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SMALL-BOWEL CANCER SURVEILLANCE WITH CAPSULE ENDOSCOPY IN LYNCH SYNDROME – A SYSTEMATIC REVIEW WITH META-ANALYSIS

Pablo Cortegoso Valdivia 1, Ulrik Deding 2,3, Thomas Bjørsum-Meyer 2,3, Marco Pennazio 4, Federica Gaiani 1,5, Anastasios Koulaouzidis 6,2,7,8, Luigi Andrea Laghi 1,5,9

Affiliations

1 University Hospital of Parma, University of Parma, Parma, Italy

2 University of Southern Denmark, Odense, Denmark

3 Odense University Hospital, Svendborg, Denmark

4 City of Health and Science University Hospital, University of Turin, Turin, Italy

5 University of Parma, Parma, Italy

6 OUH Svendborg Sygehus, Svendborg, Denmark

7 Odense University Hospital, Odense, Denmark

8 Pomeranian Medical University, Szczecin, Poland

9 IRCSS Humanitas Research Hospital, Rozzano, Milan, Italy

Summary

AI Generated

Meta-analysis of five studies comprising 583 asymptomatic Lynch syndrome patients found capsule endoscopy screening for small-bowel cancer yielded 8% detection in first round but 0% histologically-confirmed pathology in second-round screening at 2-year intervals, suggesting this surveillance strategy is not effective.

Pooled diagnostic yield for capsule endoscopy-identified pathology was 8% (95% CI 4-12%) in first screening round and 6% (95% CI 2-10%) in second round, but histologically-confirmed pathology yield in second round dropped to 0% (95% CI 0-6%).
Sixteen patients with adenomas or adenocarcinomas were identified across studies, with adenomas detected at median age 47.5 years and adenocarcinomas at median age 62.5 years, suggesting a 15-year delay between lesion types.
MLH1 was the most commonly involved pathogenic variant (9 of 16 patients), followed by MSH2 (5 patients) and MSH6 (2 patients); no adenocarcinomas were detected in MSH6 carriers.
The authors conclude that small-bowel cancer surveillance with capsule endoscopy at 2-year intervals in asymptomatic Lynch syndrome patients is not an effective screening strategy and suggest consideration of longer intervals starting at age 50.

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

The role of capsule endoscopy (CE) for the surveillance of small-bowel (SB) cancer in asymptomatic Lynch syndrome (LS) patients has been questioned in recent years, with contradicting results. The overall lifetime risk of SB cancer in this population is around 4-5%, with an age-dependent pattern [1]. Besides, recent data highlight that, depending on the affected path_MMR gene, the frequencies of tumors other than colorectal cancer vary and that affected patients develop subsequent cancers later in life. The aim of this meta-analysis is to evaluate the diagnostic yield (DY) of CE as a screening tool in asymptomatic LS patients.

Aims & Methods

A systematic literature search was conducted in Pubmed, Embase and Web of Science to identify all studies evaluating SB cancer surveillance with CE in asymptomatic LS patients. The primary outcome was the evaluation of the DY of CE in consecutive screening rounds, for both CE-identified pathology and histologically-confirmed pathology (i.e., adenoma or adenocarcinoma). Pooled estimates of DY were calculated from random effects models.

Results

Five studies including 583 patients were identified for data extraction and statistical analysis [2-6] [Table]. The estimated pooled DY for CE-identified pathology was 8% in the first screening round (95% confidence interval [CI] 4-12%) and 6% in the second (95% CI 2-10%). Limiting the analysis to histologically-confirmed pathology, the pooled DY of the second-round screening dropped to 0% (95% CI 0-6%). The time interval between screening rounds was approximately 2 years.
Adenomas were detected in 8 patients (4 males) with a median age of 47.5 years (interquartile range [IQR] 19), while adenocarcinomas were diagnosed in 8 patients (5 males) with a median age of 62.5 years (IQR 17.25). MLH1 was the most involved path_MMR pathogenic variant (9 out of 16 patients), followed by MSH2 and MSH6 (5 and 2 patients, respectively). No adenocarcinomas were detected in MSH6 carriers, as only adenomas were found in 2 patients, with a considerably higher median age than MSH2 and MLH1 adenoma carriers (70.5 years versus 43.5 and 45). No predominance was observed according to the anatomical location (duodenum, n=6; jejunum, n=6; ileum, n=4).

