7q31.2

AUTS9,DFNB97,HGFR,RCCP2,c-Met

Hereditary papillary renal carcinoma and Sporadic papillary renal carcinoma (HPRC, SPRC)

An inherited autosomal dominant form of renal carcinoma with reduced penetrance comprising 10% of all carcinomas of the kidney. Affected family members develop, in the fourth or fifth decade of life, bilateral, multifocal renal tumors with a papillary growth pattern which can be subdivided by histology into type 1 and type 2. Multiple tumors were shown to arise from independent clones. Sporadic PRCs are usually solitary tumors with microscopic papillary lesions in the surrounding renal parenchyma. It is important to note that patients with germline mutations in the MET gene are predisposed to develop papillary renal carcinoma type 1 specifically. These mutations are not known to predispose to any other type of malignant disease.

HPRC is a rare disease with an estimate incidence of 1 in 1 million. The age of development of PRCs is best studied in patients with H1112R mutation, because an elevated number of them has been described. By age 55, one half of H1112R mutation carriers have developed a detectable disease. Also, in H1112R mutation carriers has been observed that 26 % of patients develop distant metastases. The complete expression of the PRC phenotype may be affected by modifier genes. In fact, not only the age of onset varies among individuals but also the severity of the disease: in one patient were found at least 100 renal tumors, whereas his two brothers had a total of 1.

Papillary renal tumors are characterized by trisomy of chromosome 7 and 17, loss of Y in males. Only type 1 sporadic and hereditary PRCs harbor MET mutations with nonrandom duplication of the chromosome 7 bearing the mutant MET allele.

MET was first identified as the product of a human oncogene, tpr-MET, which derives from the fusion of two distinct genetic loci: tpr (translocated promoter region), which contributes two leucine zipper motifs (a protein-protein dimerization domain), and MET, which contributes the intracellular kinase domain of the MET receptor. The tpr gene sequence involved in the tpr-MET fusion is found on 1q25, though this gene is located at 1q31 in a database

The tpr-MET chimeric protein is dimerized and activated in ligand-independent manner and therefore possesses constitutive kinase activity and transforming ability.

MET/HGF signaling has been implicated in the generation and progression of a variety of tumors. The coexpression of wild type MET and HGF in the same cell (which generates an autocrine stimulatory loop) induces oncogenic transformation.
All investigated naturally occurring MET mutants show increased tyrosine phosphorylation level and enhanced kinase activity. In general, somatic mutations cause higher level of enzymatic activity compared to germline mutants. The kinase domain mutations cause ligand-independent activation and increase the tyrosine kinase activity. The juxtamembrane P1009I mutation does not cause ligand-independent activation but results in prolonged HGF-activated MET response.
The M1268T mutation identified in PRC   homologous to the M918T mutation of RET in multiple endocrine neoplasia type 2b   results not only in increased level of catalytic activity but also in a change of substrate specificity. Whereas c-Src is transiently activated by wild type MET, M1268T mutant MET is stably associated with c-Src, which is thereby constitutively phosphorylated and activated. Also, wild type MET does not phosphorylate substrate for cytosolic kinase c-Abl, whereas M1268T MET does. Moreover, expression of M1268T MET in NIH3T3 causes activation of the b-catenin pathway.
Different mutations act through distinct mechanisms and result in variable transforming activity. D1246H/N and M1268 mutants (that activate the Ras pathway) have high transforming ability. Y1248C and L1213V have less transforming ability but promote cell migration and invasion via activation of the PI3K/AKT pathway
3D molecular modeling studies using the crystal structure of the insulin receptor tyrosine kinase domain as a model suggest that disease-causing MET mutations interfere with the intrasteric mechanism of tyrosine kinase auto-inhibition to destabilize the inactive form and facilitate transition to the active form. Mutations V1110I, Y1248H/D/C, M1268T can affect contact between residues of the activation loop in its inhibitory conformation. Mutations M1149T and L1213V may increase flexibility of the tertiary structure. D1246N can stabilize the kinase in its active conformation. This structural work gives hints to understanding the switch of substrate specificity by mutant receptors.