General lessons from large-scale studies to identify human cancer predisposition genes

Area of Science:

• Genetics
• Oncology
• Population Genetics

Background:

• Mendelian inherited cancer syndromes explain only a small fraction of familial cancer clustering.
• Increased familial cancer risk likely involves low- or moderate-penetrance genes.
• Identifying low-penetrance cancer predisposition genes has been challenging.

Purpose of the Study:

• To review findings from cancer genome-wide association studies (GWASs).
• To discuss the challenges in identifying disease-causing variants.
• To explore the roles of common and rare variants in cancer predisposition.

Main Methods:

• Genome-wide association studies (GWASs) using tagging SNPs.
• Analysis of the 'common disease-common variant' model.
• Discussion of 'common disease-rare variant' models and other variations like copy number polymorphisms.

Main Results:

• GWASs have identified numerous common risk alleles for cancer.
• The 'common disease-common variant' model is a significant contributor to cancer susceptibility.
• Identifying specific disease-causing variants from GWAS findings remains difficult.

Conclusions:

• A continuous approach considering both common and rare variants is more appropriate for understanding cancer predisposition.
• Further research is needed to identify rarer variants and other forms of cancer-predisposing variation.
• Understanding genetic susceptibility is crucial for addressing familial cancer clustering.