Affiliations of authors: A. Geurts van Kessel, H. Wijnhoven, D. Bodmer, M. Eleveld, M. Weterman, M. Ligtenberg, D. Smeets, A. Smits (Department of Human Genetics), L. Kiemeney (Departments of Epidemiology and Urology), P. Mulders (Department of Urology), University Hospital Nijmegen, The Netherlands.
Correspondence to: Ad Geurts van Kessel, Ph.D., Department of Human Genetics, University Hospital, P. O. Box 9101, 6500 HB Nijmegen, The Netherlands.
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).
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 patient in family #4 with t(3;4)(p13;p16). Based on the age- and
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 = 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 in the literature (Fig. 1
;
unpublished and published, respectively) indicate that the overall incidence of RCC in
chromosome 3 translocation families is strikingly high, in particular, when taking into account
the fact that our series includes several small families with only a few translocation carriers at a
relatively young age (i.e., #5, #7, #8, and #9) and the expected wide range in penetrance as based
on the concept of somatic mosaicism (7). Another interesting observation
is that the familial translocations at risk exhibit breakpoints in the proximal p- and q-arms of
chromosome 3. Taking into consideration the fact that the 3p-arm is thought to harbor several
tumor suppressor loci relevant to RCC development (positioned in the region 3p25-p14) (9), one might speculate that breakpoints more distal on 3p (#1 and #2)
may interfere with the above-mentioned two-step model. In analogy, distal breakpoints on 3q (#9
and #10) would, according to the proposed twostep model, lead to somatic loss of the major part
of chromosome 3. Such a loss may not be compatible with the survival of (renal) epithelial cells,
thus explaining the absence of RCCs in this set of families. This latter suggestion is in full
agreement with observations made in sporadic cases of RCC (10).
Alternative options are that mitotic recombination (11) and/or genes
located at or near the pericentromeric chromosome 3 translocation breakpoints [e.g., the
fragile histidine triad gene (12)] may play a critical role(s) in tumor
development.
|
NOTES
Supported by the Dutch Kidney Foundation.
We thank the members of the Division of Cytogenetics for their expert technical assistance. We also thank H. R. Oosten, M. I. Koolen, E. van den Berg, and R. F. Suijkerbuijk for their advice and support.
REFERENCES
1
Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335:865-75.
2 Gnarra JR, Lerman MI, Zbar B, Linehan WM. Genetics of renal cell carcinoma and evidence for a critical role for von Hippel-Lindau in renal tumorigenesis. Semin Oncol 1995;22:3-8.[Medline]
3 Cohen AJ, Li FP, Berg S, Marchetto DJ, Tsai S, Jacobs SC, et al. Hereditary renal-cell carcinoma associated with a chromosomal translocation. N Engl J Med 1979;301:592-5.[Medline]
4 Kovacs G, Brusa P, De Riese W. Tissue-specific expression of a constitutional 3;6 translocation: development of multiple bilateral renal-cell carcinomas. Int J Cancer 1989;43:422-7.[Medline]
5 Kovacs G, Hoene E. Loss of der(3) in renal carcinoma cells of a patient with constitutional t(3;12). Hum Genet 1988;78:148-50.[Medline]
6 Koolen MI, van der Meyden AP, Bodmer D, Eleveld M, van der Looij E, Brunner H, et al. A familial case of renal cell carcinoma and a t(2;3) chromosome translocation. Kidney Int 1998;53:273-5.[Medline]
7 Bodmer D, Eleveld M, Ligtenberg MJ, Weterman MA, Janssen BA, Smeets DF, et al. An alternative route for multistep tumorigenesis in a novel case of hereditary renal cell cancer and a t(2;3)(q35;q21) chromosome translocation. Am J Hum Genet 1998;62:1475-83.[Medline]
8 Visser O, Coebergh JW, Schouten LJ. Incidence of cancer in The Netherlands. Utrecht (The Netherlands): Netherlands Cancer Registry; 1997.
9 van den Berg A, Buys CH. Involvement of multiple loci on chromosome 3 in renal cell cancer development. Genes Chromosomes Cancer 1997;19:59-76[Medline]
10 Meloni AM, Bridge J, Sandberg AA. Reviews on chromosome studies in urological tumors. I. Renal tumors. J Urol 1992;148(2 Pt 1):253-65.[Medline]
11 Kovacs G, Kung HF. Nonhomologous chromatid exchange in hereditary and sporadic renal cell carcinomas. Proc Natl Acad Sci U S A 1991;88:194-8.[Abstract]
12 Ohta M, Inoue H, Cottocelli MG, Kastury K, Baffa R, Palazzo J, et al. The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal cell carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell 1996;84:587-97.[Medline]
Manuscript received March 4, 1999; accepted May 7, 1999.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |