Molecular profiling of longitudinally observed small colorectal polyps: A cohort study

M. C. J. van Lanschot; B. Carvalho; C. Rausch; P. Snaebjornsson; M. van Engeland; E. J. Kuipers; J. Stoker; C. J. Tutein Nolthenius; E. Dekker; G. A. Meijer

doi:10.1016/j.ebiom.2018.12.009

Molecular profiling of longitudinally observed small colorectal polyps: A cohort study

M. C. J. van Lanschot, B. Carvalho, C. Rausch, P. Snaebjornsson, M. van Engeland, E. J. Kuipers, J. Stoker, C. J. Tutein Nolthenius, E. Dekker, G. A. Meijer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes ('cancer associated events' or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps.

Methods: Small (6-9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resectecl. Using DNA isolated from ITPE polyp tissues, low-coverage whole genomc sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed.

Findings: Out of 68 polyps resectecl at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% Cl 13-169), p.023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ?2 mutations compared to lesions with only 0-1 mutations (difference 99% growth (95% CI 9-189), p.032). All samples were MMR proficient. No relation between growth and CIMP was observed.

Interpretation: Molecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers.

Original language	English
Pages (from-to)	292-300
Number of pages	9
Journal	EBioMedicine
Volume	39
DOIs	https://doi.org/10.1016/j.ebiom.2018.12.009
Publication status	Published - Jan 2019

Keywords

Colorectal polyps
Natural behaviour
Growth
Molecular profiling
CT COLONOGRAPHY
MICROSATELLITE INSTABILITY
CANCER
GENOME
COLONOSCOPY
PHENOTYPE
EVOLUTION
ADENOMAS
PATHWAYS
GROWTH

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@article{e036d9474a214ff2824fc7c71f571550,

title = "Molecular profiling of longitudinally observed small colorectal polyps: A cohort study",

abstract = "Background: Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes ('cancer associated events' or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps.Methods: Small (6-9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resectecl. Using DNA isolated from ITPE polyp tissues, low-coverage whole genomc sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed.Findings: Out of 68 polyps resectecl at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% Cl 13-169), p.023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ?2 mutations compared to lesions with only 0-1 mutations (difference 99% growth (95% CI 9-189), p.032). All samples were MMR proficient. No relation between growth and CIMP was observed.Interpretation: Molecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers.Fund: Alpe d'Huzes-Dutch Cancer Society (project number NKI2013-6338). (C) 2018 The Authors. Published by Elsevier B.V.",

keywords = "Colorectal polyps, Natural behaviour, Growth, Molecular profiling, CT COLONOGRAPHY, MICROSATELLITE INSTABILITY, CANCER, GENOME, COLONOSCOPY, PHENOTYPE, EVOLUTION, ADENOMAS, PATHWAYS, GROWTH",

author = "{van Lanschot}, {M. C. J.} and B. Carvalho and C. Rausch and P. Snaebjornsson and {van Engeland}, M. and Kuipers, {E. J.} and J. Stoker and Nolthenius, {C. J. Tutein} and E. Dekker and Meijer, {G. A.}",

note = "Funding Information: JS is research consultant Robarts Clinical Trials. ED has endoscopic equipment on loan of Olympus and FujiFilm, receives a research grant from FujiFilm, and recieves a honorarium for consultancy from FujiFilm, Tillots and Olympus. GAM has research collaborations with Exact Sciences and Sysmex for other studies regarding early detection of colorectal cancer. The companies provide materials, equipment or (sample) analyses. Funding Information: MCJvL receives funding from Alpe d'Huzes, Dutch Cancer Society (project number NKI2013-6338 ). The funders had no role in study design, data collection, analysis and interpretation, decision to publish, or writing of the report. GAM, ED, BC and MCJvL had full access to all the data in the study and GAM had final responsibility to submit for publication. Funding Information: MCJvL receives funding from Alpe d'Huzes, Dutch Cancer Society (project number NKI2013-6338). The funders had no role in study design, data collection, analysis and interpretation, decision to publish, or writing of the report. GAM, ED, BC and MCJvL had full access to all the data in the study and GAM had final responsibility to submit for publication. Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2019",

month = jan,

doi = "10.1016/j.ebiom.2018.12.009",

language = "English",

volume = "39",

pages = "292--300",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier",

}

TY - JOUR

T1 - Molecular profiling of longitudinally observed small colorectal polyps

T2 - A cohort study

AU - van Lanschot, M. C. J.

AU - Carvalho, B.

AU - Rausch, C.

AU - Snaebjornsson, P.

AU - van Engeland, M.

AU - Kuipers, E. J.

