Purpose: A single nucleotide polymorphism (SNP) in exon-4 of the TP53 gene (Arg72Pro) has been associated with an increased risk of developing various human malignancies. Since a 16-base pair polymorphism (insertion/duplication) intron-3 (PIN3) is in linkage disequilibrium with Arg72Pro of TP53, we assessed whether these two polymorphisms serve as breast cancer risk alleles for African Americans (AAs) and non-Hispanic Caucasians (CAs).

Methods: Genomic DNA was extracted from formalin-fixed, paraffin-embedded invasive ductal carcinoma tissues [cases, n = 120 (AAs = 55 and CAs = 65)] and from blood of healthy women [controls, n = 152 (AA = 74 and CAs = 78)]. Exon-4 of TP53 was amplified by PCR using exon-specific primers, followed by Sanger sequencing. Identification of SNP was done by using DNASTAR software. TP53 PIN3 polymorphism was detected by amplifying genomic DNA using specific primers followed by gel electrophoresis. The A1 allele (no duplication) resulted in 162 bp fragment and the A2 allele (with 16 bp duplication) resulted in 178 bp fragment. The phenotypes of Arg72Pro (Arg/Arg, Arg/Pro, and Pro/Pro) were correlated with PIN3 status, clinicopathologic features, race/ethnicity, and patient survival using the χ2 test and Kaplan-Meier analyses. A p value of <0.05 was considered statistically significant.

Results: In cases, the Arg/Arg/, Pro/Arg, and Pro/Pro phenotypes were 15%, 31%, and 55% in AAs and 57%, 29%, and 14% in CAs (p<0.001), respectively. A similar distribution was observed in controls (16%, 42%, and 42% in AAs and 56%, 37%, and 6% in CAs) (p<0.001). When compared to ER positive, a higher frequency of Arg/Pro or Pro/Pro was noted in estrogen-negative breast cancers (p = 0.03) in both racial groups. However, no significant survival difference in these racial groups was observed when Pro carriers were compared with Arg/Arg cases (log rank, p = 0.565). Frequencies of PIN3 polymorphisms (A1A1, A1A2, and A2A2) were similar in both cases and controls; however, overall A1A1 frequency was higher than the other two genotypes of PIN3. The phenotype Pro/Pro, was strongly associated with A1A1 polymorphism in both racial groups of breast cancer patients (p<0.000078).

Conclusion: These preliminary findings suggest that Arg72Pro polymorphism and PIN3 in TP53 are related with higher breast cancer susceptibility for both African American and non-Hispanic Caucasian patients. This work was supported by a pilot grant from UAB Breast SPORE grant of the National Institutes of Health/National Cancer Institute (5P50CA089019).

Citation Format: Trafina Jadhav, Jesus Salazar-Gonzalez, Shantel Hebert-Magee, Michael Behring, Balananda-Dhurjati Putcha, Jeehyun Helen Bae, Andra Frost, Isam-Eldin Eltoum, Sejong Bae, Upender Manne. Codon 72 and Intron-3 polymorphisms in TP53 are risk factors for breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2776. doi:10.1158/1538-7445.AM2015-2776