Diese Präsentation wurde erfolgreich gemeldet.
Wir verwenden Ihre LinkedIn Profilangaben und Informationen zu Ihren Aktivitäten, um Anzeigen zu personalisieren und Ihnen relevantere Inhalte anzuzeigen. Sie können Ihre Anzeigeneinstellungen jederzeit ändern.
Renal Cell Carcinoma
MOLECULAR BIOLOGY
• Kidney cancer is not a single disease .
• It is classified into several histologic subtypes .
• Over the past 2 decades ...
Pathologic subtypes
• Clear cell (75 to 85 percent of tumors)
• Papillary (chromophilic) (10 to 15 percent)
• Chromophobe ...
Von Hippel-Lindau (VHL)syndrome
• Inherited, autosomal dominant syndrome .
• VHL-gene loss -somatic mutation , deletion ,
...
pVHL performs several important cellular
functions, including
• Maintenance of the primary cilium.
• Regulation of cytokin...
Systemic manifestation of VHL
• Hemangioblastomas of the central nervous
system
• Retinal hemangioblastomas
• Clear cell r...
• In sporadic renal cell cancers, inactivation
of VHL through somatic mutation of both
alleles is very common
• The VHL protein (pVHC) forms a stable
complex with several other proteins including
elongin B, elongin C, and cullin 2.
...
• Hypoxia-inducible factor-1 and 2 — Hypoxia-
inducible factor-1 alpha and 2 alpha (HIF1a and
HIF2a) are two of the major ...
Hypoxia- No hydroxylation,HIFa and HIF2a are
not bound to the VHL protein complex.
• The levels of HIF1a and HIF2a rise.
•...
Increased HIF1a and HIF2a induces
• (1) vascular endothelial growth factor (VEGF),
• (2)platelet-derived growth factor (PD...
Hereditary papillary renal carcinoma
• Type 1 papillary renal cell carcinomas (RCCs)
• HPRC gene (the MET protooncogene)
•...
• This gene codes hepatocyte growth factor
(HGF)
• It has an intracellular tyrosine kinase domain.
Mutations in MET consti...
• In patients with distant metastases or
unresectable disease, agents targeting the
MET pathway are being developed.
• A p...
Germline MET mutation analysis is
recommended
• Patients with HPRC.
• Techniques are being developed to
detect carriers of...
Birt-Hogg-Dubé (BHD) syndrome
• Inherited syndrome ,caused by mutations in the
folliculin (FLCN) gene (also known as the B...
• The FLCN gene may be involved in energy,
metabolism, and nutrient sensing through the
mammalian target of rapamycin (mTO...
• The penetrance of renal cancer in patients
with BHD is up to 30 percent .
• The histology of renal tumors in patients wi...
• Dermatologic manifestations - fibrofolliculomas,
which are benign hamartomatous tumors of hair
follicles . These whitish...
Tuberous Sclerosis
• Hereditary condition that is due to mutations in
one of two interacting tumor-suppressor gene
product...
• Less than 5 percent of patients with TSC
develop renal cell carcinoma (RCC).
• TSC-associated RCC tumors occurred at a
y...
GERMLINE MUTATIONS OF THE TRICARBOXYLIC ACID CYCLE
ENZYMES
• Inherited mutations involving enzymes of the
tricarboxylic ac...
• Two enzyme mutations have been
characterized:
• (A)Fumarate hydratase- hereditary
leiomyomatosis and RCC,
• (B) Succinat...
Papillary type 2 renal cell carcinomas
(RCCs).
• Fumarate hydratase enzyme mutations.
• Hereditary leiomyomatosis and rena...
• Succinate dehydrogenase (SDH) is comprised
of four subunits (SDHA, SDHB, SDHC, and
SDHD).
• Each subunit has been associ...
• The histologic type of kidney cancer varies.
• In most cases, pathologic analysis showed
either a clear cell or chromoph...
Testing for SDH mutations is advised
• patients with early-onset kidney cancer (ie,
age <45 years)
• Bilateral or multifoc...
• PBRM1 gene mutaion-It is also a tumor
supressor gene and located at 3p25
chromosome.
• BAPI1 gene- BRCA1 associated prot...
Ubiquitin mediated proteolysis pathway (UMPP)
• It is an important pathway for protein
degradation .
• VHL &BAP1 are membe...
Translocation associated carcinoma
• It is associated with fusion of the TFE3 gene
to a number of genes on Xp11.
• Occurs ...
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ
Nächste SlideShare
Wird geladen in …5
×

Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ

RENAL CELLL CARCINOMA BIOLOGY

  • Loggen Sie sich ein, um Kommentare anzuzeigen.

Molecular BIOLOGY OF RENAL CELL CARCINOMA BY DR.PRASHANT KUMBHAJ

  1. 1. Renal Cell Carcinoma MOLECULAR BIOLOGY
  2. 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. 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. 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. 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. 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. 7. • In sporadic renal cell cancers, inactivation of VHL through somatic mutation of both alleles is very common
  8. 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. 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. 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.
  11. 11. Increased HIF1a and HIF2a induces • (1) vascular endothelial growth factor (VEGF), • (2)platelet-derived growth factor (PDGF)- beta, • (3)transforming growth factor (TGF)-alpha increases.
  12. 12. 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.
  13. 13. • 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
  14. 14. • 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 .
  15. 15. 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 .
  16. 16. 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
  17. 17. • 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
  18. 18. • 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
  19. 19. • 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 .
  20. 20. 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.
  21. 21. • 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.
  22. 22. 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.
  23. 23. • Two enzyme mutations have been characterized: • (A)Fumarate hydratase- hereditary leiomyomatosis and RCC, • (B) Succinate dehydrogenase-hereditary paraganglioma , pheochromocytoma, and rarely, RCC
  24. 24. 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
  25. 25. • 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 .
  26. 26. • The histologic type of kidney cancer varies. • In most cases, pathologic analysis showed either a clear cell or chromophobe type RCC
  27. 27. 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 .
  28. 28. • 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 .
  29. 29. 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 .
  30. 30. 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).

×