Abstract
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.
Highlights
In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC
The molecular knowledge of primary CRC has contributed to a better understanding of its pathogenesis, cancerrelated 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]
Based on a previously described whole-genome sequencing (WGS) data analysis algorithm[9 14] samples (3%) were scored as microsatellite instable (MSI), which is in concordance with the observed microsatellite instability (MSI) frequency in metastatic CRC (mCRC) in literature (4%)[10]
Summary
In contrast to primary colorectal cancer (CRC) little is known about the genomic landscape of metastasized CRC. The genomic landscape of mCRC shows defined changes compared to primary CRC, is affected by prior treatments and contains features with potential clinical relevance. 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]. These studies yielded extensive knowledge on the presence of specific genomic aberrations in mCRC, they do not necessarily reflect its complete molecular landscape. The only other study which reported in detail on WGS data of colorectal metastases included 12 patients[4]
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