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Published on: July 3, 2013
K-ras Mutations as the Earliest Driving Force in a Subset of Colorectal Carcinomas
Nikolaos Margetis1,2, Myrsini Kouloukoussa2, Kyriaki Pavlou2
1"Athens Euroclinic", Athens, Greece nmargetis@yahoo.gr.
Abstract:
K-ras oncogene is a key factor in colorectal cancer. Based on published and our data we propose that K-ras could be the oncogene responsible for the inactivation of the tumor-suppressor gene APC, currently considered as the initial step in colorectal tumorigenesis. K-ras fulfills the criteria of the oncogene-induced DNA damage model, as it can provoke well-established causes for inactivating tumor-suppressors, i.e. DNA double-strand breaks (causing allele deletion) and ROS production (responsible for point mutation). The model we propose is a variation of the currently existing model and hypothesizes that, in a subgroup of colorectal carcinomas, K-ras mutation may precede APC inactivation, representing the earliest driving force and, probably, an early biomarker of colorectal carcinogenesis. This observation is clinically useful, since it may modify the preventive colorectal cancer strategy, restricting numerically patients undergoing colonoscopies to those bearing K-ras mutation in their colorectum, either in benign polyps or the normal accompanying mucosa.
Insights
K-ras mutations may initiate colorectal cancer by inactivating the APC tumor suppressor gene, preceding current models. This finding could refine cancer prevention strategies by targeting patients with K-ras mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Colorectal cancer (CRC) development is complex, with APC gene inactivation traditionally viewed as an early event.
- The role of K-ras oncogene in CRC pathogenesis is established, but its precise initiation timing is debated.
Purpose of the Study:
- To propose a revised model of colorectal tumorigenesis where K-ras mutation precedes APC inactivation.
- To investigate K-ras as a potential early driver and biomarker in a subset of colorectal carcinomas.
Main Methods:
- Review and synthesis of published data and novel findings.
- Evaluation of K-ras against the oncogene-induced DNA damage model criteria.
- Hypothesizing a mechanistic link between K-ras activity and APC inactivation (DNA double-strand breaks, ROS production).
Main Results:
- K-ras oncogene activation can induce DNA damage (double-strand breaks, ROS production) capable of inactivating tumor suppressor genes like APC.
- A subgroup of colorectal carcinomas may exhibit K-ras mutation preceding APC inactivation.
- This sequence represents a potential earliest driving force in colorectal carcinogenesis.
Conclusions:
- K-ras mutation may initiate colorectal cancer by preceding APC inactivation, challenging current models.
- K-ras mutation could serve as an early biomarker for colorectal carcinogenesis.
- This insight may lead to targeted preventive strategies, focusing colonoscopies on individuals with K-ras mutations.
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