W. Marston Linehan, M.D.
Urologic Oncology Branch
Molecular Genetic Analysis of Genetic Events Associated With Initiation and Progression of Urologic Malignancies
Characterization of the VHL Suppressor Gene Product
The VHL tumor suppressor gene is the gene for both von Hippel-Lindau disease as well as sporadic, clear-cell renal carcinoma. Germline mutations in the VHL gene predispose individuals to a variety of tumors, including renal carcinoma, CNS hemangioblastoma, islet cell tumors of the pancreas, and pheochromocytoma.
The cellular transcription factor Elongin (SIII) has been identified as a functional target of the VHL protein. The VHL protein has been shown to bind tightly and specifically to the Elongin B and C subunits and to inhibit Elongin (SIII) transcriptional activity in vitro. The VHL protein is found both in the nucleus and in the cytosol of transiently transfected cells. There is a tightly regulated, cell density-dependent transport of VHL into and/or out of the nucleus. A putative nuclear localization signal, a nuclear export signal, and a cytoplasmic retention locus have been identified in the VHL protein. These findings provide the initial indication of a novel cell density-dependent pathway that is responsible for the regulation of VHL cellular localization.
In order to further study the function of the VHL gene, additional studies of VHL-associated proteins have been carried out. Recently, Hs-CUL-2, a member of the recently identified multigene family, the cullins, has been shown to specifically associate with the trimeric pVHL-elongin B-C (VBC) complex in vitro and in vivo. Nearly 70 percent of naturally occurring cancer-predisposing mutations of VHL disrupt this interaction. Immunofluorescence studies show Hs-CUL-2 to be a cytosolic protein that can be translocated to the nucleus by pVHL. Hs-CUL-2 may be required for VHL function and, therefore, may be a candidate human tumor suppressor gene.
We have recently developed an improved method of detecting germline mutations in the von Hippel-Lindau disease tumor suppressor gene. We currently can detect mutations in a high percentage of kindreds with this hereditary cancer syndrome (nearly 100 percent). We have also recently identified a new phenotype associated with complete deletion of the VHL gene and are studying the somatic events associated with the development of cancer in this syndrome. We hope that understanding the molecular mechanism leading to cancer will lead to the development of new strategies for early detection, prevention, and treatment.
Characterization of the Hereditary Papillary Renal Cell Carcinoma Gene
A new hereditary cancer syndrome, hereditary papillary renal cell carcinoma (HPRC), has been described. Affected individuals with this hereditary form of renal cell carcinoma are at risk of developing multifocal, bilateral hereditary papillary renal cell carcinoma. Families with HPRC have been evaluated and linkage analysis has localized the HPRC to a locus on chromosome 7. The c-Met oncogene has been determined to be the HPRC gene. We have detected germline and somatic mutations in the tyrosine kinase domain of the Met proto-oncogene in papillary renal carcinomas and developed a strategy for predictive testing in this hereditary cancer syndrome. We have characterized the nonrandom duplication of the chromosome bearing the mutated Met in HPRC and demonstrated that this implicates this event in tumorigenesis.
Molecular Genetic Events Associated with Initiation and Progression of Prostate Cancer
The molecular genetic events associated with the initiation and progression of prostate cancer are poorly understood. Using a novel technique to microdissect tissue under direct microscopic visualization, pure populations of prostate carcinoma have been procured from prostate specimens. This microdissection has allowed the accurate examination of both DNA content and RNA expression in prostate carcinoma. Loss of heterozygosity at a locus on chromosome 8 in a high percentage of tumors from patients with prostate carcinoma has been detected and the area of minimal deletion on chromosome 8p12-21 determined. The identical genetic loss has been shown to be associated with prostate intraepithelial neoplasia (PIN), a precursor lesion in prostate cancer.
In collaboration with scientists in the Laboratory of Pathology, a technique for recovering and analyzing RNA from microdissected prostate cancer and by differential gene expression analysis has been developed, and a novel zinc finger gene upregulated in prostate cancer has been identified. cDNA libraries have been developed from normal, low-grade PIN, high-grade PIN, and prostate cancer. These libraries will be used in the microarray analysis to evaluate differentially expressed genes involved in initiation and progression of prostate cancer.
