![]() Within the group of prior-treated patients, 13 different combinations of treatment regimens were defined as specified in the materials and methods and listed in Table 1.įor 91 cases RNA-seq data were available, allowing us to determine their Consensus Molecular Subtype (CMS). The observed metastatic molecular landscape is compared to WGS data of primary CRC cohorts (Supplementary Table 1), associated with prior treatments as well as treatment response, and evaluated for clinical utility.īased on the treatment data, the cohort can be divided in patients who did ( n = 284) and who did not ( n = 124) receive any systemic treatment prior to the moment the biopsy was taken. In addition, matched RNA-seq data are available for 91 patients. We use WGS data obtained from a large multicenter, prospective collection of snap-frozen metastatic tissue biopsies from 429 patients starting a new line of systemic treatment 9. Here, we provide a comprehensive description of the molecular landscape of metastatic CRC (mCRC). To date, the only other study which reported in detail on WGS data of colorectal metastases included 12 patients 4. In addition, clinically relevant genetic alterations within noncoding regions were recently reported in primary CRC 8. Next to this, WGS simultaneously allows for the determination of MSI, structural rearrangements, chromothripsis, and kataegis. ![]() ![]() For optimal identification of mutational signatures, the power provided by whole-genome sequencing (WGS) data greatly exceeds that of WES 7. Although these studies yielded extensive knowledge on the presence of specific genomic aberrations in mCRC, they do not necessarily reflect its complete molecular landscape. To date, in-depth analyses of large series of colorectal cancer metastases are limited to studies using either whole-exome sequencing (WES) or targeted sequencing of cancer-associated genes 4, 5, 6. Mutations in KRAS and BRAF predict failure to treatment with EGFR-inhibitors, whereas copy number alterations of ERBB2 or IGF2, and the occurrence of chromosomal translocations leading to fusion genes such as NAV2/TCF7L1, are potentially drug targetable 1, 3.Īlthough the molecular knowledge of primary CRC has contributed to a better understanding of its pathogenesis, cancer-related mortality usually occurs as a consequence of distant metastases, in which ongoing mutational processes and selective treatment pressure can result in altered molecular characteristics 4. Molecular analysis of CRC revealed specific genetic alterations with clinical implications. Parallel to the described genomic subtype division, transcriptomic analysis was used to identify four consensus molecular subtypes (CMSs) with distinguishing features including prognosis 2. ![]() Primary colorectal cancer (CRC) can be divided into a major group of chromosomally instable tumors and a minor group of hypermutated, chromosomally stable tumors due to microsatellite instability (MSI) or POLE mutations 1. 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. 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 addition, we identify specific genes preferentially affected by microsatellite instability. Compared to primary CRC, we identify additional putative (non-coding) driver genes and increased frequencies in driver gene mutations. 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. Here we present whole genome sequencing data of metastases of 429 CRC patients participating in the pan-cancer CPCT-02 study (NCT01855477). In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC.
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