Renal Cell Carcinoma

MOLECULAR BIOLOGY

• 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.

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)

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.

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.

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

• 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.

• This VBC complex targets several proteins for proteasomal degradation, thereby regulating their levels within the cell

• 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.

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.

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.

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.

• 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

• 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 .

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 .

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

• 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

• 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

• 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 .

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.

• 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.

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.

• Two enzyme mutations have been characterized:

• (A)Fumarate hydratase- hereditary leiomyomatosis and RCC,

• (B) Succinate dehydrogenase-hereditary paraganglioma , pheochromocytoma, and rarely, RCC

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

• 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 .

• The histologic type of kidney cancer varies.

• In most cases, pathologic analysis showed either a clear cell or chromophobe type RCC

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 .

• 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 .

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 .

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).