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Int. J. Cancer: 77, 494–497 (1998)
r 1998 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
GENETIC ANALYSIS OF 2 CASES OF CLEAR CELL RENAL CANCER
IN 2 SISTERS
Siebe D. BOS1*, Eva VAN DEN BERG2, Trynie DIJKHUIZEN2, Anke VAN DEN BERG2, Tineke G. DRAAIJERS2 and Han J.A. MENSINK3
1Department of Urology, Medical Centre Alkmaar, Alkmaar, The Netherlands
2Department of Medical Genetics of the University of Groningen, Groningen, The Netherlands
3Department of Urology, University Hospital Groningen, Groningen, The Netherlands
Two sisters affected with renal cell carcinoma (RCC) is an
extremely rare finding, and may indicate a hereditary pattern
or the presence of other predisposing factors. We describe
here 2 sisters presenting with clear cell renal cell cancer.
Examination for von Hippel-Lindau (VHL)-related features
and tuberous sclerosis (M. Bourneville) was negative and both
had a normal constitutional karyotype. Cytogenetic analysis
of the tumor tissue of both patients showed a translocation
involving chromosomes 3 and 5, resulting in loss of 3p
sequences and gain of part of 5q. The 5q breakpoints were
similar, but the breakpoints at 3p appeared to differ. Allelic
imbalance analysis supported our observations. Microsatellite analysis revealed that both sisters inherited different
chromosome 3 parental alleles. For chromosome 5, 3 different haplotypes could be deduced, but the chromosome 5
alleles overrepresented in the different tumor tissues were
from different parental origin. The development of the 2
RCCs in these 2 sisters thus cannot be explained by the
inheritance of a mutated VHL gene located at 3p25, nor by the
inheritance of other gene defects at chromosomes 3p or 5q.
Although the chance that 2 sisters develop sporadic RCC is
very low, in the presented case it is probably coincidental or
related to another genetic predisposition. Int. J. Cancer 77:494–
497, 1998.
r 1998 Wiley-Liss, Inc.
Renal cell cancer (RCC) accounts for 85% of all malignant
neoplasms of the kidney. Of all adult malignancies, 2–3% are
RCCs. The annual incidence in the general population is 7.5 per
100,000 and there is a male to female ratio of 2:1. Clear cell RCC,
responsible for 75% of RCC and originating in the proximal tubule
of the nephron, is characterized by deletions of the short arm of
chromosome 3 (Yamakawa et al., 1991; Foster et al., 1994;
Lubinski et al., 1994; van den Berg et al., 1996). Evidence is
accumulating that different regions at 3p are involved in the
development of these tumors (van den Berg et al., 1997). Trisomy
of 5q is the second most common aberration in clear cell RCC and
often arises concurrent with loss of 3p sequences by the formation
of an unbalanced t(3;5). Gain of the smallest overlapping region at
5q22 is important in the development of these tumors as well
(Kenck et al., 1997).
Most cases of RCC are sporadic in origin. Familial or inherited
forms of RCC account for 1–2% of RCC cases (Griffin et al.,
1967). These are characterized by a frequent bilateral and/or
multicentric appearance and an early age of onset. The most
common hereditary form of RCC is associated with the dominantly
inherited von Hippel Lindau (VHL) disease. The VHL gene, located
at 3p25, has been cloned, mutations of which have been detected in
VHL patients as well as in sporadic clear cell RCC (Gnarra et al.,
1994, 1996; Shuin et al., 1994; Foster et al., 1994; Latif et al.,
1993). RCC families with constitutionally balanced translocations
between chromosomes 3 and 6 or 8 have also been described
(Cohen et al., 1979; Kovacs et al., 1989).
The incidence of ‘‘pure’’ familial RCC with no VHL or other
predisposing genetic syndromes is extremely low. Until now, only
39 family aggregates of RCC have been reported (Yao and Shuin,
1995), but the true incidence probably should be higher, due to the
fact that not all cases are reported. Environmental factors contributing to the development of RCC are poorly understood but smoking,
particularly in men, and obesity, especially in women, have been
related to RCC development (Mellemgaard et al., 1995; McLaughlin et al., 1995). Occupational exposure to various hydrocarbons
and asbestos also increases the risk of having this disease (Mandel
et al., 1995). A higher incidence of RCC is also found in patients
with tuberous sclerosis, acquired cystic kidney disease and endstage renal disease.
We describe here 2 sisters presenting with clear cell RCC. Both
patients were examined for VHL-related features and tuberous
sclerosis. Genetic analysis was performed on tumor and normal
kidney tissue of both patients in an attempt to find a hereditary
cause.
MATERIAL AND METHODS
A 51-year-old woman, without antecedents of smoking or
obesity, was referred to our outpatient department with a right
kidney tumor. The tumor was found during an abdominal hysterectomy for menorrhagia and dysmenorrhoea due to adenomyosis.
