Beyond Tumors: Reduced survival linked to pathogenic PIK3CA and TP53 post-zygotic variants in uninvolved mammary tissue of breast cancer patients with recurrent disease

Normal-appearing mammary tissue from breast cancer patients can harbor significant genetic alterations. We analyzed DNA variants in both normal-looking tissue and tumors from 77 poor-prognosis patients, 49 patients without prognosis bias, and mammary gland samples from 15 non-cancerous individuals. Whole exome sequencing revealed a higher prevalence of pathogenic post-zygotic variants (29%) in poor-prognosis patients, affecting genes like AKT1, PIK3CA, PTEN, TBX3, and TP53, compared to 12.5% in those without prognosis criteria (p=0.0008578). Prevailing PIK3CA variants were recurrent across patients, while TP53 variants were present only in those with adverse prognoses. Duplex sequencing detected low-frequency pathogenic PIK3CA and TP53 variants in distant normal tissues of poor-prognosis patients. Disease recurrence significantly reduced survival rates, with poor prognosis patients experiencing higher mortality within 24 months (p=0.0088), further worsened by the presence of pathogenic post-zygotic variants. These findings highlight the importance of genetic monitoring even in normal-appearing mammary tissue.