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.

研究癌症基因组学以开发乳腺癌的个性化治疗和药物：原发性乳腺癌及其转移肿瘤的全外显子组测序分析。

• 批准号: 22310123
• 负责人: HOSODA Fumie
• 金额: $ 10.98万
• 依托单位: National Cancer Center Japan
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22310123/
• 关键词: 乳癌; リンパ節転移; エクソンシークエンス; 個別化医療; 遺伝子変異; ゲノム構造異常解析

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.

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基因改变，但转移性肿瘤特有的基因改变尚未得到充分研究。为了研究转移过程中发生的关键遗传变化，我们通过大规模并行测序对 14 个三样本进行了全外显子组测序：原发性乳腺癌、其转移性淋巴结肿瘤以及来自同一患者的匹配非癌组织。比较这三个基因组，我们发现了多种体细胞变异，原发肿瘤中有 26-676 个（中位数 = 46）个突变，转移性淋巴结肿瘤中有 8-1034 个（中位数 = 37）个突变。个体患者的突变率差异（最低 34 个单核苷酸变异（SNV），最高 1710 个 SNV）表明肿瘤发展的不同过程和肿瘤环境中存在不同的选择压力。我们分别鉴定了 132 个和 189 个原发肿瘤和淋巴结肿瘤特异的复发突变，并通过统计排序方法评估了其显着性。我们的研究结果将为乳腺肿瘤转移的机制以及未来的个性化治疗和分子医学提供新的见解。

项目成果

Mouse model for ROS1-rearranged lung cancer.

• DOI: 10.1371/journal.pone.0056010
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Arai Y;Totoki Y;Takahashi H;Nakamura H;Hama N;Kohno T;Tsuta K;Yoshida A;Asamura H;Mutoh M;Hosoda F;Tsuda H;Shibata T
• 通讯作者: Shibata T

Comparison of genetic alterations in primary breast cancer and its metastatic tumor

原发性乳腺癌与其转移瘤的基因改变比较

• 发表时间: 2011
• 作者: Hosoda F;Totoki Y;et al
• 通讯作者: et al

Genetic variations in primary breast cancer and its metastatic tumor.

原发性乳腺癌及其转移性肿瘤的遗传变异。

• 发表时间: 2012
• 作者: Hosoda F;et al.
• 通讯作者: et al.

DEK oncoprotein regulates transcriptional modifiers and sustains tumor initiation activity in high-grade neuroendocrine carcinoma of the lung

• DOI: 10.1038/onc.2010.217
• 发表时间: 2010-08-01
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Shibata, T.;Kokubu, A.;Hirohashi, S.
• 通讯作者: Hirohashi, S.

Comparison of genetic alterations in primary breast cancer and its metastatic tumor.

原发性乳腺癌与其转移性肿瘤的基因改变的比较。

• 发表时间: 2011
• 作者: Hosoda F;Totoki Y;Arai Y;Tsuda H;Imoto I;Inazawa J;Ohki M;Shibata T
• 通讯作者: Shibata T