Abstract 16: Impact of germline TP53 mutations and polymorphisms in women with premenopausal breast cancer
Authors: Samuel Nardin , Novokmet Ana , Hudson Thomas J. , Malkin David 
Published: May 2015

Abstract
Aim: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome that confers a high lifetime risk of developing malignancies, including pre-menopausal breast cancer. Although many families with classic LFS phenotypes harbor germline TP53 mutations, approximately 25% do not. We observe a high frequency of polymorphic TP53 variants in LFS patients not found to harbor deleterious mutations. We sought to determine if the spectrum of TP53 variants in pre-menopausal breast cancer patients influences cancer risk.
Methods: Germline DNA was obtained from whole blood of 90 ethnically diverse patients diagnosed with pre-menopausal breast cancer, as well as patients diagnosed with breast cancer in addition to another primary malignancy. The median age at first cancer diagnosis was 35 years. Sanger sequencing of exons 2-11, and flanking intron regions of the TP53 gene was performed. HapMap population frequencies for TP53 polymorphisms were used as reference values.
Results: Five of 90 patients in our study were found to harbor known deleterious mutations in TP53, consistent with LFS. The most commonly observed single nucleotide polymorphism (SNP) across all samples was the c.215C&gt;G (p.Pro72Arg) in exon 4 (rs1042522). This polymorphism is a common variant that has G allele frequencies of 76.7%, 51.1% and 33.1% in European, Asian (Han Chinese) and Sub-Saharan African populations, respectively. We observe a G allele frequency of 66.0% in our study group. There was no significant difference in age at cancer diagnosis between any of the three genotypic groups (C/C: 33 years; C/G: 34 years: G/G: 36 years). Three additional low-frequency SNPs in TP53 were observed: the exon 4: c.108G&gt;A (p.Pro36Pro) variant was found in 2 patients, exon 6: c.639A&gt;G (p.Arg213Arg) was found in 9 patients and intron 9: c.993+12T&gt;C was found in 4 patients. There was no observed distinct signature of TP53 polymorphism spectrum in patients who developed multiple primary malignancies.
Discussion: This study represents a genetic survey of TP53 in pre-menopausal breast cancer patients of diverse ethnicities. TP53 polymorphisms alone were not sufficient to make clinical predictions about age at breast cancer diagnosis. The TP53 polymorphism, rs1042522, was observed in a large proportion of patients in this study, consistent with its reported frequencies in SNP databases. Parallel studies of CpG methylation of the TP53 promoter and shore regions flanking the locus are being conducted to investigate alternate hypotheses linking TP53 and risk of early-onset breast cancer in the absence of germline TP53 mutations.
Citation Format: Nardin Samuel, Ana Novokmet, Thomas J. Hudson, David Malkin. Impact of germline TP53 mutations and polymorphisms in women with premenopausal breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 16. doi:10.1158/1538-7445.CANSUSC14-16