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Genetic predisposition to cancer — insights from population genetics

Key Points

  • Genes involved in DNA repair, cell-cycle control and cell death have key roles in cancer progression.

  • The same genetic pathways mutated somatically in cancer progression often have inherited mutations that increase predisposition to cancer.

  • The rare occurrence of new mutations and the common elimination of highly penetrant, early onset mutations by natural selection cause severe predisposition for early onset cancer to be infrequent.

  • Most inherited effects on cancer predisposition arise from a combination of many different mutations, each mutation having only a small effect on the tendency to develop cancer.

  • Families that show a strong genetic tendency for breast cancer develop the disease more frequently at earlier ages, but have a lower increase in incidence with age than families that do not show this tendency.

  • Families that show predisposition to cancer might start further along a sequence of stages in cancer progression than other families, perhaps because they inherit certain mutations that must be acquired somatically in other families.

  • The normal mechanisms that regulate cell proliferation and cell death provide robust protection against cancer. Such robustness also protects against deleterious mutations and allows cancer-predisposing mutations to increase in frequency.

Abstract

Individuals differ in their inherited tendency to develop cancer. Major single-gene defects that cause early cancer onset have been known for many years from their inheritance patterns, and inherited defects that have weaker effects on predisposition were also suspected to exist. Recent progress in cancer genetics has identified specific loci that are involved in cancer progression, many of which have key roles in DNA repair, cell-cycle control and cell-death pathways. Those loci, which are often mutated somatically during cancer progression, sometimes also contain inherited mutations. Recent genetic studies and quantitative population-genetic analyses provide a framework for understanding the frequency of inherited mutations and the consequences of these mutations for increased predisposition to cancer.

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Figure 1: Pathways involved in the response to DNA double-strand breaks.
Figure 2: Risk of breast cancer caused by BRCA1 and BRCA2 mutations.
Figure 3: Allele frequencies for DNA-repair genes.
Figure 4: Effects of multistage progression on age-related changes in cancer risk.

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Acknowledgements

Work in the author's laboratory is supported by the National Science Foundation and the National Institutes of Health.

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The author declares no competing financial interests.

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DATABASES

Cancer.gov

Breast cancer

colorectal cancer

ovarian cancer

retinoblastoma

Wilms' Tumour

Entrez Gene

APC

BRCA1

BRCA2

CDK4

MET

p53

RET

RB

OMIM

Xeroderma pigmentosum

FURTHER INFORMATION

Steven Frank's web site

Glossary

PENETRANCE

The frequency with which individuals that carry a given gene will show the manifestations associated with the gene. If a disease allele is 100% penetrant then all individuals carrying that allele will express the associated disorder.

POPULATION BOTTLENECK

Severe reduction in population size, during which previously rare genetic variants can become common by chance.

CONFIDENCE INTERVAL

Range of values estimated from data that are likely to contain the true value of a parameter.

QUANTITATIVE TRAIT

A measurable trait that depends on the cumulative action of many genes and that can vary among individuals over a given range to produce a continuous distribution of phenotypes. Common examples include height, weight and blood pressure.

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Frank, S. Genetic predisposition to cancer — insights from population genetics. Nat Rev Genet 5, 764–772 (2004). https://doi.org/10.1038/nrg1450

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