High-penetrance mutations in several genes have been identified that contribute to hereditary colorectal cancer. The role of these mutations in cancer pathogenesis is well understood and their detection is successfully used in clinical diagnosis. In stark contrast, our understanding of the influence of low-penetrance mutations that account for most of the remaining familial cases of colorectal cancer, as well as an unknown proportion of sporadic cases, is far less advanced. Extensive ongoing research into low-penetrance, multifactorial predisposition to colorectal cancer is now beginning to bear fruit, with important implications for understanding disease aetiology and developing new diagnostic, preventive and therapeutic strategies.
Cancer is a genetic disease. Most cancer-causing mutations are somatic, occurring in the affected tissue during the course of carcinogenesis; however, most cancers also have a hereditary component that is caused by predisposing mutations that affect the germline, are heritable and contribute to the initiation of carcinogenesis.
Colorectal cancer is probably the type of cancer for which the most is known about the genes affected by cancer-causing mutations, their normal functions and their carcinogenic effects when mutated.
High-penetrance mutations confer predisposition to colorectal cancer mainly in Lynch syndrome (which involves mutations in mismatch-repair genes) and in familial adenomatous polyposis (which involves mutations in the APC tumour suppressor). Together, these conditions account for 5% or less of all cases of colorectal cancer.
Determining carriership for the mutations that underlie these conditions is important in the management and prevention of cancer in these patients and their families.
Low-penetrance mutations account for a high proportion of all the attributable risk of colorectal cancer, in both familial and sporadic cases. These mutations are more difficult to identify, but — mainly due to the implementation of association studies — are increasingly being detected and characterized.
The identification of both high- and low-penetrance mutations contributes significantly to our understanding of the molecular genetic processes occurring in cancer. This understanding facilitates the development of therapeutic drugs and preventive strategies.
Gene–gene and gene–environment interactions have a significant influence on susceptibility to colorectal cancer. Our current understanding of these interactions is limited, and concerted research efforts in this area will be important for a full understanding of predisposition to this cancer.
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The author wishes to thank R. Davuluri, C. Eng, J. Green, J. Groden, P. Peltomäki and B. Vogelstein for advice. The author's work is funded by grants from the United States National Institutes of Health and from the State of Ohio Biomedical Research and Technology Transfer Commission. The content reflects the views of the Grantee and does not necessarily reflect the views of the State of Ohio Biomedical Research and Technology Transfer Commission.
The author declares no competing financial interests.
- DUKE'S STAGE A
At this stage, cancer has spread beyond the innermost lining of the colon to the second and third cell layers and involves the inside wall of the colon. The cancer has not spread to the outer wall of the colon or outside the colon.
- DUKE'S STAGE D
At this stage, cancer has spread outside the colon to other parts of the body, such as the liver or the lungs. The tumour can be any size and might or might not include affected lymph nodes.
The family member who was initially ascertained (that is, who came to the attention of the researcher) in a study of familial aggregation of cancer (or other disease).
The frequency with which individuals who carry a given mutation show the phenotype associated with that mutation. If the penetrance of a disease allele is 100%, then all individuals carrying that allele will express the associated phenotype.
A benign overgrowth of tissue that is composed of cells that are normally present at that site. In the gastrointestinal tract, hamartomas typically have a marked expansion of the muscular and fibrous tissue layer.
- MODIFIER GENE
A gene that alters the phenotype of another gene, or that of a mutation in another gene.
- HYPOMORPHIC MUTATION
A mutation that does not completely inactivate the product of a gene.
- MISMATCH REPAIR
DNA repair in response to incorrect pairing of bases.
- CpG ISLANDS
Regions of DNA with a high density of cytosine– phosphoguanine nucleotides, which are usually located in the promoter region or the first exons of a gene. CpG islands are involved in the regulation of transcription, because their methylation can lead to permanent silencing of the associated gene.
- MUTATOR PHENOTYPE
Genetic or epigenetic abnormality that leads to an increased rate of mutation. Often caused by defects in the DNA mismatch-repair pathway.
- MICROSATELLITE INSTABILITY
Characterized by expansion or contraction of short repeated DNA sequences (that is, microsatellite repeats) caused by insertion or deletion of repeated units. This instability, also known as a 'mutator phenotype' or 'replication error', indicates probable defects in mismatch-repair genes.
The type of involvement or extent to which a particular organ or structure is affected by a specific genotype.
An experimentally determined profile of genetic markers that are present on a single chromosome of any given individual.
- ASHKENAZI JEWS
A Jewish population originating from eastern or central Europe. Because of isolation from other communities until the past few generations, this population has a less diverse gene pool than most other groups and represents a typical founder population.
A situation in which a loss-of-function phenotype is produced by mutation of one allele of a gene in a diploid cell, even though the other allele is wild-type.
- COMPOUND HETEROZYGOUS
Carrying two different mutations in each allele of a gene.
- CONCORDANT TWINS
A pair of twins in which the same trait is observed in each twin.
- DISCORDANT TWINS
A pair of twins in which the same trait is not observed in each twin.
- RELATIVE RISK
Indicates how much greater or smaller the lifetime risk of disease is in a carrier of the allele than in a non-carrier. A typical value is a twofold greater risk.
- ATTRIBUTABLE RISK
The proportion of all cases of a disease in population that is caused by a specific allele.
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