	Study characteristics					First-round screening				Second-round screening
Reference, year		Type of study	MINORS score (0-14)	No. of included patients	Age (mean)	No. of performed CE procedures	No. of CE with positive detection (% rate)	N. of patients with histologically-confirmed findings (% rate)	Time interval (years)	N. of performed CE procedures	No. of CE with positive detection (% rate)	N. of patients with histologically-confirmed findings (% rate)
Saurin, 2010		Prospective, multicenter	12	35	47	35	3 (8.6 %)	3 (8.6 %)	3.3	7	0 (0 %)	0 (0 %)
Haanstra, 2015		Prospective, multicenter	10	200	50.4	200	23 (11.5 %)	2 (1 %)	2.2	-	-	-
Haanstra, 2017		Prospective, multicenter	10	155	51.6	-	-	-	2.2	155	15 (9.7 %)	0 (0 %)
Perrod, 2020		Retrospective, single center	9	135	52.7 (median)	135	6 (4.4 %)	6 (4.4 %)	2	87	4 (4.6 %)	4 (4.6 %)
DeJesse, 2021		Retrospective, single center	10	58	56 (median)	58	5 (8.6 %)	0 (0 %)	NA	-	-	-

Conclusion

The detection of adenocarcinoma appeared to have a 15-year delay compared to adenomas, supporting a rather slow adenoma to carcinoma transition.
A surveillance strategy starting from the age of 50, with a time interval between procedures lengthened to at least 5 years (instead of 2) could likely be more effective in reducing the burden of advanced disease, both in terms of cost-effectiveness and efficacy. Prospective data may reveal whether a potential SB surveillance might benefit from gene-associated differences in cancer risk, similar to the recent de-escalation of CRC screening recommendations in MSH6 and PMS2 carriers [7].
In conclusion, although the DY of CE is high in detecting SB lesions in LS, the low number of positive examinations eventually resulted in an even lower number of true-positive patients, with a pooled yield proximate to 0%.
The results of this study confirm that SB cancer surveillance with CE with a 2-year interval in asymptomatic LS individuals is not an effective screening strategy.

References

[1] Dominguez-Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database. Genet Med 2020;22:15–25.
[2] Saurin J-C, Pilleul F, Soussan EB, et al. Small-bowel capsule endoscopy diagnoses early and advanced neoplasms in asymptomatic patients with Lynch syndrome. Endoscopy 2010;42:1057–62.
[3] Haanstra JF, Al-Toma A, Dekker E, et al. Prevalence of small-bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Gut 2015;64:1578–83.
[4] Haanstra JF, Al-Toma A, Dekker E, et al. Incidence of small bowel neoplasia in Lynch syndrome assessed by video capsule endoscopy. Endosc Int Open 2017;5:E622–E626.
[5] Perrod G, Samaha E, Perez-Cuadrado-Robles E, et al. Effectiveness of a dedicated small bowel neoplasia screening program by capsule endoscopy in Lynch syndrome: 5 years results from a tertiary care center. Ther Adv Gastroenterol 2020;13:1756284820934314.
[6] DeJesse J, Vajravelu RK, Dudzik C, et al. Uptake and outcomes of small intestinal and urinary tract cancer surveillance in Lynch syndrome. World J Clin Oncol 2021;12:1023–36.
[7] Peltomäki P, Nyström M, Mecklin J-P, et al. Lynch syndrome genetics and clinical implications. Gastroenterology 2023 Jan 24;S0016-5085(23)00050-1. doi:10.1053/j.gastro.2022.08.058 [Online ahead of print]

