Krøigård Anne Bruun, Larsen Martin Jakob, Lænkholm Anne-Vibeke, Knoop Ann S, Jensen Jeanette D, Bak Martin, Mollenhauer Jan, Kruse Torben A, Thomassen Mads
Department of Clinical Genetics, Odense University Hospital, 5000 Odense C, Denmark.
Human Genetics, Institute of Clinical Research, University of Southern Denmark, 5000 Odense C, Denmark.
Oncotarget. 2015 Mar 20;6(8):5634-49. doi: 10.18632/oncotarget.3111.
Evolution of the breast cancer genome from pre-invasive stages to asynchronous metastasis is complex and mostly unexplored, but highly demanded as it may provide novel markers for and mechanistic insights in cancer progression. The increasing use of personalized therapy of breast cancer necessitates knowledge of the degree of genomic concordance between different steps of malignant progression as primary tumors often are used as surrogates of systemic disease. Based on exome sequencing we performed copy number profiling and point mutation detection on successive steps of breast cancer progression from one breast cancer patient, including two different regions of Ductal Carcinoma In Situ (DCIS), primary tumor and an asynchronous metastasis. We identify a remarkable landscape of somatic mutations, retained throughout breast cancer progression and with new mutational events emerging at each step. Our data, contrary to the proposed model of early dissemination of metastatic cells and parallel progression of primary tumors and metastases, provide evidence of linear progression of breast cancer with relatively late dissemination from the primary tumor. The genomic discordance between the different stages of tumor evolution in this patient emphasizes the importance of molecular profiling of metastatic tissue directing molecularly targeted therapy at recurrence.
乳腺癌基因组从癌前阶段到异时性转移的演变过程复杂且大多未被探索，但由于其可能为癌症进展提供新的标志物和机制性见解，因此备受关注。乳腺癌个性化治疗的日益普及，需要了解恶性进展不同阶段之间的基因组一致性程度，因为原发性肿瘤常被用作全身性疾病的替代物。基于外显子组测序，我们对一名乳腺癌患者乳腺癌进展的连续阶段进行了拷贝数分析和点突变检测，包括导管原位癌（DCIS）的两个不同区域、原发性肿瘤和一个异时性转移灶。我们发现了一个显著的体细胞突变图谱，该图谱在乳腺癌进展过程中一直存在，且每个阶段都会出现新的突变事件。我们的数据与转移性细胞早期播散以及原发性肿瘤和转移灶平行进展的模型相反，提供了乳腺癌线性进展且从原发性肿瘤相对较晚播散的证据。该患者肿瘤演变不同阶段之间的基因组不一致性强调了对转移性组织进行分子分析以指导复发时分子靶向治疗的重要性。
