TY - JOUR
T1 - Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features
AU - Mendelaar, Pauline A J
AU - Smid, Marcel
AU - van Riet, Job
AU - Angus, Lindsay
AU - Labots, Mariette
AU - Steeghs, Neeltje
AU - Hendriks, Mathijs P
AU - Cirkel, Geert A
AU - van Rooijen, Johan M
AU - Ten Tije, Albert J
AU - Lolkema, Martijn P
AU - Cuppen, Edwin
AU - Sleijfer, Stefan
AU - Martens, John W M
AU - Wilting, Saskia M
N1 - Funding Information: We thank the Hartwig Medical Foundation, and Stichting Stelvio for Life for financial support of clinical studies and WGS analyses. We thank the Center for Personalized Cancer Treatment for proving the clinical data. We would like to thank all local principal investigators, medical specialists, and nurses of all contributing centers for their help with patient accrual. We are particularly grateful to all participating patients and their families. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099772327&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-020-20887-6
DO - https://doi.org/10.1038/s41467-020-20887-6
M3 - Article
C2 - 33495476
SN - 2041-1723
VL - 12
SP - 574
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 574
ER -