Conference

UEG Week Copenhagen 2023

Topics

Small Intestine & Nutrition

Submission format

Abstract

Session

PP 03 Small intestinal (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

More Like This:

BRIDGING THE GAP IN COLORECTAL CANCER DETECTION BIOMARKER DISCOVERY: INTEGRATING SYSTEMATIC EVIDENCE AND MACHINE LEARNING TO IDENTIFY A 5-GENE PLASMA SIGNATURE FOR ENHANCING NON-INVASIVE ASSESSMENT

Luis Lima

COMPARATIVE WHOLE TRANSCRIPTOME ANALYSIS OF PAIRED GASTRIC CANCER AND ADJACENT NON-NEOPLASTIC MUCOSA REVEALS MOLECULAR SIGNATURES OF GASTRIC CARCINOGENESIS

Juozas Kupcinskas

TSPAN8 FACILITATES CANCER-ASSOCIATED FIBROBLAST-INDUCED GASTRIC CANCER PROGRESSION VIA WNT SIGNALING

Qinglin Zhang

FAMILIAL COLORECTAL CANCER HISTORY IS ASSOCIATED WITH A DISTINCT IMMUNE–GENOMIC PHENOTYPE IN MICROSATELLITE-STABLE RECTAL CANCER: A PROSPECTIVE MULTICENTRE COHORT STUDY

Marco Scarpa

Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

Evelien Dekker

Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

UEG Presentation

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BRIDGING THE GAP IN COLORECTAL CANCER DETECTION BIOMARKER DISCOVERY: INTEGRATING SYSTEMATIC EVIDENCE AND MACHINE LEARNING TO IDENTIFY A 5-GENE PLASMA SIGNATURE FOR ENHANCING NON-INVASIVE ASSESSMENT

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BRIDGING THE GAP IN COLORECTAL CANCER DETECTION BIOMARKER DISCOVERY: INTEGRATING SYSTEMATIC EVIDENCE AND MACHINE LEARNING TO IDENTIFY A 5-GENE PLASMA SIGNATURE FOR ENHANCING NON-INVASIVE ASSESSMENT

Mariana Eiras 1,2,3, Janine Soares 1,2,4, Miguel Gonzalez-Santos 1,2,4, Daniela A. R. Santos 1,5,6, Renato Caldevilla 1,5,6, Lúcio Lara Santos 1,2,7, Mario Dinis-Ribeiro 8,9,10, Ana Carina Pereira 2,11,12, Andreia Brandao 2,11,13, Luis Lima 1,2,4

Affiliations

1 Experimental Pathology and Therapeutics Group, IPO Porto Research Center (CI-IPO Porto), Porto, Portugal

2 Porto Comprehensive Cancer Center Raquel Seruca (Porto. CCC), Porto, Portugal

3 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of

4 RISE – Associate Laboratory (Health Research Network), Porto, Portug

5 Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

6 School of Health, Polytechnic Institute of Porto, Port

7 Department of Surgical Oncology, Portuguese Institute of Oncology (I

8 Precancerous Lesions and Early Cancer Management Group, IPO Porto Research Center (CI‐IPO Porto), Porto, Portugal

9 Department of Gastroenterology, Portuguese Institute of Oncology (IPO-Porto), Porto, Portugal

10 Faculty of Medicine of the University of Po

11 RISE – Associate Laboratory (Health Research Network), Porto, Portugal

12 Precancerous Lesions and Early Cancer Management Group, IPO Porto Research Center (CI‐IPO Porto), Port

13 Cancer Genetics Group, IPO Porto Research Center (CI-IPO Porto), Porto, Portugal

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Abstract

Introduction

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, where early detection is the primary determinant of a 90% 5-year survival rate. Current non-invasive screening methods, such as the fecal immunochemical test (FIT), are hindered by suboptimal specificity, resulting in a high false-positive rates and an unnecessary burden of colonoscopies. While RNA-based biomarkers offer a promising non-invasive alternative, their clinical translation remains limited by significant heterogeneity in study design, methodological bias, and a systemic lack of external validation. Although multi-class RNA integration has shown superior diagnostic potential in other oncological contexts, it remains critically underexplored in CRC identification.

