Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: A prospective cohort study

Margriet R. Timmer, Pierre Martinez, Chiu T. Lau, Wytske M. Westra, Silvia Calpe, Agnieszka M. Rygiel, Wilda D. Rosmolen, Sybren L. Meijer, Fiebo J W ten Kate, Marcel G W Dijkgraaf, Rosalie C. Mallant-Hent, Anton H J Naber, Arnoud H A M van Oijen, Lubbertus C. Baak, Pieter Scholten, Clarisse J M Böhmer, Paul Fockens, Carlo Maley, Trevor A. Graham, Jacques J G H M BergmanKausilia K. Krishnadath

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Objective The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). Conclusions A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

Original languageEnglish (US)
JournalGut
DOIs
StateAccepted/In press - Jun 23 2015
Externally publishedYes

Fingerprint

Barrett Esophagus
Tumor Biomarkers
Cohort Studies
Prospective Studies
Adenocarcinoma
Biomarkers
Fluorescence In Situ Hybridization
Genetic Markers
Proportional Hazards Models
ROC Curve
Area Under Curve
Cell Biology
Multivariate Analysis
Outcome Assessment (Health Care)
DNA

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Timmer, M. R., Martinez, P., Lau, C. T., Westra, W. M., Calpe, S., Rygiel, A. M., ... Krishnadath, K. K. (Accepted/In press). Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: A prospective cohort study. Gut. https://doi.org/10.1136/gutjnl-2015-309642

Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus : A prospective cohort study. / Timmer, Margriet R.; Martinez, Pierre; Lau, Chiu T.; Westra, Wytske M.; Calpe, Silvia; Rygiel, Agnieszka M.; Rosmolen, Wilda D.; Meijer, Sybren L.; ten Kate, Fiebo J W; Dijkgraaf, Marcel G W; Mallant-Hent, Rosalie C.; Naber, Anton H J; M van Oijen, Arnoud H A; Baak, Lubbertus C.; Scholten, Pieter; Böhmer, Clarisse J M; Fockens, Paul; Maley, Carlo; Graham, Trevor A.; H M Bergman, Jacques J G; Krishnadath, Kausilia K.

In: Gut, 23.06.2015.

Research output: Contribution to journalArticle

Timmer, MR, Martinez, P, Lau, CT, Westra, WM, Calpe, S, Rygiel, AM, Rosmolen, WD, Meijer, SL, ten Kate, FJW, Dijkgraaf, MGW, Mallant-Hent, RC, Naber, AHJ, M van Oijen, AHA, Baak, LC, Scholten, P, Böhmer, CJM, Fockens, P, Maley, C, Graham, TA, H M Bergman, JJG & Krishnadath, KK 2015, 'Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: A prospective cohort study', Gut. https://doi.org/10.1136/gutjnl-2015-309642
Timmer, Margriet R. ; Martinez, Pierre ; Lau, Chiu T. ; Westra, Wytske M. ; Calpe, Silvia ; Rygiel, Agnieszka M. ; Rosmolen, Wilda D. ; Meijer, Sybren L. ; ten Kate, Fiebo J W ; Dijkgraaf, Marcel G W ; Mallant-Hent, Rosalie C. ; Naber, Anton H J ; M van Oijen, Arnoud H A ; Baak, Lubbertus C. ; Scholten, Pieter ; Böhmer, Clarisse J M ; Fockens, Paul ; Maley, Carlo ; Graham, Trevor A. ; H M Bergman, Jacques J G ; Krishnadath, Kausilia K. / Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus : A prospective cohort study. In: Gut. 2015.
@article{0327517ecb8547e391ea427fe84183e4,
title = "Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus: A prospective cohort study",
abstract = "Objective The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95{\%} CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95{\%} CI 0.66 to 0.86). Conclusions A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.",
author = "Timmer, {Margriet R.} and Pierre Martinez and Lau, {Chiu T.} and Westra, {Wytske M.} and Silvia Calpe and Rygiel, {Agnieszka M.} and Rosmolen, {Wilda D.} and Meijer, {Sybren L.} and {ten Kate}, {Fiebo J W} and Dijkgraaf, {Marcel G W} and Mallant-Hent, {Rosalie C.} and Naber, {Anton H J} and {M van Oijen}, {Arnoud H A} and Baak, {Lubbertus C.} and Pieter Scholten and B{\"o}hmer, {Clarisse J M} and Paul Fockens and Carlo Maley and Graham, {Trevor A.} and {H M Bergman}, {Jacques J G} and Krishnadath, {Kausilia K.}",
year = "2015",
month = "6",
day = "23",
doi = "10.1136/gutjnl-2015-309642",
language = "English (US)",
journal = "Gut",
issn = "0017-5749",
publisher = "BMJ Publishing Group",

}

TY - JOUR

T1 - Derivation of genetic biomarkers for cancer risk stratification in Barrett's oesophagus

T2 - A prospective cohort study

AU - Timmer, Margriet R.

AU - Martinez, Pierre

AU - Lau, Chiu T.

AU - Westra, Wytske M.

AU - Calpe, Silvia

AU - Rygiel, Agnieszka M.

AU - Rosmolen, Wilda D.

AU - Meijer, Sybren L.

AU - ten Kate, Fiebo J W

AU - Dijkgraaf, Marcel G W

AU - Mallant-Hent, Rosalie C.

AU - Naber, Anton H J

AU - M van Oijen, Arnoud H A

AU - Baak, Lubbertus C.

AU - Scholten, Pieter

AU - Böhmer, Clarisse J M

AU - Fockens, Paul

AU - Maley, Carlo

AU - Graham, Trevor A.

AU - H M Bergman, Jacques J G

AU - Krishnadath, Kausilia K.

PY - 2015/6/23

Y1 - 2015/6/23

N2 - Objective The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). Conclusions A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

AB - Objective The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. Methods In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. Results A total of 428 patients participated (345 men; median age 60 years) with a cumulative follow-up of 2019 patient-years (median 45 months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). Conclusions A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.

UR - http://www.scopus.com/inward/record.url?scp=84932636390&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84932636390&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2015-309642

DO - 10.1136/gutjnl-2015-309642

M3 - Article

C2 - 26104750

AN - SCOPUS:84932636390

JO - Gut

JF - Gut

SN - 0017-5749

ER -