GTS5:Hereditary papillary renal carcinoma (MET)
Genetic Tumour Syndromes (Who Classification, 5th ed.)
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Primary Author(s)*
Farid Ullah, MS, PhD
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Genetic Tumour Syndromes (5th ed.) |
| Category | Growth factor receptors and related signalling pathways |
| Family | Growth factor receptors |
| Type | Hereditary papillary renal carcinoma (MET) |
| Subtype(s) | N/A |
Related Terminology
| Acceptable | N/A |
| Not Recommended | N/A |
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. [1][2] 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 [3], 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.[4][5] 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.[6]
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)[7] However, HPRC families with identical germline MET pathogenic variants who do not share a common ancestral haplotype have also been reported[8]
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,[9] 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).[10] 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.[11] The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities[12]
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
T3640C (M1149D) G3810T (V1206L) G3906A (V1238I) G3930A (D1246N) A3937G (Y1248C) |
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 Mutation Tumor
| Gene | Genetic Variant or Variant Type | Molecular Pathogenesis | Inheritance, Penetrance, Expressivity | Notes |
|---|---|---|---|---|
| MET | Missense
C3831G (L1213V) G3930C (D1246H) T3936C (Y1248H) T3997C (M1268D |
Somatic |
Genes and Main Pathways Involved
Hippo, mTOR or p53
| 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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- ↑ Zbar, B.; et al. (1994-03). "Hereditary papillary renal cell carcinoma". The Journal of Urology. 151 (3): 561–566. doi:10.1016/s0022-5347(17)35015-2. ISSN 0022-5347. PMID 8308957. Check date values in:
|date=(help) - ↑ Zbar, B.; et al. (1995-03). "Hereditary papillary renal cell carcinoma: clinical studies in 10 families". The Journal of Urology. 153 (3 Pt 2): 907–912. ISSN 0022-5347. PMID 7853572. Check date values in:
|date=(help) - ↑ Shuch, Brian; et al. (2014-02-10). "Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management". Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 32 (5): 431–437. doi:10.1200/JCO.2013.50.8192. ISSN 1527-7755. PMC 3912328. PMID 24378414.
- ↑ Zbar, B.; et al. (1995-03). "Hereditary papillary renal cell carcinoma: clinical studies in 10 families". The Journal of Urology. 153 (3 Pt 2): 907–912. ISSN 0022-5347. PMID 7853572. Check date values in:
|date=(help) - ↑ Metwalli, Adam R.; et al. (2014-09). "Nephron-sparing surgery for multifocal and hereditary renal tumors". Current Opinion in Urology. 24 (5): 466–473. doi:10.1097/MOU.0000000000000094. ISSN 1473-6586. PMC 4441729. PMID 25014245. Check date values in:
|date=(help) - ↑ Lubensky, I. A.; et al. (1999-08). "Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype". The American Journal of Pathology. 155 (2): 517–526. doi:10.1016/S0002-9440(10)65147-4. ISSN 0002-9440. PMC 1866853. PMID 10433944. Check date values in:
|date=(help) - ↑ Schmidt, L.; et al. (1998-04-15). "Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene". Cancer Research. 58 (8): 1719–1722. ISSN 0008-5472. PMID 9563489.
- ↑ Schmidt, Laura S.; et al. (2004-10). "Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene". The Journal of Urology. 172 (4 Pt 1): 1256–1261. doi:10.1097/01.ju.0000139583.63354.e0. ISSN 0022-5347. PMID 15371818. Check date values in:
|date=(help) - ↑ Komada, M.; et al. (1993-08-09). "Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin". FEBS letters. 328 (1–2): 25–29. doi:10.1016/0014-5793(93)80958-w. ISSN 0014-5793. PMID 8344430.
- ↑ Bottaro, D. P.; et al. (1991-02-15). "Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product". Science (New York, N.Y.). 251 (4995): 802–804. doi:10.1126/science.1846706. ISSN 0036-8075. PMID 1846706.
- ↑ Gherardi, Ermanno; et al. (2012-01-24). "Targeting MET in cancer: rationale and progress". Nature Reviews. Cancer. 12 (2): 89–103. doi:10.1038/nrc3205. ISSN 1474-1768. PMID 22270953.
- ↑ Gherardi, Ermanno; et al. (2012-01-24). "Targeting MET in cancer: rationale and progress". Nature Reviews. Cancer. 12 (2): 89–103. doi:10.1038/nrc3205. ISSN 1474-1768. PMID 22270953.
Notes
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