Colorectal cancers are widely believed to develop through an adenoma-cancer sequence. By this paradigm, all cancers should be preventable with surveillance and polypectomy. However, in most surveillance studies, some cancers inevitably appear only a few years after negative clinical examinations. It is uncertain how such """"""""interval"""""""" cancers appear, but either an adenoma was missed during the last """"""""negative"""""""" examination, or there was an unexpected """"""""rapid"""""""" mode of progression. A large number of such interval cancers have been found during an ongoing clinical surveillance program of high risk individuals with germline mutations in DNA mismatch repair genes (MMR), or hereditary nonpolyposis colorectal cancer (HNPCC). These interval cancers provide unique opportunities to rigorously understand why prevention fails. The key emerging technology is a new capability that infers time from cancer mutations. A molecular tumor clock can quantitatively infer times since MMR loss, and ages of final cancer expansions---the more mutations in a cancer, the greater these intervals. Distinguishing between failure from inadequate surveillance (""""""""missed adenomas""""""""), and failure due to the unique biology of HNPCC colorectal cancers (""""""""rapid histologic or genetic progression""""""""), is critical for the development of more effective strategies to prevent and treat colorectal cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33CA111940-02
Application #
7105101
Study Section
Special Emphasis Panel (ZCA1-SRRB-C (O1))
Program Officer
Thurin, Magdalena
Project Start
2005-08-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$239,550
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Siegmund, Kimberly D; Marjoram, Paul; Tavaré, Simon et al. (2011) High DNA methylation pattern intratumoral diversity implies weak selection in many human colorectal cancers. PLoS One 6:e21657
Woo, Yen-Jung; Siegmund, Kimberly D; Tavaré, Simon et al. (2009) Older individuals appear to acquire mitotically older colorectal cancers. J Pathol 217:483-8
Chu, Michelle; Siegmund, Kimberly D; Hao, Qian-Lin et al. (2008) Inferring relative numbers of human leucocyte genome replications. Br J Haematol 141:862-71
Shibata, Darryl (2008) Stem cells as common ancestors in a colorectal cancer ancestral tree. Curr Opin Gastroenterol 24:59-63
Kern, Scott E; Shibata, Darryl (2007) The fuzzy math of solid tumor stem cells: a perspective. Cancer Res 67:8985-8
Nicolas, Pierre; Kim, Kyoung-Mee; Shibata, Darryl et al. (2007) The stem cell population of the human colon crypt: analysis via methylation patterns. PLoS Comput Biol 3:e28