Candidate gene association studies: successes and failures

Area of Science:

• Oncology
• Genetics
• Epidemiology

Background:

• Epidemiologic twin studies suggest 20-40% of common cancers are inherited.
• High-penetrance tumor susceptibility genes (e.g., APC, BRCA1/2) explain only a small fraction of familial cancer risk.
• Low to moderate penetrance genes are likely responsible for the majority of inherited cancer predisposition.

Purpose of the Study:

• To review the identification and significance of low to moderate penetrance tumor susceptibility genes.
• To highlight the role of translational research in uncovering novel cancer-related genotypes and phenotypes.
• To discuss the contribution of various genetic approaches to understanding the genetic basis of cancer.

Main Methods:

• Identification of candidate tumor susceptibility genes through tumor-specific mutations, in vitro experiments, and animal models.
• Translational studies linking in vitro/in vivo discoveries to human cancer phenotypes and genotypes.
• Case-control studies, validation, meta-analyses, and genome-wide association studies (GWAS) to identify novel susceptibility genes.

Main Results:

• Several novel tumor susceptibility genes have been identified.
• Genes involved in metabolizing enzymes and the TGF-beta signaling pathway are implicated.
• Candidate gene approaches and GWAS are crucial for advancing cancer genetics research.

Conclusions:

• Low to moderate penetrance genes play a substantial role in familial cancer risk.
• Translational research is vital for discovering new cancer-associated genetic factors.
• Continued research integrating candidate gene and genome-wide approaches promises to elucidate the genetic basis of cancer.