TP53 and Basal Cell Carcinomas
Researchers identified a variant that confers susceptibility to BCCs and other cancers.
Based on the presence of mutations found in sporadic basal cell carcinoma (BCC) and those arising in the context of basal cell nevus (Gorlin) syndrome, researchers have established TP53, PTCH1, PTCH2, and SUFU as important susceptibility genes in BCC pathogenesis. To identify new risk variants for cutaneous BCC, investigators performed a genome-wide association study (GWAS) using 16 million single-nucleotide polymorphisms identified through the DNA sequencing of 457 Icelanders.
The strongest association with BCC risk (odds ratio = 2.36) was with a polymorphism in the polyadenylation sequence of TP53. Polyadenylation (the addition of adenines to the ends of messenger RNA [mRNA] transcripts) promotes transport and stability, thus enhancing translation. Affected cells made slightly less TP53 mRNA transcript than wild-type cells, and proper termination of the TP53 transcript was disrupted with this variant. Using multiple validation sets, the researchers also associated this variant with increased risk for colorectal adenoma (OR = 1.39), prostate cancer (OR = 1.44), and glioma (OR = 2.35).
Comment: Mutations in TP53 in humans (e.g., Li-Fraumeni syndrome) and mice reveal that different variants produce vastly different biological responses, altering both tumor spectrum and aggressiveness. It is certainly plausible that this variant affects TP53 function. Previous research has shown that polyadenylation defects cause human disease. Mutation of the polyadenylation sequence of the hemoglobin alpha 2 gene (HBA2) results in excess beta-globin chains and alpha-thalassemia. How such a mechanism may affect p53 protein levels or protein complexes (analogous to alpha-thalassemia) remains to be shown.
Published in Journal Watch Dermatology November 23, 2011
Stacey SN et al. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nat Genet 2011 Sep 25; 43:1098.
- Medline abstract (Free)
