Genome instability is a hallmark of virtually all tumors. This instability takes at least two forms:

1. Chromosomal loss or gross rearrangements

2. Subtle DNA sequence changes that largely do not affect the overall integrity of the chromosomes.


Genomic instability is the result of cellular gene inactivation(s) that ultimately results in elevated mutation rates. Genes that control mutation rates have been termed “Mutator” genes since their discovery in the early 1950’s. The majority of Mutator genes are involved in DNA repair processes that survey the genome for DNA damage. Alterations in these DNA repair genes affects the combination and arrangement of genes on chromosomes as well as the primary DNA sequence within chromosomes. The observation of widespread genome instability in cancers supports a model for tumor development that involves cycles of enhanced mutation and is based on genetic selection (Mutator Hypothesis). A more than 20 yr old prediction that is based on the Mutator Hypothesis is that tumors should be genetically heterogeneous with a dozen or so mutations that actually “drive” cancer, embedded in a sea of perhaps a hundred background “passenger” mutations. The recent publications of cancer genome sequences from the Cancer Genome Atlas have clearly underpinned the validity of this prediction. (see here)




The Cancer Problem


Accumulating genetic data suggests that solid tumors contain on average about 10 “driver mutations” that inactivate oncogenes and tumor suppressor genes to cause cancer.  Most of those driver genes are members of a pathway where on average any one of 10 pathway genes will have the same phenotypic effect.  A simplistic calculation suggests that the number of 10 gene combinations by taking one mutation from each of the 10 gene pathways of “driver” oncogenes/tumor suppressors is 1010!  That is 10 billion genetic combinations of oncogenes/tumor suppressor genes that may cause cancer in a world population of 7 billion.  These numbers imply that it is unlikely that the driver mutations in any two tumors will be genetically identical.  In addition, the driver mutations are bathed in a background of perhaps a hundred even more random “passenger” mutations that may alter the metabolism, cell surface, and/or other cellular factors.  Finally, cycles of mutation and selection suggest a type of microevolution within the tumor that implies the pattern of genetic alterations within each tumor will be remarkably heterogeneous.  It is this large heterogeneous combination of “driver” mutations embedded in a unique background of “passenger” mutations that defines the cancer problem.  One could reasonably assume that every tumor will respond to cancer therapeutics differently and that resistance to therapeutics could be easily selected from the large pool of heterogeneous mutations within any single tumor.


Figure: Cascade of mutations during tumor progression. In the case of solid tumors, epidemiological evidence indicates that as many as 20 years pass between the time an individual is exposed to a carcinogen to the clinical appearance of a tumor. Various barriers to tumor progression exist, including DNA repair processes, the availability of nutrition, the requirement of angiogenesis to allow the tumor to increase in size and responses to hypoxia. Circles represent mutations in genes that result in enhanced mutagenesis, triangles indicate driver mutations that are selected on the basis of changes in the tumor microenvironment and white rectangles represent passenger mutations. (Adapted from L. Leob. Nature Reviews Cancer. 11: 450, 2011)



Understanding the Mutator gene functions that drive tumorigenesis has helped to appreciate the cancer problem.  There is a growing body of evidence in organisms from bacteria to man that suggests the loss of multiple Mutator pathways results in mutation rates that are too high for cells to tolerate.  These observations may open a useful therapeutic and chemopreventive window for cancer patients.


The Fishel laboratory studies the fundamental genetic and biophysical mechanisms of human Mutators.  We focus on two human DNA repair systems that when defective have been found to be Mutators that cause cancer:  1.) mismatch repair (MMR), and 2.) homologous recombination repair (HRR).  MMR recognizes and repairs polymerase misincorporation errors that arise during DNA replication.  


Loss of MMR is the cause of Lynch syndrome/hereditary nonpolyposis colorectal cancer (LS/HNPCC) as well as 10-40% of sporadic colorectal, gastric, endometrial, ovarian and upper urinary tract tumors. 


HRR is the most faithful mechanism for repairing DNA double-stranded breaks (DSBs) that result from chemical and physical damage to chromosomes.  Defects in DSB recombinational repair have been linked to hereditary breast cancer (BRCA1/2) as well as hematopoietic and other solid tumors (Ataxia telangiectasia mutated, ATM; Nijmegen breakage syndrome, NBS1; Fanconia anemia, FANC; Bloom’s syndrome, BLM; among others).  HRR utilizes the homologous DNA sequence of a sister or homologous chromosome to bridge the DNA gap of a broken chromosome that ultimately preserves the entire primary DNA sequence.  Other DSB recombinational repair processes such as Non-Homologous End Joining (NHEJ) and Single Stranded Annealing (SSA) often destroy the DNA sequence at the DSB end during the repair.


The selection of homologous DNA sequences to bridge the DNA gap during HRR is essential for faithful repair.  An additional overlapping role for MMR is to recognize when HRR is attempting to repair a gap with less than fully homologous sequences (i.e. there are mismatched nucleotides).  In this case, MMR aborts the HRR repair event. 


It is this intersection between HRR and MMR, the unknown biophysical and mechanistic questions associated with HRR and MMR as well as the large number of components in both these pathways that have been found to be associated with hereditary and sporadic cancers that underlines their importance as research models.


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