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Home > Living Well > Health Library > Hereditary Papillary Renal Carcinoma (PDQ®): Genetics - Health Professional Information [NCI]
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Hereditary papillary renal carcinoma (HPRC) is an autosomal dominant syndrome with a predisposition to the development of bilateral and multifocal type 1 papillary renal cell carcinoma (RCC).
Individuals are at the greatest risk of developing HPRC if they have a biologic relative with bilateral multifocal type 1 papillary RCC and/or a known activating pathogenic variant in the tyrosine kinase domain of the MET proto-oncogene.[2,3]
No specific environmental risk factors have been reported to cause hereditary or sporadic type 1 papillary RCC.
The METgene is located on chromosome 7q31.2 and encodes a 1,390 amino-acid protein. 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. 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.
Prevalence and Founder Effects
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.
Penetrance ofMETPathogenic Variants
HPRC is highly penetrant (approaching 100%).[5,6,7]
To date, all cases of HPRC present with type 1 papillary renal cell carcinoma.[5,6,8,9,10] Extra-renal manifestations associated with this condition have not been reported.
All germline METpathogenic variants in hereditary papillary renal carcinoma (HPRC) reported to date are missense variants in the tyrosine kinase domain; this leads to constitutive activation of the MET kinase and drives the development of papillary renal cell carcinoma (RCC).[1,2,3]
Renal tumors from HPRC-affected patients commonly show polysomy of chromosome 7 upon cytogenetic analysis. Polysomy 7 in the HPRC renal tumor tissue results from nonrandom duplication of the chromosome bearing the wild-type allele. Approximately 15% to 20% of sporadic type 1 papillary RCCs have somatic METmissense mutations.[1,6,7]
To date, the only recognized manifestation of hereditary papillary renal carcinoma (HPRC) is kidney cancer. The mean and median age of onset are 42 and 41 years, respectively. The age at onset may vary widely between families (range, 19–66 y), perhaps influenced by specific genotypes. Unlike sporadic tumors, which occur more frequently in males, both sexes appear to be similarly affected by HPRC-associated renal cell carcinoma (RCC). Renal tumors in HPRC are most commonly bilateral and multifocal.[3,4] In contrast with many other RCC syndromes, renal cysts are less common in HPRC.[3,4] However, the presentation of HPRC is similar to other forms of kidney cancer in that small tumors may present incidentally, whereas large lesions can cause the classic triad of flank pain, hematuria, and an abdominal mass. When HPRC renal tumors become large, they can metastasize, most commonly to the lungs.
The histopathologic classification of type 1 papillary renal cell carcinoma (RCC) is defined by small basophilic cells with pale cytoplasm, small oval nuclei, and inconspicuous nucleoli organized in single layers in papillae and tubular structures.[1,2] The hereditary papillary renal carcinoma (HPRC) phenotype is limited to the type 1 papillary renal carcinoma histopathology. Incipient microscopic lesions, including adenomas and papillary lesions, are commonly found in the adjacent renal parenchyma. It has been estimated that patients with HPRC may develop up to 3,400 renal tumors or incipient lesions per kidney. These pathologic findings should raise suspicion for a germline variant in the METgene.[4,5] Hereditary and sporadic type 1 papillary RCCs with METpathogenic variants have a similar distinctive morphological phenotype, which includes the presence of macrophages and psammoma bodies. In HPRC, type 1 papillary RCC histology is often well differentiated/low grade; however, high-grade tumors can also be observed in HPRC patients.
It is important that patients with known hereditary papillary renal carcinoma (HPRC) undergo regular surveillance. Papillary renal cell carcinomas (RCCs), particularly type 1 papillary RCCs, possess specific imaging characteristics that differ from clear cell RCCs. Type 1 papillary renal tumors are generally hypovascular and enhance only 10 to 30 Hounsfield units after intravenous administration of contrast material. Papillary renal tumors can be mistaken for renal cysts, unless evaluated by careful attenuation measurements before and after contrast enhancement. Ultrasonography can be particularly misleading if no other imaging tests are used because the small renal tumors in HPRC are often isoechoic and may be missed on repeat examinations.
If kidney function is normal and the patient is not allergic to contrast, cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is considered the best initial imaging technique for identifying these hypovascular renal tumors. Renal ultrasonography is often inadequate for detecting papillary tumors, even when the tumor is clearly present on CT or MRI. Occasionally, ultrasonography may complement cross-sectional imaging by aiding in the identification of cystic structures.
