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.

转移是癌症患者治疗失败和死亡的主要原因。在原发性乳腺肿瘤中已经发现了许多遗传改变，但对转移性肿瘤的遗传改变还没有很好的研究。为了研究转移过程中发生的关键遗传变化，我们对14个三重标本进行了全外显子组测序：原发性乳腺癌，转移性淋巴结肿瘤和来自同一患者的匹配非癌组织。比较这三种基因组，我们鉴定了各种各样的体细胞变异，原发性肿瘤中有26-676（中位数=46）个突变，转移性淋巴结肿瘤中有8-1034（中位数=37）个突变。个体患者中突变率的差异（最低34个单核苷酸变异（SNV），最高1710个SNV）表明肿瘤发展的各种过程和不同的选择压力存在于肿瘤环境中。我们分别鉴定了132个和189个原发性和淋巴结肿瘤特异性复发突变，并用统计学排序方法评估了其意义。我们的研究结果将为乳腺癌转移机制和未来的个体化治疗及分子医学提供新的见解。

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.