Hereditary Papillary Renal Carcinoma (PDQ®)

Health Professional Version

PDQ Cancer Genetics Editorial Board.

Publication Details

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of hereditary papillary renal carcinoma (HPRC). It is intended as a resource to inform and assist clinicians who care for HPRC patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Introduction

Hereditary papillary renal carcinoma (HPRC) is an autosomal dominant syndrome that predisposes individuals to bilateral and multifocal type 1 papillary renal cell carcinoma (RCC).[1]

Individuals are at the greatest risk of developing HPRC if they have a biological 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.

References

  1. Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [PubMed: 8308957]
  2. 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: 9140397]
  3. 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: 7853572]

Genetics

MET Gene

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,[2] 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).[3] 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.[4] The RAS-ERK activation is associated with morphogenetic effects, while PI3K/AKT coordinates cell survival activities.[4]

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).[5] However, HPRC families with identical germline MET pathogenic variants who do not share a common ancestral haplotype have also been reported.[6]

Penetrance of MET Pathogenic Variants

HPRC is highly penetrant (approaching 100%).[5-7]

Genotype-Phenotype Correlations

To date, all cases of HPRC present with type 1 papillary renal cell carcinoma.[5,6,8-10] Extra-renal manifestations associated with this condition have not been reported.

References

  1. 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. [PMC free article: PMC299079] [PubMed: 2819873]
  2. 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: 8344430]
  3. 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: 1846706]
  4. Gherardi E, Birchmeier W, Birchmeier C, et al.: Targeting MET in cancer: rationale and progress. Nat Rev Cancer 12 (2): 89-103, 2012. [PubMed: 22270953]
  5. 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: 9563489]
  6. 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: 15371818]
  7. 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. [PMC free article: PMC3912328] [PubMed: 24378414]
  8. 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: 7853572]
  9. Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [PubMed: 8308957]
  10. 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: 9140397]

Molecular Biology

All germline MET pathogenic 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).[1-3]

Renal tumors from HPRC-affected patients 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.[5] Approximately 15% to 20% of sporadic type 1 papillary RCCs have somatic MET missense mutations.[1,6,7]

References

  1. 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: 10327054]
  2. 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: 9140397]
  3. 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: 11354004]
  4. 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. [PMC free article: PMC299079] [PubMed: 2819873]
  5. 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: 9731534]
  6. 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. [PMC free article: PMC4775252] [PubMed: 26536169]
  7. 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: 28592388]

Clinical Manifestations

Kidney Cancer

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.[1] The age at onset may vary widely between families (range, 19–66 y), perhaps influenced by specific genotypes.[2] 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.[5]

References

  1. 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. [PMC free article: PMC3912328] [PubMed: 24378414]
  2. 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: 15371818]
  3. 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: 7853572]
  4. Zbar B, Tory K, Merino M, et al.: Hereditary papillary renal cell carcinoma. J Urol 151 (3): 561-6, 1994. [PubMed: 8308957]
  5. 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. [PMC free article: PMC1866853] [PubMed: 10433944]

Histopathology

The histopathological 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.[3] These pathological findings should raise suspicion for a germline variant in the MET gene.[4,5] Hereditary and sporadic type 1 papillary RCCs with MET pathogenic variants have a similar distinctive morphological phenotype, which includes the presence of macrophages and psammoma bodies.[6] In HPRC, type 1 papillary RCC histology is often well differentiated/low grade; however, high-grade tumors can also be observed in HPRC patients.[7]

References

  1. Delahunt B, Eble JN: Papillary renal cell carcinoma: a clinicopathologic and immunohistochemical study of 105 tumors. Mod Pathol 10 (6): 537-44, 1997. [PubMed: 9195569]
  2. 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: 9307203]
  3. 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: 10647647]
  4. 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: 9563489]
  5. 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: 15371818]
  6. 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. [PMC free article: PMC1866853] [PubMed: 10433944]
  7. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PubMed: 12511666]

Management

Surveillance

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.[1]

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.[2] Occasionally, ultrasonography may complement cross-sectional imaging by aiding in the identification of cystic structures.[3]

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.[4] 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 radiological surveillance until one or more of the tumors reach 3 cm. At that point, surgical intervention is recommended. For more information, see the Treatment section.

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:

  • A family history of HPRC.
  • A biologically related family member who tested positive for a pathogenic variant in the tyrosine kinase domain of MET.
  • A personal history of greater 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 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.[5-7] 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.

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 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%.[8] 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.

References

  1. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PubMed: 12511666]
  2. 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: 19448113]
  3. 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: 9294565]
  4. 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: 10210376]
  5. 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. [PMC free article: PMC299079] [PubMed: 2819873]
  6. 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: 9140397]
  7. Duh FM, Scherer SW, Tsui LC, et al.: Gene structure of the human MET proto-oncogene. Oncogene 15 (13): 1583-6, 1997. [PubMed: 9380410]
  8. 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. [PMC free article: PMC3532390] [PubMed: 23213094]

Prognosis

Hereditary papillary renal carcinoma (HPRC)-related type 1 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.[1] 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.[2]

References

  1. Choyke PL, Glenn GM, Walther MM, et al.: Hereditary renal cancers. Radiology 226 (1): 33-46, 2003. [PubMed: 12511666]
  2. Kiuru M, Kujala M, Aittomäki K: Inherited forms of renal cell carcinoma. Scand J Surg 93 (2): 103-11, 2004. [PubMed: 15285561]

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 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,[1] 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.

References

  1. 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. [PMC free article: PMC3532390] [PubMed: 23213094]

Latest Updates to This Summary (12/28/2022)

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.

Editorial changes were made to this summary.

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® Cancer Information for Health Professionals 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 hereditary papillary renal carcinoma. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Hereditary Papillary Renal Carcinoma are:

  • Alexandra Perez Lebensohn, MS, CGC (National Cancer Institute)
  • Brian Matthew Shuch, MD (UCLA Health)
  • Ramaprasad Srinivasan, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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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>. [PMID: 33724750]

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