GTS5:Hereditary papillary renal carcinoma (MET)

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Primary Author(s)*

Farid Ullah, MS, PhD

WHO Classification of Disease

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Structure	Disease
Book
Category
Family
Type
Subtype(s)

Related Terminology

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Definition/Description of Disease

Hereditary papillary renal cell carcinoma (HPRCC) is an autosomal dominant syndrome characterized by the occurrence of bilateral and multifocal, classic type papillary renal cell carcinomas. In 1994, Zbar and colleagues first described HPRCC in a family spanning three generations with 9 of 15 members who presented with bilateral papillary renal cell neoplasms. Subsequently, 41 patients in 10 families affected with papillary renal cell carcinomas were reported from the same group. HPRCC manifests exclusively in the kidney clinically. Non-renal manifestations associated with this syndrome have not been reported. HPRCC occurs over a wide age range from 19 to 66 years with median and mean ages of 41 and 42 years, respectively , but typically occur later than other forms of hereditary RCC. There is no sex predisposition and both male and female appear to be similarly affected. Family history of renal tumor is always present. HPRCC are mostly bilateral and multifocal, but renal cysts are less common compared to other hereditary RCC. Clinical presentation of HPRCC is similar to sporadic papillary renal cell carcinomas which are often detected incidentally or during screening of asymptomatic members of renal cell carcinoma families. Renal tumor in large size may present a classic triad of flank pain, hematuria, and an abdominal mass. Distant metastasis can rarely occur.

Epidemiology/Prevalence

A novel pathogenic variant was identified in exon 16 of the MET gene in two large hereditary papillary renal carcinoma (HPRC) families in North America. Affected members of the two families shared the same haplotype located within and immediately distal to the MET gene, suggesting a common ancestor (founder effect) However, HPRC families with identical germline MET pathogenic variants who do not share a common ancestral haplotype have also been reported

Genetic Abnormalities: Germline

The MET gene is located on chromosome 7q31.2 and encodes a protein with 1,390 amino-acids.[1] The functional MET receptor is a heterodimer made of an alpha chain (50 kDa) and a beta chain (145 kDa). The primary single-chain precursor protein is posttranslationally cleaved to produce the alpha and beta subunits, which are disulfide-linked to form the mature receptor. Two transcript variants, which encode different isoforms, have been found for this gene.The beta subunit of MET possesses tyrosine kinase activity and was identified as the cell-surface receptor for hepatocyte growth factor (HGF). MET transduces signals from the extracellular matrix into the cytoplasm by binding to the HGF ligand; it also regulates cell proliferation, scattering, morphogenesis, and survival.[4] Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain, which provides docking sites for downstream signaling molecules. After activation by its ligand, MET interacts with the PI3K subunit PI3KR1, PLCG1, SRC, GRB2, or STAT3, or the adapter GAB1. Recruitment of these downstream effectors by MET leads to the activation of several signaling cascades, including RAS-ERK, PI3K/AKT, and PLC-gamma/PKC. The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities

Expression was autosomal dominant with incomplete penetrance. These tumors are often bilateral and multifocal ranging from papillary adenomas to papillary renal cell carcinomas. Noting that these tumors had a papillary morphology, often retained trisomy chromosome 17 and 7 with a partial duplication of the mutant MET allele of 7q21-q35, and yet lacked chromosome 3p deletion, these tumors were postulated to be molecularly distinct from sporadic papillary renal cell carcinoma

Gene		Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
MET		Missense	The tumorigenic hallmark of HPRCC is MET germline proto-oncogene mutations, which are often missense, leading to activation of the tyrosine kinase domain of c-MET sans endogenous HGF/SF. The activation subsequently triggers downstream signaling pathways that promote cell survival, proliferation, angiogenesis and inhibition of apoptosis.	Dominant, HPRC is highly penetrant (approaching 100%)

Genetic Abnormalities: Somatic

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Gene	Genetic Variant or Variant Type	Molecular Pathogenesis	Inheritance, Penetrance, Expressivity	Notes
EXAMPLE: BRCA1	EXAMPLE: Biallelic inactivation variants	EXAMPLE: Second hit mutation can occur as copy neutral LOH, inactivating mutation, deletion, promoter hypermethylation, or a structural abnormality disrupting the gene.
EXAMPLE: BRCA1	EXAMPLE: Reversion mutation	EXAMPLE: After exposure to certain therapies (e.g. PARP inhibitors), a second mutation may restore gene function as a resistance mechanism.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

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Additional Information

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References

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Notes

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