Aims & Methods

This study aimed to (1) systematically review the current landscape of RNA biomarkers to identify methodological barriers and (2) implement an unbiased, Machine Learning (ML)-driven approach to integrate multiple RNA classes and identify a reproducible plasma signature to refine CRC detection.
First, we conducted a PRISMA-compliant systematic review of 81 discovery-based studies (2015-2025), evaluating the diagnostic performance of multiple RNA classes. Risk of bias and clinical applicability were assessed using the QUADAS-2 tool. Second, to address the identified scarcity of integration and further independent validation, we implemented an in silico discovery phase using large-scale plasma-derived RNA sequencing data from the GEO database (n=89). Four ML algorithms (Random Forest, Boosted Tree, Logistic Regression, and Neural Network) were trained with cross-validation to identify cancerous lesions and a common signature. To ensure robustness, model performance was evaluated using confusion matrices and receiver operating characteristic (ROC) curves, followed by validation on a fully independent plasma dataset (n=96).

Results

The systematic review revealed that while multi-RNA panels often achieve AUC values exceeding 0.90, methodological flaws are prevalent. Specifically, 62% of studies lack a complete discovery-training-validation pipeline, and only 3% reported independent external validation, indicating limited reproducibility across studies and overall risk of overfitting. By applying our integrative ML framework to overcome these biases, we isolated a 5-gene plasma signature (TEF, METRNL, PIM3, PLEKHA4, ABCA2) consistently selected by at least three algorithmic models. Although the pipeline evaluated lncRNA and mRNA candidates, the ML models prioritized this specific mRNA-only signature, showing superior cross-platform stability and detection performance during feature selection. Random Forest and Boosted Tree emerged as the most promising prediction algorithms, with AUC values of 0.83. Crucially, upon validation, the Random Forest model's performance was confirmed, achieving an AUC of 0.85. This diagnostic stability suggests consistent performance across independent cohorts.

Conclusion

This study highlights critical methodological limitations hindering the clinical translation of RNA-based biomarkers, particularly regarding validation and reproducibility. By combining a systematic evidence synthesis with a rigorous ML-driven discovery pipeline and independent testing, we identified a stable 5-gene diagnostic signature across datasets. Further independent, prospective validation in plasma samples is needed to assess its potential to improve CRC diagnosis strategies, potentially reducing the burden of unnecessary colonoscopies.

Event

UEG Week Barcelona 2026

Topics

Mechanisms & Personalised Medicine Immunology Digestive Oncology Small Intestine & Nutrition

Submission format

Abstract

Session

The gut talks back

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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BRIDGING THE GAP IN COLORECTAL CANCER DETECTION BIOMARKER DISCOVERY: INTEGRATING SYSTEMATIC EVIDENCE AND MACHINE LEARNING TO IDENTIFY A 5-GENE PLASMA SIGNATURE FOR ENHANCING NON-INVASIVE ASSESSMENT

Luis Lima

COMPARATIVE WHOLE TRANSCRIPTOME ANALYSIS OF PAIRED GASTRIC CANCER AND ADJACENT NON-NEOPLASTIC MUCOSA REVEALS MOLECULAR SIGNATURES OF GASTRIC CARCINOGENESIS

Juozas Kupcinskas

TSPAN8 FACILITATES CANCER-ASSOCIATED FIBROBLAST-INDUCED GASTRIC CANCER PROGRESSION VIA WNT SIGNALING

Qinglin Zhang

FAMILIAL COLORECTAL CANCER HISTORY IS ASSOCIATED WITH A DISTINCT IMMUNE–GENOMIC PHENOTYPE IN MICROSATELLITE-STABLE RECTAL CANCER: A PROSPECTIVE MULTICENTRE COHORT STUDY

