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Assessment of nuclear ZEB2 as a biomarker for colorectal cancer outcome and TNM risk stratification

Assessment of nuclear ZEB2 as a biomarker for colorectal cancer outcome and TNM risk stratification
Assessment of nuclear ZEB2 as a biomarker for colorectal cancer outcome and TNM risk stratification

Importance: At present, patients with colorectal cancer (CRC) are risk stratified using TNM histologic features. More recently, an association between a mesenchymal phenotype and a high risk of disease recurrence and micrometastases has been recognized.

Objective: To investigate the association of the epithelial to mesenchymal transition (EMT)-inducing transcription factor ZEB2 (zinc finger E box-binding homeobox 2), survival outcomes, and the efficacy of ZEB2 as a biomarker when added as refinement to TNM staging after curative intent surgery for CRC.

Design, Setting, and Participants: ZEB2 expression was assessed using a previously validated scoring system as part of a prospective, observational, masked diagnostic study from January 1, 2008, to December 31, 2013. Data were prospectively collected and analyzed for association with oncologic outcomes from January 1, 2017, to December 31, 2018. An initial test cohort from an academic university medical center of 126 consecutive patients with CRC and, subsequently, an independent validation cohort of 210 patients were examined. ZEB2 positivity was scored by 2 independent, masked pathologists. External validity was tested using an open access gene expression portal. Nomograms were developed with or without ZEB2.

Main Outcomes and Measures: Systemic and local recurrence of CRC.

Results: The test cohort consisted of 126 consecutive patients (mean [SD] age, 72.7 [11.7] years; 61 [48.4%] male) and the validation cohort of 210 patients (mean [SD] age, 72.0 [10.6] years; 111 [52.9%] male). A total of 52 tumors (41.3%) in the test cohort and 104 (49.5%) in the validation cohort were scored nuclear ZEB2 positive. Survival analysis by the log-rank test found that ZEB2 expression was associated with a significant reduction in overall survival and disease-free survival in both cohorts. Cox proportional hazards regression analysis highlighted ZEB2 as an independent biomarker of shorter overall survival and disease-free survival. Analysis of node-negative disease (n = 222) identified ZEB2 as an independent biomarker of early recurrence and reduced survival. External validation confirmed these findings. Addition of ZEB2 expression to nomograms composed of conventional TNM risk factors improved the ability to identify patients at high risk of recurrence demonstrated by the improvement in concordance index in both test (0.73 to 0.77) and validation (0.82 to 0.87) cohorts.

Conclusions and Relevance: The findings suggest that expression of ZEB2 is associated with poor oncologic outcome and distant recurrence. The study also found that the addition of ZEB2 to existing TNM classification improved the ability to stratify patients for risk of recurrence. The results of this study suggest that addition of ZEB2 expression status to the TNM staging system improves the ability to stratify patients at high risk of recurrence.

Journal Article
e183115
Sreekumar, Rahul
436bd002-4ddd-4dfd-8e23-f570971a0f76
Harris, Scott
19ea097b-df15-4f0f-be19-8ac42c190028
Moutasim, Karwan
af7dd711-f6df-44f7-8c57-052bf15303af
DeMateos, Ricardo
ca9e1f17-6de7-4b60-a692-ec1f4744aed2
Patel, Ashish
e94e1abf-d66d-435f-9d2d-33bcb0d699ab
Emo, Katherine
e7e558eb-a43c-4fbb-b589-4804598bd2b6
White, Sophie
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Yagci, Tamer
f2e09e8c-1299-4b37-ad56-85926d20fc56
Tulchinsky, Eugene
f0b81c60-c1cd-480b-936b-56bcd383e419
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Primrose, John N
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Sayan, A Emre
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Mirnezami, Alex H
b3c7aee7-46a4-404c-bfe3-f72388e0bc94
Sreekumar, Rahul
436bd002-4ddd-4dfd-8e23-f570971a0f76
Harris, Scott
19ea097b-df15-4f0f-be19-8ac42c190028
Moutasim, Karwan
af7dd711-f6df-44f7-8c57-052bf15303af
DeMateos, Ricardo
ca9e1f17-6de7-4b60-a692-ec1f4744aed2
Patel, Ashish
e94e1abf-d66d-435f-9d2d-33bcb0d699ab
Emo, Katherine
e7e558eb-a43c-4fbb-b589-4804598bd2b6
White, Sophie
9ca5b880-4f22-4f4c-8ce5-401e72765282
Yagci, Tamer
f2e09e8c-1299-4b37-ad56-85926d20fc56
Tulchinsky, Eugene
f0b81c60-c1cd-480b-936b-56bcd383e419
Thomas, Gareth
2ff54aa9-a766-416b-91ee-cf1c5be74106
Primrose, John N
d85f3b28-24c6-475f-955b-ec457a3f9185
Sayan, A Emre
d1dbbcad-9c53-47c1-8b7e-1b45cc56e077
Mirnezami, Alex H
b3c7aee7-46a4-404c-bfe3-f72388e0bc94

