RENAL CELL CARCINOMA
GENETIC BASIS
BACKGROUND
• 3% of adult malignancies
• 90-95% of neoplasms arising from the
kidney [tissue of origin - proximal renal
tubular epithelium]
• Lack of early warning signs, diverse clinical
manifestations
• Resistance to radiation and chemotherapy,
infrequent but reproducible responses to
immunotherapy viz. IFN-alpha and IL-2
• Targeted therapy [anti angiogenic]
Genetics
• structural alterations of ch.3p
• tumor suppressors (VHL, TSC) or
oncogenes (MET)
• 4 hereditary syndromes associated:
1. von Hippel-Lindau (VHL) syndrome,
2. hereditary papillary renal carcinoma (HPRC),
3. familial renal oncocytoma (FRO) associated with
Birt-Hogg-Dube syndrome (BHDS), and
4. hereditary renal carcinoma (HRC).
von Hippel-Lindau syndrome
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Autosomal dominant
Multiple cancers
RCC in nearly 40% of patients
del (3p) or t (3;6) or t (3;8) => VHL gene
(3p26-p25) mutated => accumulation of
hypoxia inducible factors (HIFs) that
stimulate angiogenesis through VEGF and
VEGFR
Hereditary papillary renal
carcinoma
• AD
• bilateral, multifocal papillary renal
carcinoma
• Germline missense mutations in the
tyrosine kinase domain of the MET gene
(7q31) => constitutive activation
• TFE3 mutation
• t(X;1)(p11;q21)
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Papillary renal cell tumours divided into two
groups
1. Tumours with a combined trisomy of
chromosomes 7 and 17 as well as loss of the Y
chromosome are papillary renal cell adenomas
2. Tumours with additional trisomies such as
trisomy 16, 20 or 12 are papillary renal cell
carcinomas
3. Chromophobe renal cell carcinomas show a
combination of allelic losses, which do not
occur in other types of renal tumours
MET
• β-subunit of c-Met product is the cellsurface receptor for hepatocyte growth
factor
• amplified during the transition between
primary tumors and metastasis
• metastatic potential relies on the
properties of its multifunctional docking
site
• PRC commonly show trisomy of ch.7
Familial renal oncocytoma
• usually benign tumors
• Ultrastructural characterization exhibits
dense packing of the cells with
mitochondria that show morphologic
differences from those in normal cells
[larger, abnormally shaped]
• Mutation in mtDNA within the CyC oxidase
subunit I gene
FRO
• do not show loss of alleles at loci on 3p
• Loss of ch.1 and ch.Y represent at least 1
subset of oncocytomas.
• Rearrangements involving 11q13
characterize another subset
BIRT-HOGG-DUBE SYNDROME
• BHD gene 17p11.2 [TS]
• Adult onset
• male-to-male transmission
Molecular markers for RCC
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Not very well characterised
1. CAIX – VHL mediated
For patients with nonmetastatic RCC and at high
risk for progression, low CAIX predicts worse
outcome
Overall expression of CAIX with development of
metastasis
2. Alpha-methylacyl-CoA racemase
– significant increase of AMACR mRNA levels
in papillary renal cell carcinomas only
– Also molecular marker for prostate cancer
3. B7-H1
– expression may indicate worse survival,
possibly through impaired host antitumor
immunity
4. Microsatellite instabilities
General Diagnosis
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Immunohistochemistry
Biochemical analysis
Molecular techniques – microarray, PCR
Cytogenetics – Karyotyping, FISH
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RCC
Use?
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Staging
Prognostic marker
Differential diagnosis of RCC subtypes
Pattern of DNA alterations in urine, but not
serum, found in benign renal masses - basis
to help differentiate malignant from benign
tumors and identify patients who might
benefit from a watchful waiting approach
• Likely target for therapy
Questions?