title: The genetic basis of kidney cancer: a metabolic disease.
abstract: Kidney cancer is not a single disease but comprises a number of different types of cancer that occur in the kidney, each caused by a different gene with a different histology and clinical course that responds differently to therapy. Each of the seven known kidney cancer genes, VHL, MET, FLCN, TSC1, TSC2, FH and SDH, is involved in pathways that respond to metabolic stress or nutrient stimulation. The VHL protein is a component of the oxygen and iron sensing pathway that regulates hypoxia-inducible factor (HIF) levels in the cell. HGF-MET signaling affects the LKB1-AMPK energy sensing cascade. The FLCN-FNIP1-FNIP2 complex binds AMPK and, therefore, might interact with the cellular energy and nutrient sensing pathways AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR. TSC1-TSC2 is downstream of AMPK and negatively regulates mTOR in response to cellular energy deficit. FH and SDH have a central role in the mitochondrial tricarboxylic acid cycle, which is coupled to energy production through oxidative phosphorylation. Mutations in each of these kidney cancer genes result in dysregulation of metabolic pathways involved in oxygen, iron, energy or nutrient sensing, suggesting that kidney cancer is a disease of cell metabolism. Targeting the fundamental metabolic abnormalities in kidney cancer provides a unique opportunity for the development of more-effective forms of therapy for this disease.
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, Bethesda, MD 20892-1107, USA. wml@nih.gov <wml@nih.gov>
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Ramaprasad
authors.initials: R
authors.lastname: Srinivasan
authors.forename: Laura S
authors.initials: LS
authors.lastname: Schmidt
mesh_terms: D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics; D002952:Citric Acid Cycle / Q000235:genetics; D005649:Fumarate Hydratase / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000235:genetics; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: C476078:FLCN protein, human; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D005649:Fumarate Hydratase; C497446:VHL protein, human
references.citation: Gene. 2008 May 31;415(1-2):60-7
references.pmid: 18403135
references.citation: Am J Hum Genet. 2004 Jan;74(1):153-9
references.pmid: 14685938
references.citation: J Natl Cancer Inst. 2005 Jun 15;97(12):931-5
references.pmid: 15956655
references.citation: Nat Med. 2004 Aug;10(8):789-99
references.pmid: 15286780
references.citation: Hum Genet. 1992 Sep-Oct;90(1-2):17-22
references.pmid: 1358787
references.citation: Biochem J. 2008 Jun 1;412(2):211-21
references.pmid: 18387000
references.citation: J Med Genet. 2008 Jun;45(6):321-31
references.pmid: 18234728
references.citation: Nat Genet. 1997 May;16(1):68-73
references.pmid: 9140397
references.citation: Cancer Cell. 2002 Apr;1(3):237-46
references.pmid: 12086860
references.citation: Annu Rev Med. 2010;61:329-43
references.pmid: 20059341
references.citation: Nature. 1999 May 20;399(6733):271-5
references.pmid: 10353251
references.citation: Proc Natl Acad Sci U S A. 2006 Oct 17;103(42):15552-7
references.pmid: 17028174
references.citation: Science. 2000 Feb 4;287(5454):848-51
references.pmid: 10657297
references.citation: Hum Mutat. 1998;12(6):417-23
references.pmid: 9829911
references.citation: Cancer Cell. 2002 Aug;2(2):157-64
references.pmid: 12204536
references.citation: Am J Hum Genet. 2003 Jul;73(1):95-106
references.pmid: 12772087
references.citation: PLoS Biol. 2003 Dec;1(3):E83
references.pmid: 14691554
references.citation: Am J Respir Crit Care Med. 2007 May 15;175(10):1044-53
references.pmid: 17322109
references.citation: Science. 1993 May 28;260(5112):1317-20
references.pmid: 8493574
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4726-34
references.pmid: 18676741
references.citation: Science. 1995 Sep 8;269(5229):1402-6
references.pmid: 7660122
references.citation: Cancer Cell. 2008 Dec 9;14(6):435-46
references.pmid: 19061835
references.citation: J Med Chem. 2008 Aug 14;51(15):4632-40
references.pmid: 18620382
references.citation: Nature. 1988 Mar 17;332(6161):268-9
references.pmid: 2894613
references.citation: J Natl Cancer Inst. 2008 Jan 16;100(2):140-54
references.pmid: 18182616
references.citation: Am J Hum Genet. 2001 Oct;69(4):876-82
references.pmid: 11533913
references.citation: Arch Dermatol. 1977 Dec;113(12):1674-7
references.pmid: 596896
references.citation: J Biomol Screen. 2006 Sep;11(6):678-87
references.pmid: 16858007
references.citation: Am J Pathol. 1996 Oct;149(4):1201-8
references.pmid: 8863669
references.citation: Cancer Res. 2004 Feb 15;64(4):1475-82
references.pmid: 14983893
references.citation: Cancer Res. 2010 Jan 1;70(1):288-98
references.pmid: 20028854