At-risk individuals are generally recommended to undergo periodic kidney imaging throughout their lifetimes, even when renal tumors are not present. Therefore, MRI is typically recommended to minimize the lifetime dose of radiation. One approach that has been used is to perform initial cross-sectional imaging at baseline. If there are no renal tumors present, imaging can be performed periodically. If a renal tumor smaller than 3 cm is found, imaging is repeated within the first year to assess the growth rate of the tumor. Imaging frequency can be adapted to prevent the largest tumor from exceeding 3 cm depending on the growth characteristics of the tumor and the current tumor size.
Generally, patients with HPRC-associated renal tumors are candidates for radiologic surveillance until one or more of the tumors reach 3 cm. At that point, surgical intervention is recommended. (Refer to the Treatment section of this summary for more information.)
Genetic testing for HPRC is available at Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. A health professional (usually a physician, geneticist, or genetic counselor) intermediary between the patient and the laboratory is chosen. Genetic counseling is performed, and informed consent obtained. The genetic counselor will contact the laboratory and coordinate genetic testing.
Genetic testing for HPRC may be recommended if an individual has one or more of the following:
Bidirectional DNA sequencing of the METgene using amplified genomic DNA is done to identify sequence variants in the coding exons of MET. All HPRC-associated MET pathogenic variants identified to date are located in the four exons encompassing the tyrosine kinase domain. Therefore, initially analyzing only these four exons may identify most sequence variants while reducing the cost and time involved in analyzing the entire 21-exon gene.[5,6,7] Some CLIA-approved genetic testing laboratories now offer diagnostic cancer gene panels, which use next-generation sequencing technology to examine the entire MET gene.
Genetic testing enables early definitive diagnosis of the HPRC syndrome, after which at-risk individuals can be guided to regular surveillance for syndrome-associated phenotypes.
Once HPRC renal tumors reach 3 cm in size, a nephron-sparing partial nephrectomy is usually recommended to minimize the risk of metastasis. There are no curative options available for patients with unresectable extra-renal spread of disease. However, there has been significant interest in developing MET-directed systemic therapy for patients with HPRC. Foretinib, a dual MET/VEGFR2 kinase inhibitor with additional activity against a variety of other tyrosine kinases, was evaluated in a multicenter phase II trial in patients with metastatic papillary RCC or bilateral multifocal papillary RCC. The overall response rate in patients with papillary RCC was 13.5%. However, patients with germline MET pathogenic variants were particularly sensitive to this agent, with 5 of 10 patients demonstrating a partial response, as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) criteria. In patients without germline MET pathogenic variants, only 5 of 57 demonstrated a partial response to foretinib. More-selective MET inhibitors are currently under investigation for the treatment of papillary RCC.
Hereditary papillary renal carcinoma (HPRC)-related type 1 papillary renal cell carcinomas (RCCs), particularly small tumors confined to the kidneys, tend to be indolent. Consequently, patients present later in life or die of other syndrome-unrelated causes before a renal tumor is diagnosed.Surveillance, presymptomatic screening of individuals at risk of HPRC, and specialized cancer management (tailored to the biology of syndrome-associated kidney cancer) are expected to improve disease outcome.
Development of blood-based early detection assays, and effective systemic therapy for either prevention or treatment of overt disease might provide new options for individuals with hereditary papillary renal carcinoma (HPRC). Because the penetrance of tumors in HPRC is nearly 100%, this patient population might provide an exciting avenue to study chemoprevention using MET-directed strategies. There are currently no systemic therapy options approved by the U.S. Food and Drug Administration (FDA) that specifically address the needs of patients with HPRC-associated metastatic renal cell carcinoma (RCC). On the basis of limited data from the foretinib study, agents such as cabozantinib (a multitargeted tyrosine kinase inhibitor with activity against MET, which was approved by the FDA for use in patients with metastatic RCC who have progressed on VEGFR-targeted therapy) may be considered. Newer MET inhibitors with a more-selective target profile may be clinically active, while limiting off-target side effects, in patients with HPRC-associated RCC, and such agents are currently under evaluation (NCT02019693). Because redundant signaling pathways are often activated with targeted therapy, the mechanisms of resistance to MET inhibition should be further investigated.
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Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of hereditary papillary renal carcinoma. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Cancer Genetics Editorial Board. PDQ Hereditary Papillary Renal Carcinoma. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/renal-cell-carcinoma-genetics/hprc-syndrome. Accessed <MM/DD/YYYY>.
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Last Revised: 2021-03-08
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