- Cancer Genome Atlas Research Network., Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, Wheeler DA, Murray BA, Schmidt L, Vocke CD, Peto M, Al Mamun AA, Shinbrot E, Sethi A, Brooks S, Rathmell WK, Brooks AN, Hoadley KA, Robertson AG, Brooks D, Bowlby R, Sadeghi S, Shen H, Weisenberger DJ, Bootwalla M, Baylin SB, Laird PW, Cherniack AD, Saksena G, Haake S, Li J, Liang H, Lu Y, Mills GB, Akbani R, Leiserson MD, Raphael BJ, Anur P, Bottaro D, Albiges L, Barnabas N, Choueiri TK, Czerniak B, Godwin AK, Hakimi AA, Ho TH, Hsieh J, Ittmann M, Kim WY, Krishnan B, Merino MJ, Mills Shaw KR, Reuter VE, Reznik E, Shelley CS, Shuch B, Signoretti S, Srinivasan R, Tamboli P, Thomas G, Tickoo S, Burnett K, Crain D, Gardner J, Lau K, Mallery D, Morris S, Paulauskis JD, Penny RJ, Shelton C, Shelton WT, Sherman M, Thompson E, Yena P, Avedon MT, Bowen J, Gastier-Foster JM, Gerken M, Leraas KM, Lichtenberg TM, Ramirez NC, Santos T, Wise L, Zmuda E, Demchok JA, Felau I, Hutter CM, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Zhang J, Ayala B, Baboud J, Chudamani S, Liu J, Lolla L, Naresh R, Pihl T, Sun Q, Wan Y, Wu Y, Ally A, Balasundaram M, Balu S, Beroukhim R, Bodenheimer T, Buhay C, Butterfield YS, Carlsen R, Carter SL, Chao H, Chuah E, Clarke A, Covington KR, Dahdouli M, Dewal N, Dhalla N, Doddapaneni HV, Drummond JA, Gabriel SB, Gibbs RA, Guin R, Hale W, Hawes A, Hayes DN, Holt RA, Hoyle AP, Jefferys SR, Jones SJ, Jones CD, Kalra D, Kovar C, Lewis L, Li J, Ma Y, Marra MA, Mayo M, Meng S, Meyerson M, Mieczkowski PA, Moore RA, Morton D, Mose LE, Mungall AJ, Muzny D, Parker JS, Perou CM, Roach J, Schein JE, Schumacher SE, Shi Y, Simons JV, Sipahimalani P, Skelly T, Soloway MG, Sougnez C, Tam A, Tan D, Thiessen N, Veluvolu U, Wang M, Wilkerson MD, Wong T, Wu J, Xi L, Zhou J, Bedford J, Chen F, Fu Y, Gerstein M, Haussler D, Kasaian K, Lai P, Ling S, Radenbaugh A, Van Den Berg D, Weinstein JN, Zhu J, Albert M, Alexopoulou I, Andersen JJ, Auman JT, Bartlett J, Bastacky S, Bergsten J, Blute ML, Boice L, Bollag RJ, Boyd J, Castle E, Chen YB, Cheville JC, Curley E, Davies B, DeVolk A, Dhir R, Dike L, Eckman J, Engel J, Harr J, Hrebinko R, Huang M, Huelsenbeck-Dill L, Iacocca M, Jacobs B, Lobis M, Maranchie JK, McMeekin S, Myers J, Nelson J, Parfitt J, Parwani A, Petrelli N, Rabeno B, Roy S, Salner AL, Slaton J, Stanton M, Thompson RH, Thorne L, Tucker K, Weinberger PM, Winemiller C, Zach LA, Zuna R. Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma. N Engl J Med. 2016;374(2):135-45.
- Cancer Genome Atlas Research Network.. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43-9.
- Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2011;481(7381):385-8.
- Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, Scherer SW, Zhuang Z, Lubensky I, Dean M, Allikmets R, Chidambaram A, Bergerheim UR, Feltis JT, Casadevall C, Zamarron A, Bernues M, Richard S, Lips CJ, Walther MM, Tsui LC, Geil L, Orcutt ML, Stackhouse T, Lipan J, Slife L, Brauch H, Decker J, Niehans G, Hughson MD, Moch H, Storkel S, Lerman MI, Linehan WM, Zbar B. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet. 1997;16(1):68-73.
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