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Genomic instability and radiation risk in molecular pathways to colon cancer.

Kaiser JC, Meckbach R, Jacob P - PLoS ONE (2014)

Bottom Line: Model results suggest that CIN begins during fission of intestinal crypts.Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma.Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk.

View Article: PubMed Central - PubMed

Affiliation: Institute of Radiation Protection, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.

ABSTRACT
Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI). GI appears in molecular pathways of microsatellite instability (MSI) and chromosomal instability (CIN) with clinically observed case shares of about 15-20% and 80-85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN. Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Model results suggest that CIN begins during fission of intestinal crypts. Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. An imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients, if their exposure histories are known.

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Related in: MedlinePlus

Predicted incidence rates for men (full lines) and women (dashed lines) from the two path model TP4 (red) and the contributions of the CIN pathway (green) and the MSI path (blue dot-dashed line, both sexes) in 14 intervals of attained age from 20–25 yr to 85–90 yr.
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pone-0111024-g002: Predicted incidence rates for men (full lines) and women (dashed lines) from the two path model TP4 (red) and the contributions of the CIN pathway (green) and the MSI path (blue dot-dashed line, both sexes) in 14 intervals of attained age from 20–25 yr to 85–90 yr.

Mentions: inspired by Nowak et al. [16], derived from Little and Li [17] (their Figure 2), see SI, Table S3 and Figure S2 in File S1.


Genomic instability and radiation risk in molecular pathways to colon cancer.

Kaiser JC, Meckbach R, Jacob P - PLoS ONE (2014)

Predicted incidence rates for men (full lines) and women (dashed lines) from the two path model TP4 (red) and the contributions of the CIN pathway (green) and the MSI path (blue dot-dashed line, both sexes) in 14 intervals of attained age from 20–25 yr to 85–90 yr.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214691&req=5

pone-0111024-g002: Predicted incidence rates for men (full lines) and women (dashed lines) from the two path model TP4 (red) and the contributions of the CIN pathway (green) and the MSI path (blue dot-dashed line, both sexes) in 14 intervals of attained age from 20–25 yr to 85–90 yr.
Mentions: inspired by Nowak et al. [16], derived from Little and Li [17] (their Figure 2), see SI, Table S3 and Figure S2 in File S1.

Bottom Line: Model results suggest that CIN begins during fission of intestinal crypts.Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma.Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk.

View Article: PubMed Central - PubMed

Affiliation: Institute of Radiation Protection, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany.

ABSTRACT
Colon cancer is caused by multiple genomic alterations which lead to genomic instability (GI). GI appears in molecular pathways of microsatellite instability (MSI) and chromosomal instability (CIN) with clinically observed case shares of about 15-20% and 80-85%. Radiation enhances the colon cancer risk by inducing GI, but little is known about different outcomes for MSI and CIN. Computer-based modelling can facilitate the understanding of the phenomena named above. Comprehensive biological models, which combine the two main molecular pathways to colon cancer, are fitted to incidence data of Japanese a-bomb survivors. The preferred model is selected according to statistical criteria and biological plausibility. Imprints of cell-based processes in the succession from adenoma to carcinoma are identified by the model from age dependences and secular trends of the incidence data. Model parameters show remarkable compliance with mutation rates and growth rates for adenoma, which has been reported over the last fifteen years. Model results suggest that CIN begins during fission of intestinal crypts. Chromosomal aberrations are generated at a markedly elevated rate which favors the accelerated growth of premalignant adenoma. Possibly driven by a trend of Westernization in the Japanese diet, incidence rates for the CIN pathway increased notably in subsequent birth cohorts, whereas rates pertaining to MSI remained constant. An imbalance between number of CIN and MSI cases began to emerge in the 1980s, whereas in previous decades the number of cases was almost equal. The CIN pathway exhibits a strong radio-sensitivity, probably more intensive in men. Among young birth cohorts of both sexes the excess absolute radiation risk related to CIN is larger by an order of magnitude compared to the MSI-related risk. Observance of pathway-specific risks improves the determination of the probability of causation for radiation-induced colon cancer in individual patients, if their exposure histories are known.

Show MeSH
Related in: MedlinePlus