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Hereditary papillary renal cell carcinoma (HPRC) is a rare autosomal dominant syndrome characterized by bilateral and multifocal type I papillary renal cell carcinomas. Patients often present with multiple synchronous tumors, frequently in their 30s–40s, with or without a clear family history (PMID:32039030). Genetic etiology is driven by activating germline mutations in the MET proto-oncogene, encoding a hepatocyte growth factor receptor tyrosine kinase.
Germline sequencing of HPRC families has uncovered recurrent missense variants in the MET tyrosine kinase domain. The c.3328G>A (p.Val1110Ile) mutation was reported in a Russian patient and multiple European families; c.3281A>G (p.His1094Arg) and c.3282T>G (p.His1094Gln) were described in two large North American kindreds, each co-segregating with disease and absent in controls (PMID:9563489; PMID:15371818). In aggregate, over 100 unrelated probands across more than 20 families carry pathogenic MET variants.
Segregation analysis demonstrates perfect co-segregation of MET missense mutations with HPRC in affected relatives; no unaffected carriers have been reported in over 320 control chromosomes (PMID:9563489). Additional families of Italian, Spanish, and Cuban descent carrying c.3522G>A (p.Val1110Ile) or c.3906G>C (p.Val1238Ile) further substantiate autosomal dominant inheritance (PMID:15371818).
Functional studies across multiple models confirm a gain-of-function mechanism. MET mutants display elevated kinase activity, constitutive phosphorylation, focus formation in NIH 3T3 cells, and tumorigenicity in nude mice (PMID:9326629). In Met knock-in mice, selective duplication of the mutant allele and diverse tumor spectra mirror human HPRC phenotypes (PMID:9731534; PMID:15557554).
A novel germline ~101.4 kb duplication of MET exons 5–21 has been reported in HPRC-like patients lacking classic missense mutations; classified as a VUS, it may yet represent an activating CNV pending functional validation (PMID:40564049).
Clinically, MET mutation screening in 158 French patients yielded a 12.4% pathogenic variant rate, with bilateral multifocal tumors in 84.3% and histological subtypes including biphasic squamoid alveolar PRCC1 (PMID:34882875). Targeted MET/VEGFR2 inhibitors and MET-specific TKIs show promise, especially as some N-lobe variants (e.g., p.His1086Leu, p.Ile1102Thr) require hepatocyte growth factor for full activation, informing therapeutic strategies (PMID:38135585; PMID:39980226).
In summary, definitive genetic and functional evidence establishes MET as the causative gene for HPRC. Diagnostic MET sequencing and CNV analysis enable early detection, family risk assessment, and tailored use of MET-targeted therapies. Key take-home: MET mutation screening is critical for precision diagnosis and management of hereditary papillary renal cell carcinoma.
Gene–Disease AssociationDefinitiveOver 100 probands in >20 families; autosomal dominant segregation and extensive functional/animal model concordance Genetic EvidenceStrongMultiple recurrent missense variants in TK domain (e.g., c.3328G>A, c.3281A>G) in >100 unrelated HPRC cases; co-segregation in families Functional EvidenceModerateOncogenic transformation in vitro and in vivo; constitutive phosphorylation; mouse models recapitulate tumorigenesis |