The Principles of Clinical Cytogenetics - Extra Materials - Springer

438 Jonathan Fletcher
clear cell and granular carcinomas (132–134) and trisomies of various chromosomes in papillary
carcinomas (135). Likewise, most pediatric renal tumors contain characteristic cytogenetic aberrations.
Deletion of 11p is a well-known aberration in Wilms tumors, but several other aberrations,
including additional copies of chromosome 12, are more frequent and have apparent prognostic relevance
(136,137). Another pediatric renal tumor with extremely consistent cytogenetic aberrations is
mesoblastic nephroma, in which various chromosomal trisomies are associated with oncogenic fusion
of the TEL (ETV6) and NTRK3 genes on chromosomes 12 and 15, respectively (92,93).
Renal Carcinomas
Cytogenetic analyses have proven extremely useful in the diagnostic evaluation of various histological
subtypes of renal cancer, notably renal carcinomas. These differ from carcinomas in most
other organs in that they have relatively noncomplex karyotypes and have distinctive cytogenetic
profiles that correlate well with the different renal carcinoma histologies. Indeed, the architecture of
renal cell carcinomas is quite variable. Most are composed of sheets of cells, having an abundant,
clear, cytoplasm, which are arranged in trabecular or tubular patterns. However, a minority of cases
are predominantly papillary, and smaller numbers of renal carcinomas (about 5–15% of the total)
have granular, sarcomatoid, or chromophobe histologies (138). Both nonpapillary and papillary renal
cell carcinomas are associated with distinctive genetic aberrations, and the following discussion
addresses the various histologic subtypes separately.
Clear Cell and Granular Renal Cell Carcinomas
Chromosome 3p deletion is the most frequent cytogenetic aberration in clear cell and granular
nonpapillary renal cell carcinomas. This deletion was found in 70–90% of nonpapillary tumors in
some series (132,134), and loss of heterozygosity has been confirmed for several regions of 3p in a
similar percentage of cases (139). One target of the 3p deletions is the von Hippel–Lindau tumor
suppressor gene (VHL), located near the telomeric aspect of 3p (140). Von Hippel–Lindau syndrome
results from inheritance of a defective VHL allele, which predisposes to development of bilateral and
multifocal renal cell carcinomas. Furthermore, the VHL gene is mutated in at least 50% of sporadic
nonpapillary renal cell carcinomas (141,142). Another potential target of the 3p deletions in sporadic
renal cell carcinomas is the more centromeric FHIT tumor suppressor locus in band 3p14 (143). This
gene is interrupted, and presumably inactivated, by a germline chromosomal translocation that is
associated with development of renal cell carcinoma in several kindreds (144). Diagnostic evaluation
of 3p deletions is helpful in the distinction between papillary and nonpapillary renal cell carcinomas.
More than 80% of clear cell and granular nonpapillary renal cell carcinomas have 3p deletions,
whereas fewer than 10% of papillary renal cell carcinomas have such deletions. The various 3p tumor
suppressor genes are of potential therapeutic relevance, because most nonpapillary renal cell carcinomas
have mutations that inactivate genes in this region.
Although deletion of 3p is the most frequent cytogenetic aberration in clear cell and granular
nonpapillary renal cell carcinoma, several other nonrandom cytogenetic aberrations participate in the
genesis of these tumors. Nonrandom cytogenetic aberrations found in at least 10% of cases include
extra copies of 5q, trisomy 7, deletion of 17p, and loss of the Y chromosome (134). The relevance of
isolated trisomy 7, or loss of the Y chromosome, has been a matter of contention, because these same
aberrations can be demonstrated, at low levels, in non-neoplastic kidney tissues (145–147).
Chromophobe Carcinoma
Chromophobe carcinomas account for approximately 5% of renal cell carcinomas and are characterized
by pale reticular cytoplasm, positive reaction with Hale’s acid iron colloid, and ultrastructural
presence of cytoplasmic microvesicles and dysmorphic mitochondria (148). Most chromophobe carcinomas
have extremely hypodiploid karyotypes, containing 31–37 chromosomes and typically
including monosomies of chromosomes 1, 2, 6, 10, 13, 17, and 21 (149). Some chromophobe carci-