We have developed a novel diagnostic method to detect single point mutations in transcribed genes which is based on the ability of RNAseA to recognize and cleave single base mismatches in RNA:RNA heteroduplexes, and we have applied this method to analyze the involvement of ras mutational activation in human tumorigenesis. Our data support the concept that ras oncogenes are contributing in a dominant but dose-dependent manner to the process of tumor development and progression and for the first time demonstrate the frequent involvement of somatic ras mutational activation in the early stages of human tumorigenesis. We propose in this application to continue these studies to resolve a series of issues raised by our previous findings concerning the role that mutant ras oncognees are playing in human tumorigenesis. The experimental strategy will involve a screening descriptive approach by utilization of combinations of molecular genetics diagnostic techniques to detect, characterize and estimate the relative expression level of mutant ras oncogenes in human tumors at different stages of progression, and a functional approach using animal tumorigenicity and metastasis model systems. Emphasis will be made in the analysis of human colon carcinomatogenesis, inluding benign adenomatous polyps and villous adenomas. Clinical follow-up studies will be performed in an effort to determine whether apparent corelations previously found between various aspects of the nature and expression levels of the c-K-ras onogene and the histopathological charateristics of the corresponding colon tumors could have a prognostic value for this common type of human cancer. Successful development of these studies would have direct applications for diagnosis and prognosis in human cancer and should yield useful information at the molecular genetic level on the role of oncogene activation in various basic aspects of tumor biology such as the metastatic process and the heterogeneity of solid tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA038579-09
Application #
3176657
Study Section
Pathology B Study Section (PTHB)
Project Start
1988-09-30
Project End
1993-06-30
Budget Start
1992-01-01
Budget End
1993-06-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
California Institute of Biological Research
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Schwartz Jr, Simo; Alazzouzi, Hafid; Perucho, Manuel (2006) Mutational dynamics in human tumors confirm the neutral intrinsic instability of the mitochondrial D-loop poly-cytidine repeat. Genes Chromosomes Cancer 45:770-80
Yamashita, Kentaro; Dai, Tomoko; Dai, Yuichi et al. (2003) Genetics supersedes epigenetics in colon cancer phenotype. Cancer Cell 4:121-31
Suzuki, Koichi; Dai, Tomoko; Suzuki, Ikuko et al. (2002) Low mutation incidence in polymorphic noncoding short mononucleotide repeats in gastrointestinal cancer of the microsatellite mutator phenotype pathway. Cancer Res 62:1961-5
Ohmiya, N; Matsumoto, S; Yamamoto, H et al. (2001) Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype. Gene 272:301-13
Baranovskaya, S; Soto, J L; Perucho, M et al. (2001) Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype. Proc Natl Acad Sci U S A 98:15107-12
Ionov, Y; Yamamoto, H; Krajewski, S et al. (2000) Mutational inactivation of the proapoptotic gene BAX confers selective advantage during tumor clonal evolution. Proc Natl Acad Sci U S A 97:10872-7
Yamamoto, H; Perez-Piteira, J; Yoshida, T et al. (1999) Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical features. Gastroenterology 116:1348-57
Gil, J; Yamamoto, H; Zapata, J M et al. (1999) Impairment of the proapoptotic activity of Bax by missense mutations found in gastrointestinal cancers. Cancer Res 59:2034-7
Schwartz Jr, S; Yamamoto, H; Navarro, M et al. (1999) Frameshift mutations at mononucleotide repeats in caspase-5 and other target genes in endometrial and gastrointestinal cancer of the microsatellite mutator phenotype. Cancer Res 59:2995-3002
Yamamoto, H; Sawai, H; Weber, T K et al. (1998) Somatic frameshift mutations in DNA mismatch repair and proapoptosis genes in hereditary nonpolyposis colorectal cancer. Cancer Res 58:997-1003

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