The kidney tumor was asymptomatic. Laboratory findings were
normal. A radical transabdominal nephrectomy with regional
lymph node dissection was performed and reconvalescence was
uneventful. On pathological examination, a RCC of the clear cell
type was found with one unifocal lesion, stage pT2N0M0 (Harmen
and Sobin, 1992). After a follow-up of 60 months, there is no
evidence of disease.
Her sister, 59 years old, also non-smoking and not obese, was
evaluated for nausea and vomiting and, on ultrasound, a tumor in
the left kidney was found. Laboratory findings were normal. We
performed a transabdominal nephrectomy with regional lymph
node dissection. Reconvalescence was uneventful. A unifocal RCC
of the clear cell type was found on pathological investigation, stage
pT2N0M0. After a follow-up of 16 months, there is no evidence of
disease.
Because of the rarity of such spontaneous development of RCC
in 2 sisters, both were examined for features of VHL disease, i.e.,
retinal hemangiomas, cerebellar, medullary or spinal hemangioblastomas, and pheochromocytoma. Neither had any of these features.
Screening for signs of tuberous sclerosis was also negative. No
further cases of RCC, up to the third degree of relatives, or other
VHL-associated tumors, were found in this family.
Fresh representative samples of normal and tumor tissue of both
patients were submitted to cytogenetic investigation. One part of
the tissue was cultured for 5–7 days in RPMI 1640 supplemented
with fetal calf serum (FCS) (16%), glutamine and antibiotics. The
cultures were harvested and chromosome preparations were made
according to standard cytogenetic techniques. The chromosomes
were G-banded using pancreatin, and karyotypes were described
according to the ISCN ’95 guidelines for cancer cytogenetics
(Mitelman, 1995).
Allelic imbalance analysis was carried out as described previously (van den Berg et al., 1996). Primer sequences and polymer*Correspondence to: Department of Urology, Medical Centre Alkmaar,
Wilhelminalaan 12, 1815 JD Alkmaar, The Netherlands. Fax: (31) 72-5482605. E-mail: [email protected]
Received 1 October 1997; Revised 13 February 1998
GENETICS OF CLEAR CELL RCC
ase chain reaction (PCR) conditions were retrieved from the
Genome Data Base, Johns Hopkins University, Baltimore, MD.
RESULTS
Cytogenetic analysis of the tumor tissue of both patients was
carried out. Case 1 revealed a 44,47,XX,1X, del(1)(p36),der(3)t(3;
5)(p11;q22)[cp3]/82,84,idemx2,-X,-8,-16[cp3] chromosomal pattern (Fig. 1). The composite karyotype of case 2 was 46,47,XX,
der(3)t(3;5)(p12;q22),1der(7)t(7;10)(p13;p11),add(13)(q34)[cp3] (Fig.
2). Both patients had a normal 46,XX constitution.
The RCC of case 1 showed allelic imbalance for 9 informative
markers, mapping in the 3p11-pter region (Table I). Retention of
alleles was detected for D3S1101 mapping more proximal in 3p11.
The markers D3S1317, D3S1007, D3S1029, D3S1480, D3S1210,
D3S1511, D3S1577, D3S1254, D3S276, D3S1595 and D3S1251
were all not informative. The RCC of case 2 showed allelic
imbalance for 7 informative markers, mapping in the 3p12-pter
region (Table I). Retention of alleles was detected for 2 markers,
D3S1552 and D3S1101, mapping more proximal. The same 11
markers, not informative for case 1, and D3S1217, were not
informative in case 2.
Cytogenetic analysis indicated the presence of one apparently
normal copy of chromosome 3 and one derivative chromosome 3
with loss of the distal part. This indicated that the allelic losses as
detected upon microsatellite analysis all involved the same parental
allele. Haplotypes thus can be deduced based on these loss of
heterozygosity (LOH) analyses; alleles that were retained in the
tumor most likely originated from one parental allele and alleles
that were lost in the tumor most likely originated from the other
parental allele. The haplotypes for both sisters are shown in Table II.
495
Cytogenetic analysis has indicated the presence of an extra copy
of the q-arm of chromosome 5 for both RCC samples. Allelic
imbalance analysis using 3 5q markers confirmed the cytogenetically observed gain (Table I). These results were used to deduce the
chromosome 5 haplotypes assuming that the overrepresented
marker alleles originated from one parental allele (Table II).
DISCUSSION
RCC is a heterogeneous group of tumors that constitutes 2–3%
of all cancers in adults. The chance that 2 sisters develop RCC
without hereditary or other predisposing factors is therefore
extremely rare. We encountered 2 sisters affected with clear cell
RCC. Neither the patients nor their family history revealed signs or
symptoms of VHL disease or tuberous sclerosis. In an attempt to
find evidence for a hereditary predisposition we performed a
genetic analysis on normal and tumor tissue of both patients.
