The R72P P53 mutation is associated with familial breast cancer in Jewish women

Abstract

-Aviv University, Ramat Aviv Tel Aviv, Israel BRCA1/BRCA2 mutations account for a substantial proportion of familial breast cancer, but clearly mutations in additional genes exist, one candidate being the p53 gene. To evaluate its putative involvement in inherited predisposition to breast/ovarian cancer in Jewish high-risk women, mutational analysis of the p53 gene (exons 4 -9) was carried out using exon-specific polymerase chain reaction followed by denaturing gradient gel electrophoresis (DGGE) analysis, complemented by DNA sequencing of abnormally migrating fragments. Overall, 132 Jewish breast cancer patient non-BRCA1/2 mutation carriers and 167 average risk controls (Ashkenazi (n ¼ 60), non-Ashkenazi (n ¼ 107)) were genotyped, and no inactivating p53 germline mutations were detected. Consistent migration abnormalities were noted in 167 fragments, 134 of which were shown to be the Arg72Pro polymorphism, whereas migration abnormalities in fragments containing exons 4 (n ¼ 2) and 6 (n ¼ 23) and introns 3 (n ¼ 4) and 9 (n ¼ 4) corresponded to five previously described polymorphisms. Allele distribution of the R72P missense mutation between ethnically diverse Jewish breast cancer cases and average risk controls showed significant differences: among non-Ashkenazi breast cancer cases, 62.5%, 33.3% and 4.2% were homozygous, heterozygous and homozygous for the Arg72, Arg72Pro and the Pro72 polymorphism, respectively, whereas for controls, the distribution was 22.4%, 65.4% and 12.2%, respectively (P ¼ 0.00052), and among Ashkenazi breast cancer cases, allele distribution was 68.5%, 29.6% and 1.9%, whereas for controls, the distribution was 50%, 40% and 10%, respectively (P ¼ 0.0125). We conclude that arginine homozygosity at codon 72 of the p53 gene is associated with a significant increased breast cancer risk in Jewish high-risk population.

p53 Exon 4 (codon 72) Polymorphism and Exon 7 (codon 249) Mutation in Breast Cancer Patients in Southern Region(Madurai) of Tamil Nadu

“…Keshava et al, 2002 were able to find a higher prevalence of the Arg allele in Caucasian women with breast cancer from New York, but not in Latin or African-American patients. Ohayon et al, 2005 studied jewish women with breast carcinoma, finding a higher prevalence of the Arg allele among Ashkenazi Jewish and Arab women (Alwadi et al, 2010), a high-risk population for breast cancer (Damin et al, 2006). Contradictory reports are also available in literature implicating that involvement of Arg/Pro heterozygous variant increases the risk of breast cancer from North Indian population.…”

The P53 pathway: what questions remain to be explored?

“…63 There are several studies that suggest that one or the other allele could influence the occurrence or progression of cancer. 64,65 At present however the results are confusing and a better understanding of the role of these two alleles in the pathway will be important. Recently, a polymorphism in the promoter of the human MDM-2 gene has been identified (SNP309).…”

Polymorphisms in the p53 pathway

“…Several groups have reported an association between the R72 p53 variant (binds and inactivates p73 better) and increased risk for epithelial cancer, including gastric cancer and cancer of the breast (Langerod et al, 2002;Bonafe et al, 2003;Buyru et al, 2003;Ohayon et al, 2005), ovary (Pegoraro et al, 2002), esophagus (Kawaguchi et al, 2000), skin (Dokianakis et al, 2000;Bastiaens et al, 2001;Shen et al, 2003;De Oliveira et al, 2004), lung , bladder (Soulitzis et al, 2002), prostate (Henner et al, 2001), and larynx (Sourvinos et al, 2001). In other studies, however, authors have found the opposite correlation, instead demonstrating an association between the P72 (lesser apoptotic) variant and increased risk for other cancer types, including cancer of the thyroid (Granja et al, 2004), nasopharynx (Tsai et al, 2002a, b;Tiwawech et al, 2003), prostate (Suzuki et al, 2003), skin (Chen et al, 2003), urogenital region (Kuroda et al, 2003), and lung Fan et al, 2000;Zhang et al, 2003).…”