Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing

M B Mogensen; M Rossing; O Østrup; P N Larsen; P J Heiberg Engel; L N Jørgensen; E V Hogdall; J Eriksen; P Ibsen; P Jess; M Grauslund; H J Nielsen; F C Nielsen; B Vainer; K Osterlind

doi:10.1186/s12885-018-4639-4

Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing

M B Mogensen, M Rossing, O Østrup, P N Larsen, P J Heiberg Engel, L N Jørgensen, E V Hogdall, J Eriksen, P Ibsen, P Jess, M Grauslund, H J Nielsen, F C Nielsen, B Vainer, K Osterlind

Institut for Klinisk Medicin

13 Citationer (Scopus)

20 Downloads (Pure)

Abstract

BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.

METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.

RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.

CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

Originalsprog	Engelsk
Artikelnummer	752
Tidsskrift	BMC Cancer
Vol/bind	18
Antal sider	13
ISSN	1471-2407
DOI	https://doi.org/10.1186/s12885-018-4639-4
Status	Udgivet - 20 jul. 2018

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10.1186/s12885-018-4639-4Licens: CC BY

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Mogensen, M. B., Rossing, M., Østrup, O., Larsen, P. N., Heiberg Engel, P. J., Jørgensen, L. N., Hogdall, E. V., Eriksen, J., Ibsen, P., Jess, P., Grauslund, M., Nielsen, H. J., Nielsen, F. C., Vainer, B., & Osterlind, K. (2018). Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing. BMC Cancer, 18, Artikel 752. https://doi.org/10.1186/s12885-018-4639-4

Mogensen, MB, Rossing, M, Østrup, O, Larsen, PN, Heiberg Engel, PJ, Jørgensen, LN , Hogdall, EV, Eriksen, J, Ibsen, P, Jess, P, Grauslund, M, Nielsen, HJ, Nielsen, FC, Vainer, B & Osterlind, K 2018, 'Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing', BMC Cancer, bind 18, 752. https://doi.org/10.1186/s12885-018-4639-4

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title = "Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing",

abstract = "BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.",

keywords = "Adult, Aged, Aged, 80 and over, Colorectal Neoplasms/drug therapy, DNA Copy Number Variations, Female, Genes, APC, Genomics, Humans, Liver Neoplasms/genetics, Male, Middle Aged, Mutation, Proto-Oncogene Proteins p21(ras)/genetics, Whole Exome Sequencing/methods",

author = "Mogensen, {M B} and M Rossing and O {\O}strup and Larsen, {P N} and {Heiberg Engel}, {P J} and J{\o}rgensen, {L N} and Hogdall, {E V} and J Eriksen and P Ibsen and P Jess and M Grauslund and Nielsen, {H J} and Nielsen, {F C} and B Vainer and K Osterlind",

year = "2018",

month = jul,

day = "20",

doi = "10.1186/s12885-018-4639-4",

language = "English",

volume = "18",

journal = "BMC Cancer",

issn = "1471-2407",

publisher = "BioMed Central Ltd.",

}

TY - JOUR

T1 - Genomic alterations accompanying tumour evolution in colorectal cancer

T2 - tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing

AU - Mogensen, M B

AU - Rossing, M

AU - Østrup, O

AU - Larsen, P N

AU - Heiberg Engel, P J

AU - Jørgensen, L N

AU - Hogdall, E V

AU - Eriksen, J

AU - Ibsen, P

AU - Jess, P

AU - Grauslund, M

AU - Nielsen, H J

AU - Nielsen, F C

AU - Vainer, B

AU - Osterlind, K

PY - 2018/7/20

Y1 - 2018/7/20

N2 - BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

AB - BACKGROUND: Colorectal cancer (CRC) patients with metastatic disease can become cured if neoadjuvant treatment can enable a resection. The search for predictive biomarkers is often performed on primary tumours tissue. In order to assess the effectiveness of tailored treatment in regard to the primary tumour the differences in the genomic profile needs to be clarified.METHODS: Fresh-frozen tissue from primary tumours, synchronous liver metastases and adjacent normal liver was collected from 21 patients and analysed by whole-exome sequencing on the Illumina HiSeq 2500 platform. Gene variants designated as 'damaging' or 'potentially damaging' by Ingenuity software were used for the subsequent comparative analysis. BAM files were used as the input for the analysis of CNAs using NEXUS software.RESULTS: Shared mutations between the primary tumours and the synchronous liver metastases varied from 50 to 96%. Mutations in APC, KRAS, NRAS, TP53 or BRAF were concordant between the primary tumours and the metastases. Among the private mutations were well-known driver genes such as PIK3CA and SMAD4. The number of mutations was significantly higher in patients with right- compared to left-sided tumours (102 vs. 66, p = 0.004). Furthermore, right- compared to left-sided tumours had a significantly higher frequency of private mutations (p = 0.023). Similarly, CNAs differed between the primary tumours and the metastases. The difference was mostly comprised of numerical and segmental aberrations. However, novel CNAs were rarely observed in specific CRC-relevant genes.CONCLUSION: The examined primary colorectal tumours and synchronous liver metastases had multiple private mutations, indicating a high degree of inter-tumour heterogeneity in the individual patient. Moreover, the acquirement of novel CNAs from primary tumours to metastases substantiates the need for genomic profiling of metastases in order to tailor metastatic CRC therapies. As for the mutational status of the KRAS, NRAS and BRAF genes, no discordance was observed between the primary tumours and the metastases.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Colorectal Neoplasms/drug therapy

KW - DNA Copy Number Variations

KW - Female

KW - Genes, APC

KW - Genomics

KW - Humans

KW - Liver Neoplasms/genetics

KW - Male

KW - Middle Aged

KW - Mutation

KW - Proto-Oncogene Proteins p21(ras)/genetics

KW - Whole Exome Sequencing/methods

U2 - 10.1186/s12885-018-4639-4

DO - 10.1186/s12885-018-4639-4

M3 - Journal article

C2 - 30029640

SN - 1471-2407

VL - 18

JO - BMC Cancer

JF - BMC Cancer

M1 - 752

ER -

Genomic alterations accompanying tumour evolution in colorectal cancer: tracking the differences between primary tumours and synchronous liver metastases by whole-exome sequencing

Abstract

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