Exome scale map of genetic alterations promoting metastasis in colorectal cancer

Abstract

BackgroundApproximately 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.Results> 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (10.1186/s12863-018-0673-0) contains supplementary material, which is available to authorized users.

The transition from primary colorectal cancer to isolated peritoneal malignancy is associated with an increased tumour mutational burden

“…CRC metastatic drivers are less clearly defined, apart from TP53 which is well characterised as being present in metastatic cancer 20 . Some studies have found mutations exclusive to metastatic sites 21 , 22 , whereas others found similar patterns of mutation between primary and metastasis 23 . Studies have examined the somatic mutations in CPM and their prognostic implications.…”

A decade with whole exome sequencing in haematology

“…The number of mutations generally increases with age, and the combinations of these mutations occur in a nonrandom fashion (Welch et al , ). If the number of coding variants corresponds to the number of genes (Choi et al , ; Ng et al , ), then it is highly interesting that, on average, one variant can be expected per gene, which is also supported by data submitted in relation to exome sequencing of colorectal cancer (Goryca et al , ). Furthermore, very few nonsense mutations are generally found by sequencing (Choi et al , ).…”

Downregulation of microRNA‑126 is inversely correlated with insulin receptor substrate‑1 protein expression in colorectal cancer and is associated with advanced stages of disease

“…Previous studies have demonstrated the essential roles of genetic alterations and aberrant expressions of several oncogenes or tumor suppressor genes in the development of CRC ( 4 , 5 ). Whole-exome and genome-scale transcriptome sequencing of seven liver metastases, along with their matched primary tumors and normal tissues showed that, mutations in KRAS, APC, POLE, PTPRT, PLXND1, CELSR3, BAHD1 and PNPLA6 are associated with CRC metastasis ( 6 ). Several tumor suppressor genes are associated to CRC carcinogenic process, with the APC, PTEN, FBXW7 and p53 being the common mutated ones in CRC; while oncogenes, including KRAS, CDK8, BRAF, PIK3CA, EGFR, have been shown to have mutations in patients with CRC ( 7 ).…”