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ABSTRACT

Genetic instability has long been recognized as a cardinal feature of neoplasia.1,2 However, the causal role of genetic instability in the formation of cancer has only more recently been studied. Accumulating evidence has strengthened the proposal that genetic instability is required early during tumor progression. Instability drives mutations in oncogenes and tumor suppressor genes, providing the tumor cell with a selective growth advantage.3 While numerous oncogenes and tumor suppressor genes have been identified in the last 20 years, the molecular details underlying genetic instability are just now being revealed.

INTRODUCTION

The clearest molecular evidence for the genetic instability hypothesis comes from the elucidation of the genes causing hereditary nonpolyposis colon cancer (HNPCC). Patients with HNPCC have an increased risk of tumor development over the course of their lifetime but do not display the widespread changes in the at-risk tissue cellular architecture characteristic of other inherited tumor syndromes, for instance, the thousands of polyps in familial adenomatous polyposis (FAP). Instead, they typically develop a single advanced primary tumor at an atypically young age (see Chap. 43 on HNPCC).

Indeed, the tissue specificity is even more of a mystery upon consideration of the underlying genetic defect in these patients. They inherit a mutation in one of the mismatch repair (MMR) genes, such as MSH2, MLH1, PMS1, PMS2, or GTBP(MSH6).4-11 Unlike classical tumor suppressor genes such as p53 or Rb, the MMR genes do not directly affect the growth or death of a tumor cell.12 Experimentally, this distinction can be seen upon reintroduction of a MMR gene into a tumor cell that has two mutant copies. In contrast to reintroduction of a classical tumor suppressor, there is no effect on the tumor cell growth or death.13

Instead, the loss of MMR genes imbues these tumors with an elevated nucleotide mutation rate—2 to 3 orders of magnitude higher than normal cells or MMR-proficient cancers of the same cell type14-16. Thus, there is an increased rate of mutation at oncogene and tumor suppressor loci throughout the tumor cell genome. This link between isolated cellular genetic instability and organism-wide tumorigenesis is strong evidence for the genetic instability hypothesis, as sequence instability alone is able to drive the autosomal dominant inheritance of colorectal neoplasia in these families (Fig. 33-1).

Fig. 33-1

Pathways to genetic instability. Different types of genetic instability require a different number of mutational “hits” in order to engender the respective instability phenotype. In a heterozygote with one defective nucleotide excision repair (NER) allele (step 1), inactivation of the normal allele (step 2) does not immediately lead to mutations. It additionally requires exposure to an environmental agent (i.e., ultraviolet light) (step 3) to create large numbers of mutations (NER-related instability; NIN). In contrast, in a heterozygote with one defective mismatch repair (MMR) allele (step 1), all that is required to begin ...

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