Genetics of Kidney Cancer (Renal Cell Cancer) (PDQ®)–Health Professional Version
Hereditary Papillary Renal Carcinoma
Introduction
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 cancer (RCC).[1] A germline-activating pathogenic variant in the MET proto-oncogene is associated with HPRC susceptibility.[2]
No known specific environmental risk factors have been reported to cause hereditary or sporadic type 1 papillary RCC. The known major risk factors for HPRC are 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]
Genetics
MET gene
The MET gene is located on chromosome 7q31.2 and encodes a 1,390 amino-acid protein.[4] 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,[5] which are disulfide linked to form the mature receptor. Two transcript variants encoding different isoforms have been found for this gene.
The beta subunit of MET was identified as the cell-surface receptor for hepatocyte growth factor (HGF) [6] and possesses tyrosine-kinase activity. MET transduces signals from the extracellular matrix into the cytoplasm by binding to HGF ligand and regulates proliferation, scattering, morphogenesis, and survival.[7] Ligand binding at the cell surface induces autophosphorylation of MET on its intracellular domain that 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.[7] The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities.[7]
Prevalence and founder effects
A novel pathogenic variant was identified in exon 16 of the MET gene in two large North American HPRC families. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a common ancestor (founder effect).[8] However, families with identical germline MET pathogenic variants who do not share a common ancestral haplotype have also been reported.[9]
Penetrance of MET pathogenic variants
Genotype-phenotype correlations
Molecular Biology
All germline MET pathogenic variants in HPRC reported to date are missense variants in the tyrosine kinase domain, leading to constitutive activation of the MET kinase and driving the development of papillary RCC.[2,11,12]
Renal tumors from HPRC-affected patients also commonly show polysomy of chromosome 7 upon cytogenetic analysis.[4] Polysomy 7 in the HPRC renal tumor tissue results from nonrandom duplication of the chromosome bearing the wild-type allele.[13] Approximately 15% to 20% of sporadic type 1 papillary RCCs have somatic MET missense mutations.[11,14,15]
Clinical Manifestations
Kidney cancer
To date, the only recognized manifestation of HPRC is kidney cancer. The mean and median age of onset are 42 and 41 years, respectively.[10] The age at onset may vary widely between families (range, 19–66 y), perhaps influenced by specific genotype.[9] Unlike sporadic tumors, which occur more frequently in males, both sexes appear to be similarly affected by HPRC. Renal tumors in HPRC are most commonly bilateral and multifocal.[1,3] In contrast with many other RCC syndromes, renal cysts are less common in HPRC.[1,3] 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.[16]
Histopathology
The histopathologic classification of type 1 papillary 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.[17,18] The HPRC phenotype is limited to the type 1 papillary renal tumor 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.[19] These pathologic findings should raise suspicion for a germline variant in the MET gene.[8,9] Hereditary and sporadic type 1 papillary RCCs with MET variants have a similar distinctive morphological phenotype, including macrophages and psammoma bodies.[16] In HPRC, type 1 papillary RCC histology is often well differentiated/low grade, but higher-grade tumors can also be observed.[20]
Management
Surveillance
It is recommended that patients with known HPRC undergo regular surveillance. Papillary RCCs, particularly type 1 variants, 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 used as a single imaging modality can be particularly misleading because these small tumors are often isoechoic and may be missed on repeated examinations.[20]
If kidney function is normal and there is no allergy 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.[21] Occasionally, ultrasonography may complement cross-sectional imaging by aiding in the identification of cystic structures.[22]
At-risk individuals are generally recommended to undergo periodic kidney imaging throughout their lifetimes, even when no tumors are present. Therefore, MRI is typically recommended as an imaging modality 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 tumors present, imaging can be performed periodically. If a tumor smaller than 3 cm is found, imaging should be repeated within the first year to assess the growth rate.[23] Depending upon growth characteristics and the current tumor size, imaging frequency can be adapted to prevent the largest tumor from exceeding 3 cm.
Generally, patients with renal tumors associated with HPRC are candidates for radiologic surveillance until one or more tumors reach 3 cm. At that point, surgical intervention is recommended. (Refer to the Treatment subsection of this summary for more information.)
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. A genetic counselor or geneticist first reviews the individual and family history and then provides education and counseling about various implications of genetic testing, focusing on how health care management might be altered if the patient were found to be a carrier of a pathogenic variant, and the possible psychosocial and economic impact. Informed consent may then be obtained, and the genetic counselor will assist with contacting the laboratory and coordinating the pathogenic variant testing process.
Genetic testing for HPRC may be recommended if an individual has one or more of the following:
- A family history of HPRC.
- A biologically related family member who has had genetic testing that was positive for a pathogenic variant in the tyrosine kinase domain of MET.
- More than one papillary type 1 RCC, a papillary type 1 RCC with incipient lesions of the surrounding parenchyma, or a papillary type 1 RCC diagnosed before age 45 years.
MET genetic testing
Bidirectional DNA sequencing of the MET gene using amplified genomic DNA is carried out 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 gene of 21 exons.[2,4,24] Some CLIA-approved genetic testing laboratories are now offering diagnostic cancer gene panels for analysis by next-generation sequencing technology that include 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.
Treatment
Once HPRC renal tumors reach 3 cm in size, a nephron-sparing partial nephrectomy is usually recommended to minimize the risk of metastatic spread. 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%.[25] However, patients with germline MET pathogenic variants were particularly sensitive to this agent, with 5 of 10 patients demonstrating a Response Evaluation Criteria In Solid Tumors (RECIST) partial response (overall response rate, 50%), compared with only 5 of 57 demonstrating a partial response in the group without germline MET pathogenic variants. More-selective MET inhibitors are currently under investigation for the treatment of papillary RCC.
