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 a l l e l e seg rega t ion and loss -o f 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). As a corollary of this model, we set out to evaluate whether familial chromosome 3 translocations may predispose to RCC development, irrespective of the location of the breakpoint in chromosome 3 and/or the translocation partner involved. Therefore, a series of 10 translocation families (Fig. 1, #1 to #10), referred to our Department of Human Genetics for other disorders and characterized by cytogenetic analysis as detailed earlier (6), was evaluated by use of written questionnaires and, if required, oral interviews. Relevant information could be obtained from a total of 57 chromosome 3 translocation carriers (>25 years of age; others excluded). Within this cohort, four patients (one male and three females; age range, 51– 62 years) with clinically confirmed RCC of the clear cell type were encountered in two different families, three patients in family #6 with t(3;6)(q12;q15) and one pa t i en t in fami ly #4 wi th t(3;4)(p13;p16). Based on the ageand sex-specific incidences of RCC in the Dutch population (8), only 0.204 cases of RCC were expected among the carriers. The incidence in this cohort is, therefore, increased with a factor of 19.6 (95% confidence interval 4 5.3–50.2). In families #1, #2, #3, and #10, eight, six, nine, and four translocation carriers over three generations were identified, respectively. In families #5, #7, #8, and #9, one, one, two, and three translocation carriers were identified, respectively, the majority of them (five) being between 27 and 34 years of age. Based on the anamnestic information obtained by the questionnaires, none of them had RCC. These data and the data reported