Eble JN, Sauter G., Epstein JI, Sesterhenn IA - iarc

Genetics
The first family was described by Cohen
et al. {476} with 10 RCC patients over 4
generations. All patients were carriers of
a t(3;8)(p14;q24). In a second RCC family
a t(3;6)(p13;q25) was found to segregate
and, as yet, only one person in the
first generation developed multiple bilateral
RCCs {1371}. Additionally, a single
sporadic case with a constitutional
t(3;12)(q13;q24) was reported {1374}.
Seven families have now been reported;
translocations are different but in all families
the breakpoints map to the proximal
p-and q-arms of chromosome 3.
Affected family members carry a balanced
chromosomal translocation involving chromosome
3. The mode of inheritance is
autosomal dominant. Translocations vary
among different families and this may affect
penetrance. Loss of the derivative chromosome
3 through genetic instability is considered
the first step in tumour development,
resulting in a single copy of VHL. The
remaining VHL copy may then be mutated
or otherwise inactivated. However, this
mechanism involving VHL is hypothetical
as affected family members do not develop
extra-renal neoplasms or other VHL manifestations.
The identification of at least 7 families
strongly supports the notion that constitutional
chromosome 3 translocations
may substantially increase the risk to
develop renal cell carcinoma and this
should be taken into account in the
framework of genetic counselling.
Fig. 1.15 Diagram of chromosome 3 with seven constitutional chromosome 3 translocations and the respective
breakpoint positions (left). On the right side, breakpoint frequencies (%) of chromosome 3 translocations
in 93 Dutch families are shown (grey bars), in addition to somatic chromosome 3 translocations in 157
sporadic RCCs (black bars). From F. van Erp et al. {2695}.
22 Tumours of the kidney