2. • Kidney cancer is not a single disease .
• It is classified into several histologic subtypes .
• Over the past 2 decades studies of families
with inherited carcinoma enabled the
identification of five inherited renal cancer
syndromes and their predisposing genes.
3. Pathologic subtypes
• Clear cell (75 to 85 percent of tumors)
• Papillary (chromophilic) (10 to 15 percent)
• Chromophobe (5 to 10 percent)
• Oncocytic (3 to 7 percent)
• Collecting duct (Bellini's duct) (very rare)
4. Von Hippel-Lindau (VHL)syndrome
• Inherited, autosomal dominant syndrome .
• VHL-gene loss -somatic mutation , deletion ,
hypermethylation of its promoter.
• The von Hippel-Lindau (VHL) gene located on chromosome
3p25
• Its gene product, pVHL, functions as a tumor suppressor
protein.
5. pVHL performs several important cellular
functions, including
• Maintenance of the primary cilium.
• Regulation of cytokines .
• Control of microtubule function.
• Extracellular matrix integrity.
• Regulation of the cell cycle.
6. Systemic manifestation of VHL
• Hemangioblastomas of the central nervous
system
• Retinal hemangioblastomas
• Clear cell renal cell carcinomas (RCCs)
• Pheochromocytomas
• Endolymphatic sac tumors of the middle ear
• Serous cystadenomas and neuroendocrine
tumors of the pancreas
• Papillary cystadenomas of the epididymis and
broad ligament
7. • In sporadic renal cell cancers, inactivation
of VHL through somatic mutation of both
alleles is very common
8. • The VHL protein (pVHC) forms a stable
complex with several other proteins including
elongin B, elongin C, and cullin 2.
• This VBC complex targets several proteins for
proteasomal degradation, thereby regulating
their levels within the cell
9. • Hypoxia-inducible factor-1 and 2 — Hypoxia-
inducible factor-1 alpha and 2 alpha (HIF1a and
HIF2a) are two of the major proteins regulated by
pVHL.
• In the presence of normal oxygen tension, HIF1a
and HIF2a are enzymatically hydroxylated and
rapidly degraded by proteasomes by pVHL.
10. Hypoxia- No hydroxylation,HIFa and HIF2a are
not bound to the VHL protein complex.
• The levels of HIF1a and HIF2a rise.
• Resulting in increased mRNA transcription of a
variety of proteins, thus inducing a physiologic
angiogenic response.
14. Hereditary papillary renal carcinoma
• Type 1 papillary renal cell carcinomas (RCCs)
• HPRC gene (the MET protooncogene)
• Located on the long arm of chromosome 7
• HPRC is a highly penetrant, autosomal
dominant .
• Both early and late onset form exist .
• Multifocal and bilateral,hypovascular and
grow slowly on imaging.
15. • This gene codes hepatocyte growth factor
(HGF)
• It has an intracellular tyrosine kinase domain.
Mutations in MET constitutively activate the
tyrosine kinase domain of this protein in
patients with HPRC
16. • In patients with distant metastases or
unresectable disease, agents targeting the
MET pathway are being developed.
• A phase II multicenter study of the
dual MET/vascular endothelial growth factor
receptor-2 inhibitor,foretinib demonstrated a
response in 5 out of 10 patients with HPRC .
17. Germline MET mutation analysis is
recommended
• Patients with HPRC.
• Techniques are being developed to
detect carriers of germline mutations in
family members of patients with HPRC .
18. Birt-Hogg-Dubé (BHD) syndrome
• Inherited syndrome ,caused by mutations in the
folliculin (FLCN) gene (also known as the BHD
gene).
• Development of bilateral, multifocal kidney
cancer, as well as various dermatologic and
pulmonary lesions .
• Localized to the short arm of chromosome 17 .
• FLCN is a loss-of-function, tumor suppressor
gene
19. • The FLCN gene may be involved in energy,
metabolism, and nutrient sensing through the
mammalian target of rapamycin (mTOR)
pathway.
