Journal de biologie moléculaire et méthodes

Post-zygotic Mosaic Mutation in Normal Tissue from Breast Cancer Patient

Ryong Nam Kim

Even though numerous previous investigations had shed fresh light on somatic driver mutations in cancer tissues, the mutation-driven malignant transformation mechanism from normal to cancerous tissues remains still mysterious. In this study, we performed whole exome analysis of paired normal and cancer samples from 12 breast cancer patients in order to elucidate the post-zygotic mosaic mutation that might predispose to breast carcinogenesis. We found a post-zygotic mosaic mutation PIK3CA p.F1002C with 2% variant allele fraction (VAF) in normal tissue, whose respective VAF in a matched breast cancer tissue, had increased by 20.6%. Such an expansion of the variant allele fraction in the matched cancer tissue may implicate the mosaic mutation in association with the causation underlying the breast carcinogenesis. The post-zygotic mosaic mutation is estimated to be deleterious by well-established variant annotation software programs, SIFT_pred, Polyphen2_HDIV_pred, Polyphen2_HVAR_pred, LRT_pred, MutationTaster_pred, PROVEAN_pred, fathmm. MKL_coding_pred, MetaSVM_pred, and MetaLR_pred. In addition, we discovered 61 deleterious and pathogenic mutations, including 22 stop-gain, 12 splicing site, 13 frame shift and 7 non synonymous mutations, in those patients. By performing mutational signature analysis, we identified three mutational signatures underlying breast carcinogenesis, including APOBEC cytidinedeaminase and defective DNA mismatch repair. Taken together, these results suggest that, in addition to the somatic driver mutations, post-zygotic mosaic mutation may be a critical target that is worth deserving prior attention in ascertaining the causation underlying breast carcinogenesis in the upcoming future.