Evidence for selective expression of the p53 codon 72 polymorphs: implications in cancer development
National Cancer Centre, Singapore 169610, Singapore and
Aims and Background p53 is arguably the most critical tumor suppressor gene product that prevents malignant transformation. The p53 gene can exist as two polymorphic variants, resulting in either an arginine or proline residue at codon 72, whose functional significance in physiology and carcinogenesis is controversial and not well understood. Methods We investigated p53 status using genomic DNA and RNA from Chinese, Malay and Indian healthy subjects and Chinese breast cancer samples by PCR followed by restriction digest and sequencing. Results The Chinese consisted of more arginine homozygotes compared to the Indians and Malays (35% vs 20.8% and 24%). However, all the Chinese heterozygotes preferentially expressed either the proline allele alone or both the proline and arginine alleles. By contrast, there was a distinct absence of the sole expression of the arginine allele in the healthy heterozygotes. On the contrary, about 75% of the heterozygote breast cancer samples expressed solely the arginine allele, resulting in almost 60% of all breast cancers solely expressing the arginine allele. Moreover, the histologically normal tissues from the heterozygotes showed selective expression of the arginine allele. Further analysis revealed a distinct absence of mutations in the p53 gene in most of the arginine expressing samples. Conclusions The data suggests that there is a selection pressure against the expression of the arginine allele in non-malignant tissues. The arginine allele is activated in cancers and hence, may predispose to cancer. Thus, the expression status of the p53 variants can be used as a predictive factor for predisposition to breast cancer.
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 896 (Tumor suppressor genes).