Ca. Thrashbingham et al., GENOMIC ALTERATIONS AND INSTABILITIES IN RENAL-CELL CARCINOMAS AND THEIR RELATIONSHIP TO TUMOR PATHOLOGY, Cancer research, 55(24), 1995, pp. 6189-6195
A comprehensive genome scan for loss of heterozygosity (LOH) in 33 ren
al cell carcinomas indicates that mutations of tumor suppressor genes
on several different chromosomes are required for malignant transforma
tion in this disease, In the case of nonpapillary renal carcinomas chr
omosomes 3p, 6q, 8p, 9pq, and 14q exhibit elevated levels of LOH. Alth
ough 3p is the most frequently lost chromosome arm, in no case is 3p o
bserved as the sole allelic loss because it always occurs in conjuncti
on with the loss of either 6q, 8p, or 14q, This result indicates that
the mutation of a tumor suppressor gene on 3p, most likely von Hippel-
Lindau disease (VHL), may be necessary but is not sufficient for the d
evelopment of nonpapillary renal cell carcinoma. In papillary renal tu
mors, LOH is observed most often for chromosomes 6pq, 9p, 11q, 14q, an
d 21q. This suggests that tumor suppressor genes located on chromosome
s 6q, 9pq, and 14q may be involved in the development and/or progressi
on of both nonpapillary and papillary renal cell carcinomas, However,
LOH in papillary tumors appears to be especially elevated for 11q and
21q and reduced for 3p and 8p indicating that there are also tumor sup
pressor genes specific to each form of the disease. There is no correl
ation between stage of disease and the extent of LOH, loss of a partic
ular chromosome, or the number of chromosomes that show allele inbalan
ce, Early and late stage tumors may exhibit either extensive LOB or no
apparent allele loss; similarly, allelic imbalances are observed in b
oth early and late stage renal cell carcinomas. This suggests that a g
ene (or genes) regulating mitotic chromosome stability may be mutated
in some renal tumors. Preliminary evidence points to an association be
tween genome instability and LOH of 14q. Finally, a distinct type of m
icrosatellite instability has been detected in 21% of renal cell carci
nomas and occurs at a frequency of 4.4 x 10(-4)/ locus, The most commo
n mutation is a 2-bp insertion in a CA repeat, This alteration is not
restricted to a particular histopathology or clinical stage, and it is
not associated with allelic loss of a specific chromosome, The freque
ncy of this event is similar to that which occurs spontaneously in ger
mline microsatellite loci and is probably not the result of a defect i
n a mismatch repair gene, It is possible that this type of microsatell
ite instability is general and may occur in most, if not all, carcinom
as.