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

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.

Fig. 1. Size distributions of the different types of structural variants.

Ridge-plot of the density of genomic sizes of structural variants in metastatic CRC. INV inversions (blue), DUP tandem duplications (purple), DEL deletions (orange). Source data are provided as a Source Data file.

Fig. 2. Oncoplot of metastatic CRC depicting identified driver genes and somatic mutations (SNV, InDels, and MNV).

Top panel: genes identified by dN/dS as driver genes per type of mutation; purple: frameshift variant; orange: other variant; blue: stop/gain variant; green: structural variant. Bottom panel: first track: clinical information: sex (male: orange; female: green) and second track: biopsy site. Track three (PLAT/PYR ± targeted) indicates which patients have been treated with platinum-based therapy (PLAT; e.g., oxaliplatin) and a pyrimidine-targeting drug (PYR; e.g., 5-FU), with or without the addition of another targeted treatment (±targeted; e.g., bevacizumab). Tracks four to six depict the distribution of the consensus molecular subtypes (CMS), tumor mutational burden (TMB), and the number of structural variant deletions of size 10kb–1Mb (DEL_CFS), partly associated with Common Fragile Sites (CFS), respectively. Source data are provided as a Source Data file.

Fig. 3. Mutational signatures in prior-treated cases compared to untreated cases.

Relative contribution (%) of several single and double base mutational signatures (SBS/DBS) in patients receiving prior treatment with platinum, pyrimidine antagonist, and targeted anti-EGFR treatment (PLAT/PYR + target; orange, n = 134) compared to untreated patients (blue, n = 124). Horizontal lines indicate the median. P-values are derived from the MWU test (two-sided) and corrected for multiple testing using the FDR (Hochberg) method. Source data are provided as a Source Data file.

Fig. 4. Mutational signatures in primary CRC and untreated metastatic CRC.

Relative contribution (%) of several single and double base mutational signatures (SBS/DBS) in primary CRC tumors (purple, n = 73), compared to untreated metastatic CRC tumors (green, n = 124). Horizontal lines indicate the median. P-values are derived from the MWU test (two-sided) and corrected for multiple testing using the FDR (Hochberg) method. Source data are provided as a Source Data file.

Fig. 5. Unsupervised hierarchical clustering of metastatic CRC using relative contribution of preselected mutational signatures.

Heatmap representing the median-centered relative contribution of mutational signatures between samples. Values were scaled from red (relative contribution above median) to yellow (relative contribution below median). Included single and doublet base signatures (SBS/DBS) are indicated at the right to which etiologies are added when known. Grouping of samples is shown by the dendrogram at the top. Source data are provided as a Source Data file.

Fig. 6. Actionable genes.

Data from OncoKB were matched to affected genes observed in our mCRC cohort. Numbers indicate the number (and percentage) of affected patients. Source data are provided as a Source Data file.