Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis - PubMed (original) (raw)

Review

. 2006 Feb 6;34(3):840-52.

doi: 10.1093/nar/gkj489. Print 2006.

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Review

Molecular models for the tissue specificity of DNA mismatch repair-deficient carcinogenesis

Elizabeth C Chao et al. Nucleic Acids Res. 2006.

Abstract

A common feature of all the known cancer genetic syndromes is that they predispose only to selective types of malignancy. However, many of the genes mutated in these syndromes are ubiquitously expressed, and influence seemingly universal processes such as DNA repair or cell cycle control. The tissue specificity of cancers that arise from malfunction of these apparently universal traits remains a key puzzle in cancer genetics. Mutations in DNA mismatch repair (MMR) genes cause the most common known cancer genetic syndrome, hereditary non-polyposis colorectal cancer, and the fundamental biology of MMR is one of the most intensively studied processes in laboratories all around the world. This review uses MMR as a model system to understand mechanisms that may explain the selective development of tumors in particular cell types despite the universal nature of this process. We evaluate recent data giving insights into the specific tumor types that are attributable to defective MMR in humans and mice under different modes of inheritance, and propose models that may explain the spectrum of cancer types observed.

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Figures

<b>Figure 1</b>

**Figure 1

Model of cell proliferation at constant and varying rates of cell division. The left panel shows a conceptual model of cells dividing at a constant rate. The number of cell divisions is plotted on the _y_-axis and time on the _x_-axis. The proliferation rate is constant until the tenth cell division, when proliferation stops (as denoted by a Stop sign). The right panel shows a model of cells dividing at varying rates. There are repeated episodes of sharp acceleration and deceleration (as denoted by a Stop sign) of the proliferation rate, starting at time point zero. The proliferation rate is constantly changing and is not constant. The potential selective advantages for growth and increased overall mutations in critical tumor suppressor genes for cells experiencing cycles of abrupt stop/start cell division is discussed in the section ‘ACCELERATION and deceleration of proliferation: are the rates of change of proliferation rates important?’

<b>Figure 2</b>

**Figure 2

Summary of different mechanisms contributing to the specificity of cell types that are susceptible to MMR deficiency.

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