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Intramural Research Support Program, Science Applications International Corporation-Frederick [L. S.], Advanced Biosciences Laboratories-Basic Research Program [M. J., G. V. W.], and the Laboratory of Immunobiology [K. J., G. W., B. Z.], National Cancer Institute-Frederick Cancer Research & Development Center, Frederick, Maryland 21702; Urologic Oncology Branch [M. C. W., W. M. L.], Genetic Epidemiology, Branch [G. G.], and the Laboratory of Pathology [I. L., Z. Z.], National Cancer Institute, and Department of Diagnostic Radiology [P. C.], NIH, Bethesda, Maryland 20892; and Albert Ludwig University Freiburg [H. N.], D-79106 Freiburg, Germany
Hereditary papillary renal carcinoma (HPRC) is a newly recognized inherited disorder characterized by a predisposition to develop multiple bilateral papillary renal carcinomas. Individuals affected with HPRC have been shown to have germ-line mutations in the tyrosine kinase domain of the MET proto-oncogene. We identified a novel mutation in exon 16 of the MET gene in two large North American HPRC families. The H1112R MET mutation segregated with the disease, was not present in 320 normal chromosomes, and caused malignant transformation of NIH 3T3 cells. By examining individuals with the H1112R mutation, we determined the age-dependent penetrance of this mutation and identified additional nonrenal malignancies that occurred in mutation carriers. Affected members of the two families shared the same haplotype within and immediately distal to the MET gene, suggesting a founder effect. The identification of the H1112R mutation will facilitate predictive testing in HPRC and guide future studies of the MET gene in human neoplasia.
1 Sponsored in part by the National Cancer Institute, Department of Health and Human Services, under contract with Advanced Biosciences Laboratories. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
2 To whom requests for reprints should be addressed, at Laboratory of Immunobiology. Building 560 Room 12-71, National Cancer Institute-Frederick Cancer Research & Development Center, Frederick, MD 21702.
Received 11/17/97. Accepted 2/13/98.
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