The phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene is frequently mutated in breast cancer (BCa). Sex hormone receptors (HRs), including estrogen receptor (ER) and progesterone receptor (PR) play pivotal roles in BCa. In this study, we evaluated the association between PIK3CA mutations and ER/PR expression and the prognostic role of PIK3CA mutations in BCa patients, and in particular, HR-positive BCa. Thirty-two studies involving 5719 cases of BCa obtained from database searches were examined. PIK3CA gene mutations correlated significantly with ER/PR expression (p < 0.00001) and relapse-free survival (RFS) (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59–0.98, p = 0.03) but not overall survival (OS) (HR 1.14, 95%CI 0.72–1.82, p = 0.57) in unsorted BCa patients. PIK3CA mutations were not associated with OS (HR 1.06, 95%CI 0.67–1.67, p = 0.81) or RFS (HR 0.86, 95%CI 0.53–1.40, p = 0.55) in HR-positive BCa patients. In conclusion, PIK3CA mutations were significantly related to ER/PR expression and RFS in unsorted BCa patients. However, the clinical implications of PIK3CA mutations may vary according to different mutant exons. And PIK3CA mutations alone may have limited prognostic value for HR-positive BCa patients.

Imprinted genes are vulnerable to environmental influences during early embryonic development, thereby contributing to the onset of disease in adulthood. Monoallelic methylation at several germline imprints has been reported as DNMT1-dependent. However, which of these two epigenetic attributes, DNMT1-dependence or allelic methylation, renders imprinted genes susceptible to environmental stressors has not been determined. Herein, we developed a new approach, referred to as NORED, to identify 2468 DNMT1-dependent DNA methylation patterns in the mouse genome. We further developed an algorithm based on a genetic variation-independent approach (referred to as MethylMosaic) to detect 2487 regions with bimodal methylation patterns. Two approaches identified 207 regions, including known imprinted germline allele-specific methylation patterns (ASMs), that were both NORED and MethylMosaic regions. Examination of methylation in four independent mouse embryonic stem cell lines shows that two regions identified by both NORED and MethylMosaic (Hcn2 and Park7) did not display parent-of-origin-dependent allelic methylation. In these four F1 hybrid cell lines, genetic variation in Cast allele at Hcn2 locus introduces a transcription factor binding site for MTF-1 that may predispose Cast allelic hypomethylation in a reciprocal cross with either C57 or 129 strains. In contrast, each allele of Hcn2 ASM in J1 inbred cell line and Park7 ASM in four F1 hybrid cell lines seems to exhibit similar propensity to be either hypo- or hypermethylated, suggesting a ‘random, switchable’ ASM. Together with published results, our data on ASMs prompted us to propose a hypothesis of regional ‘autosomal chromosome inactivation (ACI)’ that may control a subset of autosomal genes. Therefore, our results open a new avenue to understand monoallelic methylation and provide a rich resource of candidate genes to examine in environmental and nutritional exposure models.

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