• The folliculin-interacting protein, FNIP1,
interacts with 5' AMP-activated protein kinase
(AMPK), a key molecule for energy sensing to
negatively regulate mTOR activity
20. • The penetrance of renal cancer in patients
with BHD is up to 30 percent .
• The histology of renal tumors in patients with
BHD syndrome varies. Tumors containing a
mixed pattern of chromophobe and oncocytic
renal cancer are typical, but other histologies
may be present
21. • Dermatologic manifestations - fibrofolliculomas,
which are benign hamartomatous tumors of hair
follicles . These whitish papules are most
common on the nose and cheeks and typically
are first observed around age 20 years.
• Pulmonary manifestations-Multiple pulmonary
cysts on computed tomography (CT) of the lungs
. Spontaneous pneumothorax may be seen in up
to one-fourth of patients .
22.
23.
24.
25.
26. Tuberous Sclerosis
• Hereditary condition that is due to mutations in
one of two interacting tumor-suppressor gene
products, hamartin (TSC1) or tuberin (TSC2).
• The clinical manifestations include bilateral,
multifocal renal lesions, which typically are
angiomyolipomas.
• The predominant management issue for patients
with TSC is the risk of growth and bleeding from
the renal angiomyolipoma.
27. • Less than 5 percent of patients with TSC
develop renal cell carcinoma (RCC).
• TSC-associated RCC tumors occurred at a
younger age than sporadic tumors and
occurred primarily in women.
• Most tumors displayed clear cell histology.
28.
29.
30. GERMLINE MUTATIONS OF THE TRICARBOXYLIC ACID CYCLE
ENZYMES
• Inherited mutations involving enzymes of the
tricarboxylic acid (Krebs) cycle.
• Associated with aggressive forms of renal cell
carcinoma (RCC) that have a propensity to
metastasize even at a small size (<1 cm).
• Therefore, early surgical intervention is
warranted, even for very small tumors.
31. • Two enzyme mutations have been
characterized:
• (A)Fumarate hydratase- hereditary
leiomyomatosis and RCC,
• (B) Succinate dehydrogenase-hereditary
paraganglioma , pheochromocytoma, and
rarely, RCC
32. Papillary type 2 renal cell carcinomas
(RCCs).
• Fumarate hydratase enzyme mutations.
• Hereditary leiomyomatosis and renal cell
cancer (HLRCC) - cutaneous and uterine
leiomyomas, and/or papillary type 2 renal cell
carcinomas (RCCs).
• This syndrome is also called the multiple
cutaneous and uterine leiomyomatosis
syndrome (MCUL1) or Reed's syndrome
33.
34.
35. • Succinate dehydrogenase (SDH) is comprised
of four subunits (SDHA, SDHB, SDHC, and
SDHD).
• Each subunit has been associated with cases
of RCC .
• SDH-associated RCC presents at an early age ,
although the age at diagnosis ranges from 24
to 73 years .
36. • The histologic type of kidney cancer varies.
• In most cases, pathologic analysis showed
either a clear cell or chromophobe type RCC
37. Testing for SDH mutations is advised
• patients with early-onset kidney cancer (ie,
age <45 years)
• Bilateral or multifocal tumors.
• Family history of pheochromocytoma or
paraganglioma and kidney cancer .
38.
39.
40. • PBRM1 gene mutaion-It is also a tumor
supressor gene and located at 3p25
chromosome.
• BAPI1 gene- BRCA1 associated protein
(BAP1),located at 3p.It is a part of large
ubiquitin mediated proteolysis pathway .
41. Ubiquitin mediated proteolysis pathway (UMPP)
• It is an important pathway for protein
degradation .
• VHL &BAP1 are member of this pathway.
• Alteration in this pathway lead to similar
consequences as VHL inactivation .
42. Translocation associated carcinoma
• It is associated with fusion of the TFE3 gene
to a number of genes on Xp11.
• Occurs at a younger age in advanced stage.
• It acts more aggresively.
• It shows activation of microphthalmia
associated transcription factor(MITF).
