Goryca Krzysztof, Kulecka Maria, Paziewska Agnieszka, Dabrowska Michalina, Grzelak Marta, Skrzypczak Magdalena, Ginalski Krzysztof, Mroz Andrzej, Rutkowski Andrzej, Paczkowska Katarzyna, Mikula Michal, Ostrowski Jerzy
Depatment of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland.
BMC Genet. 2018 Sep 19;19(1):85. doi: 10.1186/s12863-018-0673-0.
Approximately 90% of colorectal cancer (CRC) deaths are caused by tumors ability to migrate into the adjacent tissues and metastase into distant organs. More than 40 genes have been causally linked to the development of CRC but no mutations have been associated with metastasis yet. To identify molecular basis of CRC metastasis we performed whole-exome and genome-scale transcriptome sequencing of 7 liver metastases along with their matched primary tumours and normal tissue. Multiple, spatially separated fragments of primary tumours were analyzed in each case. Uniformly malignant tissue specimen were selected with macrodissection, for three samples followed with laser microdissection.
100 sequencing coverage allowed for detection of genetic alterations in subpopulation of tumour cells. Mutations in KRAS, APC, POLE, and PTPRT, previously associated with CRC development, were detected in most patients. Several new associations were identified, including PLXND1, CELSR3, BAHD1 and PNPLA6.
We confirm the essential role of inflammation in CRC progression but question the mechanism of matrix metalloproteinases activation described in other work. Comprehensive sequencing data made it possible to associate genome-scale mutation distribution with gene expression patterns. To our knowledge, this is the first work to report such link in CRC metastasis context.
大约90%的结直肠癌（CRC）死亡是由肿瘤迁移至邻近组织并转移至远处器官的能力所致。超过40个基因与CRC的发生有因果关系，但尚无突变与转移相关。为了确定CRC转移的分子基础，我们对7个肝转移灶及其匹配的原发肿瘤和正常组织进行了全外显子组和基因组规模的转录组测序。每种情况下均分析了原发肿瘤多个空间分离的片段。通过宏观解剖选择均匀的恶性组织标本，对3个样本随后进行激光显微切割。
100倍的测序覆盖度能够检测肿瘤细胞亚群中的基因改变。在大多数患者中检测到了先前与CRC发生相关的KRAS、APC、POLE和PTPRT突变。还发现了一些新的关联，包括PLXND1、CELSR3、BAHD1和PNPLA6。
我们证实了炎症在CRC进展中的重要作用，但对其他研究中描述的基质金属蛋白酶激活机制提出质疑。全面的测序数据使我们能够将基因组规模的突变分布与基因表达模式联系起来。据我们所知，这是首次在CRC转移背景下报道这种联系的研究。