Marco Scarpa

Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

Evelien Dekker

Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

UEG Presentation

New

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

COMPARATIVE WHOLE TRANSCRIPTOME ANALYSIS OF PAIRED GASTRIC CANCER AND ADJACENT NON-NEOPLASTIC MUCOSA REVEALS MOLECULAR SIGNATURES OF GASTRIC CARCINOGENESIS

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COMPARATIVE WHOLE TRANSCRIPTOME ANALYSIS OF PAIRED GASTRIC CANCER AND ADJACENT NON-NEOPLASTIC MUCOSA REVEALS MOLECULAR SIGNATURES OF GASTRIC CARCINOGENESIS

Povilas Šabanas 1, Arnas Andziulis 1, Greta Gedgaudiene 1, Rūta Steponaitienė 1, Violeta Šaltenienė 1, Darja Nikitina 1, Laimas Virginijus Jonaitis 1, Paulius Jonaitis 1, Dalius Petrauskas 1, Rita Gudaityte 1, Mindaugas Kiudelis 1, Lina Poškienė 1, Juozas Kupcinskas 1

Affiliations

1 Lithuanian University of Health Sciences, Kaunas, Lithuania

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Abstract

Introduction

Gastric cancer (GC) is the fifth most common malignancy worldwide and the fifth leading cause of cancer-related mortality. Despite advances in diagnosis and treatment options, the molecular mechanisms behind the pathogenesis of GC are not fully understood. Whole transcriptome analysis enables comprehensive characterization of gene expression changes associated with malignant transformation that may contribute to the identification of novel diagnostic and therapeutic targets.

Aims & Methods

The objective of this study was to conduct transcriptome analysis of GC tissue and adjacent non-neoplastic mucosa to identify key molecular signatures involved in gastric carcinogenesis. The study cohort comprised 48 patients with paired gastric cancer and adjacent non-neoplastic mucosa samples. The mean age was (67.5 ± 10.8 years) and the majority were male (75.0%). Whole-transcriptome RNA sequencing was performed using the Illumina NovaSeq X Plus platform. Reads were quality controlled, aligned to the human reference genome (GRCh37) using STAR, and quantified with Salmon using the nf-core/rnaseq pipeline. Differential gene expression analysis between paired groups was performed with DESeq2 (FDR <0.05, |log2FC| >1). Subgroup analyses according to tumor invasion stage (T1–T2 vs T3–T4) and pathway enrichment analyses were additionally performed.

Results

Whole transcriptome analysis demonstrated clear separation between gastric cancer and matched adjacent non-neoplastic mucosa samples on principal component analysis, indicating distinct gene expression profiles. Differential expression analysis identified numerous significantly dysregulated genes in gastric cancer tissue. Among the most upregulated genes were KRT16, CHI3L1, CLDN1, INHBA and CEMIP, mainly associated with epithelial remodeling, invasion, and tumor progression. In contrast, ATP4A, ATP4B, PGA3, PGA4 and LIPF were among the most downregulated genes, reflecting loss of normal gastric secretory and metabolic functions. These findings indicate profound molecular reprogramming during gastric carcinogenesis. Additional analysis comparing the tumor invasion stage (T1-2 versus T3-4) identified 11 altered genes with the most significant overexpression of KRT4, S100A7, A2ML1 and KRT23 in tumors with deeper invasion. These findings indicate profound molecular reprogramming during gastric carcinogenesis and progression.

Conclusion

Gastric cancer tissue demonstrates distinct transcriptomic alterations involved in extracellular matrix remodeling and tumor progression. Genes linked to epithelial differentiation and cytoskeletal organization were enriched in tumors with deeper invasion, suggesting their role in disease progression. Whole transcriptome analysis may provide valuable insights into gastric carcinogenesis and identify potential molecular biomarkers and therapeutic targets.

