Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features

• Published in: Nature communications Vol. 12; no. 1; p. 574
• Main Authors: Mendelaar, Pauline A. J., Smid, Marcel, van Riet, Job, Angus, Lindsay, Labots, Mariette, Steeghs, Neeltje, Hendriks, Mathijs P., Cirkel, Geert A., van Rooijen, Johan M., Ten Tije, Albert J., Lolkema, Martijn P., Cuppen, Edwin, Sleijfer, Stefan, Martens, John W. M., Wilting, Saskia M.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 45/91; 631/67/1504/1885; 631/67/322; 631/67/69; Adult; Aged; Aged, 80 and over; Cancer; Cdc4 protein; Chemoradiotherapy - methods; Clustering; Cohort Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Epidermal growth factor receptors; F-Box-WD Repeat-Containing Protein 7 - genetics; Female; Fragile sites; Gene frequency; Gene sequencing; Genes; Genetic Predisposition to Disease - genetics; Genome, Human - genetics; Genomes; Genomics; Genomics - methods; Humanities and Social Sciences; Humans; Male; Metastases; Metastasis; Microsatellite Instability; Middle Aged; multidisciplinary; Mutation; Neoplasm Metastasis; Patients; Science; Science (multidisciplinary); Signatures; Whole genome sequencing; Whole Genome Sequencing - methods
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20887-6

In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). Unsupervised clustering using mutational signature patterns highlights three major patient groups characterized by signatures known from primary CRC, signatures associated with received prior treatments, and metastasis-specific signatures. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. In addition, we identify specific genes preferentially affected by microsatellite instability. CRC-specific 1kb-10Mb deletions, enriched for common fragile sites, and LINC00672 mutations are associated with response to treatment in general, whereas FBXW7 mutations predict poor response specifically to EGFR-targeted treatment. In conclusion, the genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance. Molecular landscapes of metastatic colorectal cancers (mCRC) have often been restricted to coding regions or low numbers of patients. Here the authors present a whole-genome landscape of 429 mCRC patients, revealing the mutational impact of prior therapies and potential actionable targets.