Hereditary RCC is associated with mutations of the VHL gene or
with the presence of a constitutionally balanced translocation
involving chromosome 3. The constitutional karyotype of our 2
patients revealed a normal 46,XX chromosomal pattern. Karyotypes of tumor cells of both patients showed a t(3;5). The
breakpoints at chromosome 5 were similar but the breakpoints at
chromosome 3 slightly differed. For the latter, allelic imbalance
analysis with markers mapping all over the p-arm indicated loss of
the distal part of 3p in both tumors. In case 1, loss of markers was
found in 3p11-pter and in case 2, loss of markers was found in
3p12-pter, confirming the cytogenetically observed differences in
chromosome 3 breakpoints.
To investigate whether or not both sisters inherited the same
chromosome 3 and/or 5 parental alleles, including a putative
mutation, allelic imbalance analysis for both chromosomes was
FIGURE 1 – Representative karyotype of case 1 showing a 47,XX,1X,del(1)(p36),der(3)t(3;5)(p11;q22) chromosomal pattern. Structural
rearrangements are indicated by arrows.
BOS ET AL.
496
FIGURE 2 – Representative karyotype of case 2 showing a 47,XX,der(3)t(3;5)(p12;q22),1der(7)t(7;10)(p13;p11),add(13)(q34) chromosomal
pattern. Structural rearrangements are indicated by arrows.
TABLE I – RESULTS OF CHROMOSOME 3- AND 5-SPECIFIC
MICROSATELLITE ANALYSIS1
Chromosome
band
3p25
3p21
3p14
3p13
3p12
3p11
5q22-q23
5q31.1-33.3
5q33.2-33.3
Marker
D3S1038
D3S643
D3S1481
D3S1233
D3S1217
D3S1284
D3S1274
D3S1776
D3S1552
D3S1101
D5S421
D5S210
C5F1R
Case 1
1
1
1
1
1
1
1
1
2
2
1
1
1
(1*/2)
(1/2*)
(2*/3)
(2*/3)
(1/2*)
(1/2*)
(1*/2)
(1*/2)
(1/2)
(1/2)
(1*/3)
(2*/3)
(1*/2)
Case 2
1
1
1
1
1
1
1
1
1
2
1
1
1
(1/2*)
(1*/2)
(1*/2)
(1*/3)
(n.i.)
(1*/2)
(1/2*)
(1/2*)
(1/2*)
(1/2)
(2/3*)
(1/3*)
(1/2*)
1Markers have been placed in their most likely order according to
published mapping data (for chromosome 3, see Naylor et al., 1996;
chromosome 5 markers are according to the Genome Data Base, Johns
Hopkins University, Baltimore, MD). 1: allelic imbalance; 2: no
allelic imbalance; *: alleles under/overrepresented in the tumor; n.i.:
not interpretable.
performed. Haplotypes were determined, assuming that imbalances
of marker alleles were confined to the same parental chromosomes.
For chromosome 3, 4 different haplotypes were observed, indicating that both sisters inherited different paternal and maternal
chromosome 3 alleles. It is thus very unlikely that these tumors
developed as part of a hereditary VHL disease or other gene defects
at 3p. Surprisingly, taking into account the reported heterozygosity
frequencies for the 3p markers used in our study, for both sisters,
about half of the markers were homozygous for the same allele. In
TABLE II – DEDUCED CHROMOSOME 3 AND 5 HAPLOTYPES
FOR THE TWO SISTERS1
Marker
D3S1038
D3S643
D3S1481
D3S1233
D3S1217
D3S1284
D3S1274
D3S1776
D3S1552
D5S421
D5S210
C5F1R
1*:
Chromosome
band
3p25
3p21
3p14
3p13
3p12
5q22-q23
5q31.1-5q33.3
5q33.2-5q33.3
Case 1
Case 2
Allele 1*
Allele 2
Allele 1*
Allele 2
1
2
2
2
2
2
1
1
2
1
3
3
1
1
2
2
1
2
1
3
3
2
2
1
1
3
1
1
2
2
2
3
3
2
1
2
2
1
1
2
1
1
1
2
1
1
alleles over/underrepresented in the tumor.
addition, a higher degree of resemblance between the marker
alleles was observed than may be expected. Genealogical investigation, however, failed to reveal consanguinity for at least 5
generations. For chromosome 5, 3 different haplotypes could be
observed, indicating that both sisters had inherited one different
allele and one identical allele (allele 2 of case 1 and allele 1 of case
2). The chromosome 5 alleles overrepresented in the tumors were
of different parental origin. Therefore, most likely, chromosome 5q
also does not carry a heritable mutation responsible for the
development of clear cell RCC in these patients.
Taken together, the finding of clear cell RCC in the present 2
sisters is probably coincidental. Furthermore, neither the 2 patients,
nor their family history, revealed signs or symptoms of VHL
GENETICS OF CLEAR CELL RCC
disease or tuberous sclerosis. There were no known environmental
risk factors such as smoking or obesity in either sister. We cannot,
however, rule out the presence of other environmental risk factors
497
for these 2 sisters, who are living in the same rural area, since the
knowledge of the influence of environmental factors on the
development of (clear cell) RCC is limited.
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