Gastrointestinal cancers of the microsatellite mutator phenotype (MMP) differ in genotype and phenotype from tumors without the MMP. APC, p53 and K-ras cancer genes are commonly mutated in MMP- tumors while mutational inactivation of TGFbetaRII and BAX is essentially restricted to MMP+ cancers. We propose that the existence and distinctive features of the MMP pathway for cancer, characteristic of tumors of the Hereditary Non-Polyposis Colorectal Cancer (HNPCC) syndrome and about 15% of sporadic gastrointestinal cancers, ultimately depends on the presence in some cancer genes of sequences target for the MMP.
In specific aim 1 we will test the hypothesis of the existence of a MMP-dependent pathway for cancer. We propose to investigate the differences in genotype between tumors with or without the MMP. We will complete the screening of mutations in the APC suppressor gene in MMP+ and MMP- colon tumors (1a); determine whether the differences in genotype between MMP+ and MMP- gastrointestinal tumors also extend to widespread somatic changes in DNA methylation that we have observed in colon, breast and prostate cancer, specifically in the homeobox gene family (1b); and exploit the peculiar phenotypic features of MMP cancer to develop diagnostic assays for hereditary and sporadic cancer of the MMP (1c).
In specific aim 2 we will test the hypothesis that the MMP unfolds gradually by the mutational inactivation of multiple mutator genes. We propose to investigate the model of the """"""""mutator that mutates another mutator"""""""". We will complete the screening of colorectal and gastric MMP+ adenocarcinomas for mutations in the known members of the DNA mismatch repair (MMR) gene family (2a); perform a functional analysis of the effect of mutations in individual MMR mutator genes and their combinations in the spectra of mutations in the tumor cells (2b); and establish the prognostic value of these findings for cancer of the MMP (2c).
In specific aim 3 we will test the hypothesis that the escape from apoptosis is a critical event in tumorigenesis of the MMP. We propose to investigate the mechanisms by which BAX mutational inactivation contributes to the escape from apoptosis and to tumorigenesis of tumors cells of the MMP. We will complete the screening of MMP+ and MMP- tumors for mutations in BAX (3a); perform a functional analysis of the role of BAX gene inactivation in cancer of the MMP by in vivo and in vitro assays (3b); and investigate the prognostic value of BAX somatic mutational inactivation for cancer of the MMP.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
2R37CA063585-07
Application #
2852230
Study Section
Special Emphasis Panel (ZRG1-MEP (02))
Program Officer
Lively, Tracy (LUGO)
Project Start
1994-05-01
Project End
2004-05-31
Budget Start
1999-08-11
Budget End
2000-05-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
009214214
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Alonso, Sergio; Dai, Yuichi; Yamashita, Kentaro et al. (2015) Methylation of MGMT and ADAMTS14 in normal colon mucosa: biomarkers of a field defect for cancerization preferentially targeting elder African-Americans. Oncotarget 6:3420-31
Kamiyama, H; Suzuki, K; Maeda, T et al. (2012) DNA demethylation in normal colon tissue predicts predisposition to multiple cancers. Oncogene 31:5029-37
Samuelsson, Johanna; Alonso, Sergio; Ruiz-Larroya, Tatiana et al. (2011) Frequent somatic demethylation of RAPGEF1/C3G intronic sequences in gastrointestinal and gynecological cancer. Int J Oncol 38:1575-7
Samuelsson, Johanna K; Alonso, Sergio; Yamamoto, Fumiichiro et al. (2010) DNA fingerprinting techniques for the analysis of genetic and epigenetic alterations in colorectal cancer. Mutat Res 693:61-76
Bilbao, Cristina; Lara, Pedro Carlos; Ramirez, Raquel et al. (2010) Microsatellite instability predicts clinical outcome in radiation-treated endometrioid endometrial cancer. Int J Radiat Oncol Biol Phys 76:9-13
Baranovskaya, Svetlana; Martin, Yolanda; Alonso, Sergio et al. (2009) Down-regulation of epidermal growth factor receptor by selective expansion of a 5'-end regulatory dinucleotide repeat in colon cancer with microsatellite instability. Clin Cancer Res 15:4531-7
Zhou, Wenyun; Alonso, Sergio; Takai, Daisaku et al. (2008) Requirement of RIZ1 for cancer prevention by methyl-balanced diet. PLoS One 3:e3390
Davalos, V; Dopeso, H; Velho, S et al. (2007) High EPHB2 mutation rate in gastric but not endometrial tumors with microsatellite instability. Oncogene 26:308-11
Gonzalez-Garcia, Isabel; Castells, Antoni (2007) New insights into a controversial topic: the methylation-cancer connection. Gastroenterology 132:2069-70;discussion 2070-1
Bilbao, Cristina; Rodriguez, German; Ramirez, Raquel et al. (2006) The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer. Int J Cancer 119:563-70

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