Genetic and epigenetic tumor suppressor gene silencing are distinct molecular phenotypes driven by growth promoting mutations in nonsmall cell lung cancer.
Both genetic and epigenetic alterations characterize human nonsmall cell lung cancer (NSCLC), but the biological processes that create or select these alterations remain incompletely investigated. Our hypothesis posits that a roughly reciprocal relationship between the propensity for promoter hypermethylation and a propensity for genetic deletion leads to distinct molecular phenotypes of lung cancer. To test this hypothesis, we examined promoter hypermethylation of 17 tumor suppressor genes, as a marker of epigenetic alteration propensity, and deletion events at the 3p21 region, as a marker of genetic alteration. To model the complex biology between these somatic alterations, we utilized an item response theory model. We demonstrated that tumors exhibiting LOH at greater than 30% of informative alleles in the 3p21 region have a significantly reduced propensity for hypermethylation. At the same time, tumors with activating KRAS mutations showed a significantly increased propensity for hypermethylation of the loci examined, a result similar to what has been observed in colon cancer. These data suggest that NSCLCs have distinct epigenetic or genetic alteration phenotypes acting upon tumor suppressor genes and that mutation of oncogenic growth promoting genes, such as KRAS, is associated with the epigenetic phenotype.
Marsit
Carmen J
CJ
Department of Pathology and Laboratory Medicine, Center for Environmental Health and Technology, Brown University, Providence, RI 02912, USA.
Houseman
E Andres
EA
Nelson
Heather H
HH
Kelsey
Karl T
KT
Cancer Res. 2005 Aug 15;65(16):7081-5
16103055
Cancer Res. 1999 Nov 1;59(21):5438-42
10554013
Nucleic Acids Res. 2000 Apr 15;28(8):E32
10734209
Cancer Res. 2006 Nov 1;66(21):10621-9
17079487
Oncogene. 2002 May 23;21(23):3792-5
12032847
J Clin Oncol. 2005 Apr 10;23(11):2513-20
15738541
Biometrics. 2007 Dec;63(4):1269-77
17484774
J Natl Cancer Inst. 1999 Dec 1;91(23):2032-8
10580029
Nat Genet. 2006 Jul;38(7):787-93
16804544
Cancer J. 2002 May-Jun;8 Suppl 1:S41-6
12075701
Int J Cancer. 2006 Mar 15;118(6):1364-9
16184554
Int J Cancer. 2005 Mar 20;114(2):219-23
15540210
Cancer Sci. 2007 Jan;98(1):96-101
17054433
Am J Pathol. 2002 May;160(5):1823-30
12000733
Cancer Res. 2003 Oct 15;63(20):6575-8
14583448
Cancer Res. 1999 Sep 15;59(18):4570-3
10493509
Cancer Res. 2001 Mar 15;61(6):2782-7
11289162
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8681-6
10411935
Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9821-6
8790415
Clin Cancer Res. 2005 Oct 1;11(19 Pt 1):6816-22
16203769
Clin Cancer Res. 2006 Mar 1;12(5):1647-53
16533793
Int J Cancer. 2003 Aug 20;106(2):198-204
12800194
Gastroenterology. 2005 Sep;129(3):837-45
16143123
Science. 2006 Oct 13;314(5797):268-74
16959974
Cancer Cell. 2003 Aug;4(2):121-31
12957287
Cancer Res. 2001 Aug 1;61(15):5727-30
11479207
Cancer Res. 2004 Feb 15;64(4):1425-30
14973053
Carcinogenesis. 2005 Sep;26(9):1481-7
15661809
Cancer Cell. 2002 Feb;1(1):49-52
12086887
Clin Cancer Res. 2001 Jul;7(7):1998-2004
11448917
J Clin Oncol. 2005 Nov 1;23(31):8081-92
16204011
Cancer Res. 2001 Apr 15;61(8):3419-24
11309302
Cancer Res. 2001 Jan 15;61(2):612-5
11212258
Cancer Res. 2006 Feb 1;66(3):1371-5
16452191
Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):710-5
10639144
Cancer Res. 1998 May 1;58(9):1804-7
9581816
Oncologist. 2007 Jan;12(1):90-8
17285735
Int J Cancer. 2003 Jan 10;103(2):153-60
12455028
Cancer Res. 1997 Jun 1;57(11):2121-3
9187107
Nat Genet. 2004 Apr;36(4):417-22
15034581
Nature. 2002 Aug 29;418(6901):934
12198537
CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30
16514137
Br J Cancer. 2001 Jan;84(2):226-31
11161381
Cancer Res. 2002 Apr 15;62(8):2370-7
11956099
Cancer Res. 2001 Jan 1;61(1):249-55
11196170
Clin Cancer Res. 2005 Feb 1;11(3):1167-73
15709185
Int J Cancer. 2006 Feb 15;118(4):924-31
16108009
Cancer Res. 2004 Dec 1;64(23):8702-7
15574780