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

Pauline A J Mendelaar; Marcel Smid; Job van Riet; Lindsay Angus; Mariette Labots; Neeltje Steeghs; Mathijs P Hendriks; Geert A Cirkel; Johan M van Rooijen; Albert J Ten Tije; Martijn P Lolkema; Edwin Cuppen; Stefan Sleijfer; John W M Martens; Saskia M Wilting

doi:10.1038/s41467-020-20887-6

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

Pauline A J Mendelaar, Marcel Smid, Job van Riet, Lindsay Angus, Mariette Labots, Neeltje Steeghs, Mathijs P Hendriks, Geert A Cirkel, Johan M van Rooijen, Albert J Ten Tije, Martijn P Lolkema, Edwin Cuppen, Stefan Sleijfer, John W M Martens, Saskia M Wilting

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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.

Original language	English
Article number	574
Number of pages	11
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20887-6
Publication status	Published - 25 Jan 2021

Keywords

Adult
Aged
Aged, 80 and over
Chemoradiotherapy/methods
Cohort Studies
Colorectal Neoplasms/genetics
F-Box-WD Repeat-Containing Protein 7/genetics
Female
Genetic Predisposition to Disease/genetics
Genome, Human/genetics
Genomics/methods
Humans
Male
Microsatellite Instability
Middle Aged
Mutation
Neoplasm Metastasis
Whole Genome Sequencing/methods

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10.1038/s41467-020-20887-6

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Mendelaar, P. A. J., Smid, M., van Riet, J., Angus, L., Labots, M., Steeghs, N., Hendriks, M. P., Cirkel, G. A., van Rooijen, J. M., Ten Tije, A. J., Lolkema, M. P., Cuppen, E., Sleijfer, S., Martens, J. W. M., & Wilting, S. M. (2021). Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features. Nature Communications, 12(1), Article 574. https://doi.org/10.1038/s41467-020-20887-6

@article{b445b1be4f1843e0bc219fa8324eeb1c,

title = "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.",

keywords = "Adult, Aged, Aged, 80 and over, Chemoradiotherapy/methods, Cohort Studies, Colorectal Neoplasms/genetics, F-Box-WD Repeat-Containing Protein 7/genetics, Female, Genetic Predisposition to Disease/genetics, Genome, Human/genetics, Genomics/methods, Humans, Male, Microsatellite Instability, Middle Aged, Mutation, Neoplasm Metastasis, Whole Genome Sequencing/methods",

author = "Mendelaar, {Pauline A J} and Marcel Smid and {van Riet}, Job and Lindsay Angus and Mariette Labots and Neeltje Steeghs and Hendriks, {Mathijs P} and Cirkel, {Geert A} and {van Rooijen}, {Johan M} and {Ten Tije}, {Albert J} and Lolkema, {Martijn P} and Edwin Cuppen and Stefan Sleijfer and Martens, {John W M} and Wilting, {Saskia M}",

note = "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: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = jan,

day = "25",

doi = "10.1038/s41467-020-20887-6",

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

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Mendelaar, PAJ, Smid, M, van Riet, J, Angus, L, Labots, M, Steeghs, N, Hendriks, MP, Cirkel, GA, van Rooijen, JM, Ten Tije, AJ, Lolkema, MP, Cuppen, E, Sleijfer, S, Martens, JWM & Wilting, SM 2021, 'Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features', Nature Communications, vol. 12, no. 1, 574. https://doi.org/10.1038/s41467-020-20887-6

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).

PY - 2021/1/25

Y1 - 2021/1/25

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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Chemoradiotherapy/methods

KW - Cohort Studies

KW - Colorectal Neoplasms/genetics

KW - F-Box-WD Repeat-Containing Protein 7/genetics

KW - Female

KW - Genetic Predisposition to Disease/genetics

KW - Genome, Human/genetics

KW - Genomics/methods

KW - Humans

KW - Male

KW - Microsatellite Instability

KW - Middle Aged

KW - Mutation

KW - Neoplasm Metastasis

KW - Whole Genome Sequencing/methods

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U2 - 10.1038/s41467-020-20887-6

DO - 10.1038/s41467-020-20887-6

M3 - Article

C2 - 33495476

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 574

ER -

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

Abstract

Keywords

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Author Correction: Whole genome sequencing of metastatic colorectal cancer reveals prior treatment effects and specific metastasis features (Nature Communications, (2021), 12, 1, (574), 10.1038/s41467-020-20887-6)

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