Sreekumar, Rahul, Harris, Scott, Moutasim, Karwan, DeMateos, Ricardo, Patel, Ashish, Emo, Katherine, White, Sophie, Yagci, Tamer, Tulchinsky, Eugene, Thomas, Gareth, Primrose, John N, Sayan, A Emre and Mirnezami, Alex H (2018) Assessment of nuclear ZEB2 as a biomarker for colorectal cancer outcome and TNM risk stratification. JAMA Network Open, 1 (6), e183115. (doi:10.1001/jamanetworkopen.2018.3115).

Record type: Article

Abstract

Importance: At present, patients with colorectal cancer (CRC) are risk stratified using TNM histologic features. More recently, an association between a mesenchymal phenotype and a high risk of disease recurrence and micrometastases has been recognized.

Objective: To investigate the association of the epithelial to mesenchymal transition (EMT)-inducing transcription factor ZEB2 (zinc finger E box-binding homeobox 2), survival outcomes, and the efficacy of ZEB2 as a biomarker when added as refinement to TNM staging after curative intent surgery for CRC.

Design, Setting, and Participants: ZEB2 expression was assessed using a previously validated scoring system as part of a prospective, observational, masked diagnostic study from January 1, 2008, to December 31, 2013. Data were prospectively collected and analyzed for association with oncologic outcomes from January 1, 2017, to December 31, 2018. An initial test cohort from an academic university medical center of 126 consecutive patients with CRC and, subsequently, an independent validation cohort of 210 patients were examined. ZEB2 positivity was scored by 2 independent, masked pathologists. External validity was tested using an open access gene expression portal. Nomograms were developed with or without ZEB2.

Main Outcomes and Measures: Systemic and local recurrence of CRC.

Results: The test cohort consisted of 126 consecutive patients (mean [SD] age, 72.7 [11.7] years; 61 [48.4%] male) and the validation cohort of 210 patients (mean [SD] age, 72.0 [10.6] years; 111 [52.9%] male). A total of 52 tumors (41.3%) in the test cohort and 104 (49.5%) in the validation cohort were scored nuclear ZEB2 positive. Survival analysis by the log-rank test found that ZEB2 expression was associated with a significant reduction in overall survival and disease-free survival in both cohorts. Cox proportional hazards regression analysis highlighted ZEB2 as an independent biomarker of shorter overall survival and disease-free survival. Analysis of node-negative disease (n = 222) identified ZEB2 as an independent biomarker of early recurrence and reduced survival. External validation confirmed these findings. Addition of ZEB2 expression to nomograms composed of conventional TNM risk factors improved the ability to identify patients at high risk of recurrence demonstrated by the improvement in concordance index in both test (0.73 to 0.77) and validation (0.82 to 0.87) cohorts.

Conclusions and Relevance: The findings suggest that expression of ZEB2 is associated with poor oncologic outcome and distant recurrence. The study also found that the addition of ZEB2 to existing TNM classification improved the ability to stratify patients for risk of recurrence. The results of this study suggest that addition of ZEB2 expression status to the TNM staging system improves the ability to stratify patients at high risk of recurrence.

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Accepted/In Press date: 31 July 2018
e-pub ahead of print date: 5 October 2018
Published date: 5 October 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 427711
URI: https://eprints.soton.ac.uk/id/eprint/427711
PURE UUID: 4b1946a6-9c90-42b9-98bf-5ef919f68e52
ORCID for John N Primrose: ORCID iD orcid.org/0000-0002-2069-7605

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Date deposited: 25 Jan 2019 17:30
Last modified: 14 Mar 2019 01:52

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