Studies on cancer genomics to develop personalized therapy and medicine in breast cancer: Whole exome sequencing analysis of primary breast cancer and its metastatic tumor.

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Metastasis is the main cause of therapeutic failure and death in cancer patients. A number of genetic alterations have been identified in primary breast tumors, but genetic changes particular to the metastatic tumors have not been well studied. To investigate critical genetic changes that occur during the metastatic process, we performed whole exome sequencing of 14 trio-specimens: the primary breast cancer, its metastatic lymph node tumor and matched non-cancerous tissue from the same patient by massively parallel sequencing. Comparing the three genomes, we identified a wide variety of somatic variations, 26-676 (median=46) mutations in the primary tumors and 8-1034 (median=37) mutations in the metastatic lymph node tumors. The differences of mutation rates (34 single nucleotide variations (SNVs) at the lowest to 1710 SNVs at the highest) in individual patients suggested that various processes of tumor development and distinct selective pressures are present within the tumor environment. We identified 132 and 189 recurrent mutations specific to the primary and lymph node tumors, respectively, and evaluated its significance with a statistical ranking method. Our findings will provide new insights for the mechanism of breast tumor metastasis and future personalized therapy and molecular medicine.