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10595-9
references.pmid: 8855223
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Hum Genet. 1991 Apr;86(6):567-77
references.pmid: 1673958
references.citation: Am J Pathol. 1999 Aug;155(2):517-26
references.pmid: 10433944
references.citation: Cancer Cell. 2008 Jul 8;14(1):90-102
references.pmid: 18598947
references.citation: Cancer Res. 1994 Jun 1;54(11):2852-5
references.pmid: 8187067
references.citation: Arch Dermatol. 2008 Dec;144(12):1584-92
references.pmid: 19075141
references.citation: BMJ. 2005 Jun 4;330(7503):1304-5
references.pmid: 15849206
references.citation: J Urol. 2003 Dec;170(6 Pt 1):2163-72
references.pmid: 14634372
references.citation: J Urol. 2005 May;173(5):1482-6
references.pmid: 15821464
references.citation: Hum Mol Genet. 1993 Mar;2(3):279-82
references.pmid: 8499917
references.citation: Mol Cancer Ther. 2009 Mar;8(3):626-35
references.pmid: 19276158
references.citation: Hum Pathol. 2002 Jan;33(1):68-79
references.pmid: 11823975
references.citation: Fam Cancer. 2009;8(3):257-60
references.pmid: 19184535
references.citation: Urol Int. 2006;77(2):184-6
references.pmid: 16888429
references.citation: PLoS One. 2008;3(10):e3581
references.pmid: 18974783
references.citation: Mol Cell Biol. 2009 Aug;29(15):4080-90
references.pmid: 19470762
references.citation: Am J Hum Genet. 2005 Jun;76(6):1023-33
references.pmid: 15852235
references.citation: J Biol Chem. 2008 Dec 12;283(50):34495-9
references.pmid: 18945681
references.citation: Cancer Cell. 2005 Aug;8(2):143-53
references.pmid: 16098467
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18722-7
references.pmid: 19850877
references.citation: N Engl J Med. 2000 Nov 2;343(18):1305-11
references.pmid: 11058675
references.citation: Am J Surg Pathol. 2007 Oct;31(10):1578-85
references.pmid: 17895761
references.citation: Carcinogenesis. 2007 Apr;28(4):785-91
references.pmid: 17127713
references.citation: Clin Cancer Res. 2003 Jan;9(1):327-37
references.pmid: 12538485
references.citation: Trends Genet. 2008 Aug;24(8):398-407
references.pmid: 18606475
references.citation: Cancer Genet Cytogenet. 2010 Jan 1;196(1):45-55
references.pmid: 19963135
references.citation: Oncogene. 2008 Sep 11;27(40):5339-47
references.pmid: 18663353
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2156-61
references.pmid: 9122164
references.citation: JAMA. 1992 Mar 4;267(9):1226-31
references.pmid: 1347089
references.citation: Science. 2001 Apr 20;292(5516):468-72
references.pmid: 11292861
references.citation: J Med Genet. 1992 Dec;29(12):902-5
references.pmid: 1362224
references.citation: Nat Genet. 2002 Apr;30(4):406-10
references.pmid: 11865300
references.citation: Clin Cancer Res. 2006 Jun 15;12(12):3657-60
references.pmid: 16778093
references.citation: Lancet Oncol. 2007 Nov;8(11):975-84
references.pmid: 17959415
references.citation: JAMA. 2004 Aug 25;292(8):943-51
references.pmid: 15328326
references.citation: Science. 1995 Sep 8;269(5229):1444-6
references.pmid: 7660130
references.citation: Am J Surg Pathol. 2002 Dec;26(12):1542-52
references.pmid: 12459621
references.citation: Cancer Cell. 2002 Apr;1(3):247-55
references.pmid: 12086861
references.citation: J Med Genet. 2006 Jan;43(1):18-27
references.pmid: 15937070
references.citation: Nat Chem Biol. 2006 Aug;2(8):406-14
references.pmid: 16850017
references.citation: N Engl J Med. 2006 Sep 28;355(13):1345-56
references.pmid: 17005952
references.citation: Nat Struct Mol Biol. 2007 May;14(5):420-6
references.pmid: 17417656
references.citation: Clin Endocrinol (Oxf). 2008 Oct;69(4):587-96
references.pmid: 18419787
references.citation: Am J Surg Pathol. 1995 Jan;19(1):1-11
references.pmid: 7528470
references.citation: Mol Cell. 2008 Dec 26;32(6):838-48
references.pmid: 19111663
references.citation: Cancer Res. 2009 Oct 1;69(19):7507-11
references.pmid: 19752085
references.citation: Nat Med. 2006 Jan;12(1):122-7
references.pmid: 16341243
references.citation: Nat Genet. 1994 May;7(1):85-90
references.pmid: 7915601
references.citation: Cancer Res. 2002 Aug 1;62(15):4316-24
references.pmid: 12154035
references.citation: Oncogene. 1999 Apr 8;18(14):2343-50
references.pmid: 10327054
references.citation: Cell. 2009 Sep 18;138(6):1051-4
references.pmid: 19766556
references.citation: Cancer Res. 2004 Oct 1;64(19):7099-109
references.pmid: 15466206
references.citation: J Natl Cancer Inst. 2008 Sep 3;100(17):1260-2
references.pmid: 18728283
references.citation: Genes Dev. 2009 Mar 1;23(5):537-48
references.pmid: 19270154
references.citation: Diabetes Care. 2010 Feb;33(2):322-6
references.pmid: 19918015
references.citation: Nat Rev Cancer. 2002 Sep;2(9):673-82
references.pmid: 12209156
references.citation: J Clin Oncol. 2009 Aug 1;27(22):3584-90
references.pmid: 19487381
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683