Significance of TP53 mutations determined by next-generation "deep" sequencing in prognosis of estrogen receptor-positive breast cancer.

Next-generation "deep" sequencing (NGS) was used for the mutational analysis of TP53, and a DNA microarray was used for the determination of the TP53 mutation-associated gene expression signature (TP53 GES) in 115 estrogen receptor (ER)-positive breast cancers. NGS detected 27 TP53 mutations, of which 20 were also detected by Sanger sequencing (SS) and seven were detected only by NGS. A significantly higher number of mutant alleles (33.9%) was detected in the tumors with TP53 mutations detected by SS compared with those with TP53 mutations detected only by NGS (11.1%). The TP53 mutations detected by NGS were more significantly associated with a large tumor size, a high histological grade, progesterone receptor-negativity, and HER2-positivity compared with those detected by SS. The TP53 mutations detected by SS, but not those detected by NGS or the p53 immunohistochemistry, exhibited a significant association with poor prognosis. In addition, the TP53 GES more clearly differentiated low- from high-risk patients for relapse than the TP53 mutations detected by SS, regardless of the other conventional prognostic factors. Thus, NGS is more sensitive for the detection of TP53 mutations, but the prognostic significance of these mutations could not be demonstrated. In contrast, the TP53 GES proved to be a powerful prognostic indicator for ER-positive tumors.