AU - Stoker, J.

AU - Nolthenius, C. J. Tutein

AU - Dekker, E.

AU - Meijer, G. A.

N1 - Funding Information: JS is research consultant Robarts Clinical Trials. ED has endoscopic equipment on loan of Olympus and FujiFilm, receives a research grant from FujiFilm, and recieves a honorarium for consultancy from FujiFilm, Tillots and Olympus. GAM has research collaborations with Exact Sciences and Sysmex for other studies regarding early detection of colorectal cancer. The companies provide materials, equipment or (sample) analyses. Funding Information: MCJvL receives funding from Alpe d'Huzes, Dutch Cancer Society (project number NKI2013-6338 ). The funders had no role in study design, data collection, analysis and interpretation, decision to publish, or writing of the report. GAM, ED, BC and MCJvL had full access to all the data in the study and GAM had final responsibility to submit for publication. Funding Information: MCJvL receives funding from Alpe d'Huzes, Dutch Cancer Society (project number NKI2013-6338). The funders had no role in study design, data collection, analysis and interpretation, decision to publish, or writing of the report. GAM, ED, BC and MCJvL had full access to all the data in the study and GAM had final responsibility to submit for publication. Publisher Copyright: © 2018 The Authors

PY - 2019/1

Y1 - 2019/1

N2 - Background: Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes ('cancer associated events' or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps.Methods: Small (6-9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resectecl. Using DNA isolated from ITPE polyp tissues, low-coverage whole genomc sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed.Findings: Out of 68 polyps resectecl at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% Cl 13-169), p.023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ?2 mutations compared to lesions with only 0-1 mutations (difference 99% growth (95% CI 9-189), p.032). All samples were MMR proficient. No relation between growth and CIMP was observed.Interpretation: Molecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers.Fund: Alpe d'Huzes-Dutch Cancer Society (project number NKI2013-6338). (C) 2018 The Authors. Published by Elsevier B.V.

AB - Background: Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time, have shown that most lesions remain stable or even completely regress. Specific DNA copy number changes ('cancer associated events' or CAEs) are associated with progression of adenomas to cancer. In this study we evaluated whether molecular features of progression correlated with growth of small polyps.Methods: Small (6-9 mm) colorectal precursor lesions detected on CT-colonography (CTC) were left in situ and re-evaluated with CTC after three years. Based on volumetric change, polyps were classified as either grown, stable or regressed. Surveillance CTC was followed by colonoscopy, during which all lesions were resectecl. Using DNA isolated from ITPE polyp tissues, low-coverage whole genomc sequencing was performed to determine DNA copy number profiles, as well as target enrichment mutation analysis and CpG island methylation phenotype (CIMP) analysis. Expression of DNA mismatch repair (MMR) proteins was determined by immunohistochemistry. Samples were marked as MMR proficient if all MMR proteins were expressed.Findings: Out of 68 polyps resectecl at colonoscopy, for 65 (96%) material was available. Of these, 31 (48%) had grown, 27 (41%) remained stable and 7 (11%) regressed. Polyps with at least one CAE had higher growth rates compared to polyps without CAEs (difference 91% growth (95% Cl 13-169), p.023). CAEs were absent in lesions that had partially regressed. Mutations occurred in 94% of the polyps, with higher growth rates being associated with polyps having ?2 mutations compared to lesions with only 0-1 mutations (difference 99% growth (95% CI 9-189), p.032). All samples were MMR proficient. No relation between growth and CIMP was observed.Interpretation: Molecular alterations associated with colorectal cancer, correlated with growth of small polyps and were absent in polyps that regressed. Therefore, this longitudinal study provides in vivo support in the human setting for the functional role of these molecular alterations, that have mostly been identified by cross sectional observations in tissue samples of colorectal adenomas and cancers.Fund: Alpe d'Huzes-Dutch Cancer Society (project number NKI2013-6338). (C) 2018 The Authors. Published by Elsevier B.V.

KW - Colorectal polyps

KW - Natural behaviour

KW - Growth

KW - Molecular profiling

KW - CT COLONOGRAPHY

KW - MICROSATELLITE INSTABILITY

KW - CANCER

KW - GENOME

KW - COLONOSCOPY

KW - PHENOTYPE

KW - EVOLUTION

KW - ADENOMAS

KW - PATHWAYS

KW - GROWTH

U2 - 10.1016/j.ebiom.2018.12.009

DO - 10.1016/j.ebiom.2018.12.009

M3 - Article

C2 - 30555044

SN - 2352-3964

VL - 39

SP - 292

EP - 300

JO - EBioMedicine

JF - EBioMedicine

ER -