Using the technique of inter-(simple sequence repeat) PCR, we have shown that genomic destabilization in human sporadic colorectal cancer begins very early in progression and is extensive, with an estimate of around ten thousand events per tumor cell. We hypothesize that this rampant instability may be the essence of this malignancy, facilitating vastly accelerated somatic evolution, which through natural selection evolves to the proliferating, invading, evolving mass of cells known as cancer. But what are these genomic events arising out of genomic instability, which we are detecting? By what mechanisms do they occur? Are they truly relevant? By characterizing events detected by inter-(simple sequence repeat) PCR, we intend to answer these questions. Molecular characterization will point to mechanisms, and localization and sequencing will test randomness. Colorectal tumors are heterogeneous, but how extensive is this at the genome level? Are cells with severely disrupted genomes only dead end side branches in the tumor progression pathway? By comparing the genomic damage in multiple microsamples in comparison to that of macrosamples, we will evaluate if lineages with severely disrupted genomes exist and continue to progress. What is the relationship between MLH3 mutation and non- microsatellite instability in sporadic colorectal cancer. We have published evidence that MLH3 may play an important role in intrachromosomal instability in sporadic colorectal cancer. This work will be tested and developed. These studies should allow us to develop a clearer picture of how genomic instability relates to human colorectal tumor progression, how it relates to tumor heterogeneity, and how it arises mechanistically.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA074127-06
Application #
6721479
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Okano, Paul
Project Start
1998-02-01
Project End
2006-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
6
Fiscal Year
2004
Total Cost
$308,683
Indirect Cost
Name
Roswell Park Cancer Institute Corp
Department
Type
DUNS #
824771034
City
Buffalo
State
NY
Country
United States
Zip Code
14263
Brenner, Bruce M; Swede, Helen; Jones, Beth A et al. (2012) Genomic instability measured by inter-(simple sequence repeat) PCR and high-resolution microsatellite instability are prognostic of colorectal carcinoma survival after surgical resection. Ann Surg Oncol 19:344-50
Darbary, Huferesh; Stoler, Daniel L; Anderson, Garth R (2009) Family cancer syndromes: inherited deficiencies in systems for the maintenance of genomic integrity. Surg Oncol Clin N Am 18:1-17, vii
Darbary, Huferesh K; Dutt, Smitha S; Sait, Sheila J et al. (2009) Uniparentalism in sporadic colorectal cancer is independent of imprint status, and coordinate for chromosomes 14 and 18. Cancer Genet Cytogenet 189:77-86
Dutt, Smitha S; Chen, Neng; Darbary, Huferesh K et al. (2008) Colorectal cancers in patients with the (9A/6A) polymorphism of TGFBR1 exhibit lesser inter-(simple sequence repeat) PCR genomic instability and present clinically at greater age. Mutat Res 645:27-32
Bartos, Jeremy D; Gaile, Daniel P; McQuaid, Devin E et al. (2007) aCGH local copy number aberrations associated with overall copy number genomic instability in colorectal cancer: coordinate involvement of the regions including BCR and ABL. Mutat Res 615:1-11
Stoler, Daniel L; Nowak, Norma J; Matsui, Sei-ichi et al. (2007) Comparative genomic instabilities of thyroid and colon cancers. Arch Otolaryngol Head Neck Surg 133:457-63
Brenner, Bruce M; Stoler, Daniel L; Rodriguez, Luz et al. (2007) Allelic losses at genomic instability-associated loci in villous adenomas and adjacent colorectal cancers. Cancer Genet Cytogenet 174:9-15
Alrawi, Sadir J; Carroll, Robert E; Hill, Hank C et al. (2006) Genomic instability of human aberrant crypt foci measured by inter-(simple sequence repeat) PCR and array-CGH. Mutat Res 601:30-8
Stoler, Daniel L; Bartos, Jeremy D; Swede, Helen et al. (2006) Genomic instability in invasive breast carcinoma measured by inter-Simple Sequence Repeat PCR. Breast Cancer Res Treat 97:107-10
Swede, Helen; Bartos, Jeremy D; Chen, Neng et al. (2006) Genomic profiles of colorectal cancers differ based on patient smoking status. Cancer Genet Cytogenet 168:98-104

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