Clinical and Translational Research
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2022; 14(11): 2195-2207
Published online Nov 15, 2022. doi: 10.4251/wjgo.v14.i11.2195
Missed colorectal cancers in a fecal immunochemical test-based screening program: Molecular profiling of interval carcinomas
Manon van der Vlugt, Beatriz Carvalho, Joelle Fliers, Nahid Montazeri, Christian Rausch, Esmée J Grobbee, Manon van Engeland, Manon C W Spaander, Gerrit A Meijer, Evelien Dekker
Manon van der Vlugt, Joelle Fliers, Evelien Dekker, Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam 1105 AZ, Netherlands
Beatriz Carvalho, Christian Rausch, Gerrit A Meijer, Department of Pathology, Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands
Nahid Montazeri, Biostatistics Unit, Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Amsterdam 1105 AZ, Netherlands
Esmée J Grobbee, Manon C W Spaander, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam 3015 CN, Netherlands
Manon van Engeland, Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht 6202 AZ, Netherlands
Author contributions: van der Vlugt M, Carvalho B, Meijer GA and Dekker E contributed to the study concept and design, acquisition of data, analysis and interpretation of data; van der Vlugt M and Carvalho B contributed to drafting of the manuscript and statistical analysis; Fliers J contributed to the study concept and design; Fliers J, Montazeri N, Rausch C, Grobbee EJ, van Engeland M, Spaander MCW, Meijer GA and Dekker E contributed to critical revision of the manuscript for important intellectual content; Montazeri N and Rausch C contributed to study design and statistical analysis; Grobbee EJ, van Engeland M and Spaander MCW contributed to the study concept and acquisition of data.
Supported by Foundation of Population Screening Mid-West Netherlands, Amsterdam, The Netherlands (BoMW); Foundation of Population Screening South-West Netherlands, Rotterdam, The Netherlands (BoZW); Netherlands Comprehensive Cancer Organization (IKNL); Netherlands Organization for Health Research and Development of the Dutch Ministry of Health (ZonMW); PALGA, the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands.
Institutional review board statement: Ethics approval for performing FIT-based screening including linkage to the Netherlands Cancer Registry was provided by the Dutch National Health Council (WBO 2642467, 2832758, 3049078 and 161536-112008, The Hague, The Netherlands). No separate ethics approval was necessary for the additional molecular analysis, as judged by the scientific ethics board of the AMC University Hospital. Collection and use of tissue and patient data were performed in compliance with the ‘Code for Proper Secondary Use of Human Tissue in the Netherlands’ (www.federa.org).
Clinical trial registration statement: This study is registered at the Dutch Trial Registry. Registration number: NTR5874 (http://www.trialregister.nl).
Informed consent statement: All screenees participating in FIT screening filled in an informed consent form.
Conflict-of-interest statement: Meijer GA has research collaborations with Exact Sciences, Sysmex and Sentinel for other studies regarding early detection of colorectal cancer. The companies provide materials, equipment or (sample) analyses. Meijer GA is CSO and shareholder of CRCbioscreen BV. Carvalho B has several patents pending. Dekker E received a research grant from FujiFilm. She has received honorarium for consultancy from FujiFilm, Olympus, Tillots, GI Supply, CPP-FAP and PAION, and speakers' fees from Olympus, Roche, GI Supply and Norgine. Spaander MC received research support of Sysmex and Sentinel. All other coauthors don’t have conflicts of interest.
Data sharing statement: Raw mutation data (concerning the mutation analysis and DNA copy number analysis) have been deposited in the European Genome-Phenome Archive with the study ID: EGAS00001004683.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Manon van der Vlugt, MD, PhD, Doctor, Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands. m.vandervlugt@amsterdamumc.nl
Received: July 26, 2022
Peer-review started: July 26, 2022
First decision: August 19, 2022
Revised: September 6, 2022
Accepted: October 2, 2022
Article in press: October 2, 2022
Published online: November 15, 2022
Abstract
BACKGROUND

For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions.

AIM

To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT [screen-detected CRCs (SD-CRCs)].

METHODS

FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio, resulting in 27 FIT-interval CRC and 54 SD-CRCs. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations (CNAs).

RESULTS

Although no significant differences were reached, FIT-interval CRCs were more often CIMP positive and MSI positive (33% CIMP in FIT-interval CRCs vs 21% in SD-CRCs (P = 0.274); 19% MSI in FIT-interval CRCs vs 12% in SD-CRCs (P = 0.469)), and showed more often serrated pathway associated features such as BRAF (30% vs 12%, P = 0.090) and PTEN (15% vs 2.4%, P = 0.063) mutations. APC mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% vs 40% in FIT-interval CRCs P = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 (P = 0.009), and more often gains at 20p13-p12.1 (P = 0.039).

CONCLUSION

Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs, while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs. This indicates that proximal serrated lesions may be overrepresented among FIT-interval CRCs.

Keywords: Fecal immunochemical test-interval colorectal cancer, Mutation analysis, Colorectal cancer screening, Serrated pathway, Adenoma-carcinoma pathway

Core Tip: Fecal immunochemical test (FIT) is effective in reducing colorectal cancer (CRC) but FIT testing is not perfect. FIT interval cancers, i.e. CRCs diagnosed after a negative FIT but before the next FIT invitation, still occur. Previous studies have shown that FIT sensitivity for sessile serrated lesions (SSLs) is low, but a correlation between the occurrence of FIT interval cancers and the serrated pathway has not been established. In our study, the serrated pathway-associated molecular features were more common in FIT-interval CRCs as compared to screen detected CRCs. This indicates that proximal serrated lesions may be overrepresented among FIT interval CRCs. The findings of this study can provide guidance on strategies to further improve stool-based CRC screening with incorporating biomarkers for SSLs, thereby reducing the number of screening interval CRCs.