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Architecture of inherited susceptibility to common cancer

Abstract

This Timeline article looks back at 40 years of research into the inherited genetic basis of cancer and the insights these studies have yielded. Early epidemiological research provided evidence for the 'two-hit' model of cancer predisposition. During the 1980s and 1990s linkage and positional cloning analyses led to the identification of high-penetrance cancer susceptibility genes. The past decade has seen a shift from models of predisposition based on single-gene causative mutations to multigenic models. These models suggest that a high proportion of cancers may arise in a genetically susceptible minority as a consequence of the combined effects of common low-penetrance alleles and rare disease-causing variants that confer moderate cancer risks.

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Figure 1: Polygenic model of cancer susceptibility.
Figure 2: Cancer susceptibility loci identified through GWA studies.

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Acknowledgements

We are grateful to M. Greaves and F. Hosking for their critical comments.

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Correspondence to Richard S. Houlston.

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Supplementary Table 1

Cancer susceptibility loci identified through genome-wide association studies (- Jan 2010) (PDF 308 kb)

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Glossary

Epistatic interaction

Any non-additive interaction between two or more variants at different loci, such that their combined effect on a phenotype deviates from the sum of their individual effects.

Founder effect

Loss of genetic variation and diversity that occurs when a new population is established by a small number of individuals from a larger population. Similar to a bottleneck, it severely reduces genetic diversity, increasing the effect of random drift.

Genetic drift

Changes in the frequency of a genetic variant in a population owing to chance alone.

Genetic linkage

The co-inheritance of alleles at two loci, which are physically close to each other on a chromosome. It can be used to map disease loci in families with multiple cases of a disease.

Genome-wide association (GWA) study

Empirical study approach that incorporates the entire genome with the goal to identify SNPs uniquely present in patients with disease (cases) relative to those without disease (controls).

Linkage analysis

Localization of disease genes by typing genetic markers in families to identify regions that are associated (linked) with disease or trait values in pedigrees more often than are expected by chance. Such linked regions are more likely to contain a causal genetic variant.

Linkage disequilibrium (LD)

Correlation between nearby variants such that the alleles at neighbouring markers (on the same chromosome) are associated in a population more often than if they were unlinked.

Log-additive model

For a 2 × 3 contingency table (for example, frequency of SNP genotypes in cases and control) a statistic is calculated for the trend across the 3 genotypes imposing weights of 0, 1 and 2 on each of the 3 genotype classes. This equates to an analysis under logistic regression.

Low-penetrance allele

Genetic variant associated with a disease phenotype, but only a relatively small proportion of carriers manifest disease.

Marginal effect

In the context of a genetic risk factor, the average effect assuming no gene–gene or gene–environment interactions.

Minor allele frequency (MAF)

Frequency of the less common of two alleles.

Population attributable risk

Difference in disease incidence observed if none of the population was exposed to the (genetic) risk factor.

Odds ratio (OR)

A measure of relative risk usually estimated from case–control studies. The odds of disease among individuals who are exposed to a risk factor compared with the odds of disease in unexposed individuals.

Tag SNP

Single nucleotide polymorphism that is correlated with, and therefore can serve as a proxy for, much of the known remaining common variation in a region.

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Fletcher, O., Houlston, R. Architecture of inherited susceptibility to common cancer. Nat Rev Cancer 10, 353–361 (2010). https://doi.org/10.1038/nrc2840

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