Breast cancer biology continues to riddle us with the heterogeneity and complexity inherent to the disease. Unique molecular subtypes faze curative treatment as incidence escalates. Patients require personalized therapy and likewise a tumor necessitates tailored approach. Our study delves deep into mutational signatures, unique mutations and exclusive downstream pathways in primary breast cancer and metastasis to help predict biology, therapeutic resistance, prognosis, and overall survival. A distinctive mutational signature pattern of predominant C:G > A:T, C:G > G:C base change in samples from 10,130 patients derived from public databases TCGA, Project GENIE, FM, CPTAC and MSK-IMPACT Clinical Sequencing Cohort points to spontaneous evolution of mutations in DNA owing to replication errors, history of viral infection, retrotransposon jumping or inflammation. Subset analysis of tumor samples from 1233 patients with breast cancer including all subtypes, from the MSK-IMPACT cohort, were shown to harbor mutations predominantly in TP53, PIK3CA, CDH1,GATA3, ESR1, KMT2C, MAP3K1, PTEN, NF1, ARID1A, AKT1, and TBX3 that drives cellular proliferation, metastatic progression and resistance to therapy. Presence of TP53, GATA3, PTEN and TBX3 mutations influenced overall survival. Genomic variation profile in metastatic setting showed novel variations and pathways, exclusive to organs involved. Our study reveals that fragment of genome alteration may be utilized as a predictive biomarker of overall survival in patients with breast cancer.
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