Hereditary papillary renal carcinoma (HPRC) is an autosomal dominant syndrome that predisposes individuals to bilateral and multifocal papillary renal cell carcinoma (RCC) (formerly known as type 1 papillary RCC).[
Individuals are at the greatest risk of developing HPRC if they have a biological relative with bilateral, multifocal papillary RCC and/or a known activating pathogenic variant in the tyrosine kinase domain of the MET proto-oncogene.[
No specific environmental risk factors have been reported to cause hereditary or sporadic papillary RCC.
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METGene
The METgene is located on chromosome 7q31.2 and encodes a protein with 1,390 amino-acids.[
The beta subunit of MET possesses tyrosine kinase activity and was identified as the cell-surface receptor for hepatocyte growth factor (HGF).[
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).[
Penetrance ofMETPathogenic Variants
HPRC is highly penetrant (approaching 100%).[
Genotype-Phenotype Correlations
All cases of HPRC have presented with papillary renal cell carcinoma, and no other histological subtypes have been detected.[
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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).[
Renal tumors from HPRC-affected patients commonly show polysomy of chromosome 7 upon cytogenetic analysis.[
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Kidney Cancer
The only recognized manifestation of hereditary papillary renal carcinoma (HPRC) is kidney cancer. The mean and median age at onset are 42 and 41 years, respectively.[
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Papillary renal cell carcinomas (RCCs) often have heterogenous morphological features. Type 1 papillary RCC was a unique classification within the papillary RCC family, but recent World Health Organization pathology updates have removed this designation. All hereditary papillary renal carcinomas (HPRCs) share type 1 papillary morphology, which is defined by small basophilic cells with pale cytoplasm, small oval nuclei, and inconspicuous nucleoli organized in single layers in papillae and tubular structures.[
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Surveillance
It is important that patients with known hereditary papillary renal carcinoma (HPRC) undergo regular surveillance. Papillary renal cell carcinomas (RCCs) possess specific imaging characteristics that differ from clear cell RCCs. 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.[
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.[
Generally, patients with HPRC-associated renal tumors are candidates for radiological surveillance until one or more of the tumors reach 3 cm. At that point, surgical intervention is recommended. For more information, see the
Genetic Testing
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:
One report suggested that it may be beneficial to expand testing for HPRC beyond familial cases.[
METgenetic testing
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.[
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.
Individuals with variants of unknown significance (VUS) in the MET tyrosine kinase domain warrant special consideration. A recent genotype-phenotype study demonstrated that three MET VUS exhibited oncogenic MET signaling in preclinical models, suggesting pathogenicity.[
Treatment
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 extrarenal 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%.[
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Hereditary papillary renal carcinoma (HPRC)-related papillary renal cell carcinomas, 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.[
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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,[
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