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

Pauline A. J. Mendelaar, Marcel Smid, Job Riet, Lindsay Angus, Mariette Labots, Neeltje Steeghs, Mathijs P. Hendriks, Geert A. Cirkel, Johan M. Rooijen, Albert J. Tije, Martijn P. Lolkema, Edwin Cuppen, Stefan Sleijfer, John W. M. Martens and Saskia M. Wilting ()
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Pauline A. J. Mendelaar: Erasmus University Medical Center Rotterdam
Marcel Smid: Erasmus University Medical Center Rotterdam
Job Riet: Erasmus University Medical Center Rotterdam
Lindsay Angus: Erasmus University Medical Center Rotterdam
Mariette Labots: Amsterdam UMC, Vrije Universiteit Amsterdam
Neeltje Steeghs: Center for Personalized Cancer Treatment
Mathijs P. Hendriks: Center for Personalized Cancer Treatment
Geert A. Cirkel: Center for Personalized Cancer Treatment
Johan M. Rooijen: Center for Personalized Cancer Treatment
Albert J. Tije: Center for Personalized Cancer Treatment
Martijn P. Lolkema: Erasmus University Medical Center Rotterdam
Edwin Cuppen: University Medical Center Utrecht
Stefan Sleijfer: Erasmus University Medical Center Rotterdam
John W. M. Martens: Erasmus University Medical Center Rotterdam
Saskia M. Wilting: Erasmus University Medical Center Rotterdam

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20887-6

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DOI: 10.1038/s41467-020-20887-6

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