Prognosis
HPRC-related type 1 papillary 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 diagnosis.[20] Surveillance and presymptomatic screening of individuals at risk of HPRC is expected to improve prognosis through early diagnosis, and specialized cancer management (tailored to the biology of syndrome-associated kidney cancer) is expected to improve disease outcome.[26]
Future Directions
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 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 metastatic RCC associated with HPRC. On the basis of limited data from the foretinib study,[25] 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 kidney cancer 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 kidney cancer and 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.
References
- Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [PUBMED Abstract]
- Schmidt L, Duh FM, Chen F, et al.: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 16 (1): 68-73, 1997. [PUBMED Abstract]
- Zbar B, Glenn G, Lubensky I, et al.: Hereditary papillary renal cell carcinoma: clinical studies in 10 families. J Urol 153 (3 Pt 2): 907-12, 1995. [PUBMED Abstract]
- Park M, Dean M, Kaul K, et al.: Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci U S A 84 (18): 6379-83, 1987. [PUBMED Abstract]
- Komada M, Hatsuzawa K, Shibamoto S, et al.: Proteolytic processing of the hepatocyte growth factor/scatter factor receptor by furin. FEBS Lett 328 (1-2): 25-9, 1993. [PUBMED Abstract]
- Bottaro DP, Rubin JS, Faletto DL, et al.: Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science 251 (4995): 802-4, 1991. [PUBMED Abstract]
- Gherardi E, Birchmeier W, Birchmeier C, et al.: Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12 (2): 89-103, 2012. [PUBMED Abstract]
- Schmidt L, Junker K, Weirich G, et al.: Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res 58 (8): 1719-22, 1998. [PUBMED Abstract]
- Schmidt LS, Nickerson ML, Angeloni D, et al.: Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172 (4 Pt 1): 1256-61, 2004. [PUBMED Abstract]
- Shuch B, Vourganti S, Ricketts CJ, et al.: Defining early-onset kidney cancer: implications for germline and somatic mutation testing and clinical management. J Clin Oncol 32 (5): 431-7, 2014. [PUBMED Abstract]
- Schmidt L, Junker K, Nakaigawa N, et al.: Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene 18 (14): 2343-50, 1999. [PUBMED Abstract]
- Miller M, Ginalski K, Lesyng B, et al.: Structural basis of oncogenic activation caused by point mutations in the kinase domain of the MET proto-oncogene: modeling studies. Proteins 44 (1): 32-43, 2001. [PUBMED Abstract]
- Zhuang Z, Park WS, Pack S, et al.: Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 20 (1): 66-9, 1998. [PUBMED Abstract]
- Linehan WM, Spellman PT, Ricketts CJ, et al.: Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med 374 (2): 135-45, 2016. [PUBMED Abstract]
- Pal SK, Ali SM, Yakirevich E, et al.: Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling. Eur Urol 73 (1): 71-78, 2018. [PUBMED Abstract]
- Lubensky IA, Schmidt L, Zhuang Z, et al.: Hereditary and sporadic papillary renal carcinomas with c-met mutations share a distinct morphological phenotype. Am J Pathol 155 (2): 517-26, 1999. [PUBMED Abstract]
- Delahunt B, Eble JN: Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10 (6): 537-44, 1997. [PUBMED Abstract]
- Störkel S, Eble JN, Adlakha K, et al.: Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 80 (5): 987-9, 1997. [PUBMED Abstract]
- Ornstein DK, Lubensky IA, Venzon D, et al.: Prevalence of microscopic tumors in normal appearing renal parenchyma of patients with hereditary papillary renal cancer. J Urol 163 (2): 431-3, 2000. [PUBMED Abstract]
- Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PUBMED Abstract]
- Vikram R, Ng CS, Tamboli P, et al.: Papillary renal cell carcinoma: radiologic-pathologic correlation and spectrum of disease. Radiographics 29 (3): 741-54; discussion 755-7, 2009 May-Jun. [PUBMED Abstract]
- Choyke PL, Walther MM, Glenn GM, et al.: Imaging features of hereditary papillary renal cancers. J Comput Assist Tomogr 21 (5): 737-41, 1997 Sep-Oct. [PUBMED Abstract]
- Walther MM, Choyke PL, Glenn G, et al.: Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol 161 (5): 1475-9, 1999. [PUBMED Abstract]
- Duh FM, Scherer SW, Tsui LC, et al.: Gene structure of the human MET proto-oncogene. Oncogene 15 (13): 1583-6, 1997. [PUBMED Abstract]
- Choueiri TK, Vaishampayan U, Rosenberg JE, et al.: Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 31 (2): 181-6, 2013. [PUBMED Abstract]
- Kiuru M, Kujala M, Aittomäki K: Inherited forms of renal cell carcinoma. Scand J Surg 93 (2): 103-11, 2004. [PUBMED Abstract]
Changes to This Summary (11/01/2019)
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added Treatment of pancreatic manifestations as a new subsection.
The Somatic fumarate hydratase (FH) mutations subsection was renamed from Somatic FH pathogenic variants.
This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
About This PDQ Summary
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of kidney cancer. 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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- Thai H. Ho, MD, PhD (Mayo Clinic)
- Brian Matthew Shuch, MD (UCLA Health)
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PDQ® Cancer Genetics Editorial Board. PDQ Genetics of Kidney Cancer (Renal Cell Cancer). Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/kidney/hp/kidney-genetics-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389510]
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