Krøigård Anne Bruun, Larsen Martin Jakob, Lænkholm Anne-Vibeke, Knoop Ann S, Jensen Jeanette Dupont, Bak Martin, Mollenhauer Jan, Thomassen Mads, Kruse Torben A
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
PLoS One. 2018 Jan 2;13(1):e0189887. doi: 10.1371/journal.pone.0189887. eCollection 2018.
Cancer results from alterations at essential genomic sites and is characterized by uncontrolled cell proliferation, invasion and metastasis. Identification of driver genes of metastatic progression is essential, as metastases, not primary tumors, are fatal. To gain insight into the mutational concordance between different steps of malignant progression we performed exome sequencing and validation with targeted deep sequencing of successive steps of malignant progression from pre-invasive stages to asynchronous distant metastases in six breast cancer patients. Using the ratio of non-synonymous to synonymous mutations, a surprisingly large number of cancer driver genes, ranging between 3 and 145, were estimated to confer a selective advantage in the studied primary tumors. We report a substantial amount of metastasis specific mutations and a number of novel putative metastasis driver genes. Most notable are the DCC, ABCA13, TIAM2, CREBBP, BCL6B and ZNF185 genes, mainly mutated exclusively in metastases and highly likely driver genes of metastatic progression. We find different genes and pathways to be affected at different steps of malignant progression. The Adherens junction pathway is affected in four of the six studied patients and this pathway most likely plays a vital role in the metastatic process.
癌症源于关键基因组位点的改变，其特征为细胞不受控制地增殖、侵袭和转移。确定转移进展的驱动基因至关重要，因为致命的是转移灶而非原发性肿瘤。为深入了解恶性进展不同阶段之间的突变一致性，我们对6例乳腺癌患者从癌前阶段到不同步远处转移的恶性进展连续阶段进行了外显子组测序，并通过靶向深度测序进行验证。使用非同义突变与同义突变的比例，估计在研究的原发性肿瘤中有数量惊人的癌症驱动基因（3至145个不等）赋予了选择性优势。我们报告了大量转移特异性突变以及一些新的假定转移驱动基因。最值得注意的是DCC、ABCA13、TIAM2、CREBBP、BCL6B和ZNF185基因，主要仅在转移灶中发生突变，极有可能是转移进展的驱动基因。我们发现在恶性进展的不同阶段，不同的基因和通路会受到影响。在6例研究患者中的4例中，黏着连接通路受到影响，该通路很可能在转移过程中发挥重要作用。