Event

UEG Week Barcelona 2026

Topics

Oesophagus Stomach & H. Pylori Mechanisms & Personalised Medicine Digestive Oncology

Submission format

Abstract

Session

Translational advances in upper gastrointestinal tract malignancies

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

BRIDGING THE GAP IN COLORECTAL CANCER DETECTION BIOMARKER DISCOVERY: INTEGRATING SYSTEMATIC EVIDENCE AND MACHINE LEARNING TO IDENTIFY A 5-GENE PLASMA SIGNATURE FOR ENHANCING NON-INVASIVE ASSESSMENT

Luis Lima

COMPARATIVE WHOLE TRANSCRIPTOME ANALYSIS OF PAIRED GASTRIC CANCER AND ADJACENT NON-NEOPLASTIC MUCOSA REVEALS MOLECULAR SIGNATURES OF GASTRIC CARCINOGENESIS

Juozas Kupcinskas

TSPAN8 FACILITATES CANCER-ASSOCIATED FIBROBLAST-INDUCED GASTRIC CANCER PROGRESSION VIA WNT SIGNALING

Qinglin Zhang

FAMILIAL COLORECTAL CANCER HISTORY IS ASSOCIATED WITH A DISTINCT IMMUNE–GENOMIC PHENOTYPE IN MICROSATELLITE-STABLE RECTAL CANCER: A PROSPECTIVE MULTICENTRE COHORT STUDY

Marco Scarpa

Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

Evelien Dekker

Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

UEG Presentation

New

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

TSPAN8 FACILITATES CANCER-ASSOCIATED FIBROBLAST-INDUCED GASTRIC CANCER PROGRESSION VIA WNT SIGNALING

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TSPAN8 FACILITATES CANCER-ASSOCIATED FIBROBLAST-INDUCED GASTRIC CANCER PROGRESSION VIA WNT SIGNALING

Xiaoyi Zhao 1, Qiang Zhan 1, Qinglin Zhang 1

Affiliations

1 Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China

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Abstract

Introduction

Gastric cancer (GC) progression is strongly shaped by stromal signals within the tumor microenvironment. However, epithelial determinants governing tumor cell responsiveness to cancer-associated fibroblast (CAF)-derived cues remain incompletely defined.

Aims & Methods

We integrated transcriptomic network analysis using a public scRNA-seq profile (OMIX001073) to identify epithelial malignant programs. TSPAN8 expression and clinical relevance were evaluated using public databases and immunohistochemistry in GC and adjacent tissues. Functional roles were assessed by TSPAN8 knockdown in AGS cells and overexpression in HGC-27 cells via proliferation and migration assays. Primary CAFs from GC patients were used in co-culture experiments to examine pathway activation.

Results

Co-expression network analysis identified an epithelial-enriched module in which TSPAN8 emerged as a central hub gene and localized predominantly to epithelial clusters. TSPAN8 was significantly upregulated in GC and associated with poor overall survival. Functionally, TSPAN8 depletion suppressed GC cell proliferation and migration, whereas TSPAN8 overexpression enhanced these malignant phenotypes. CAF-derived cues promoted proliferation and motility, but these effects were attenuated by TSPAN8 knockdown and amplified by TSPAN8 overexpression, indicating that TSPAN8 is a critical mediator of CAF-driven tumor-promoting activity. Ligand-receptor inference from scRNA-seq data suggested preferential CAF-to-epithelium signaling toward TSPAN8-high cells, with enrichment of Wnt-related interactions. Consistently, CAF co-culture increased β-catenin levels in GC cells, and this induction was further strengthened by TSPAN8 overexpression.

Conclusion

Our findings establish TSPAN8 as an epithelial hub and prognostic indicator in GC, revealing a TSPAN8-CAF-Wnt/β-catenin axis that amplifies CAF-driven progression. Targeting TSPAN8-mediated stromal-epithelial communication may represent a therapeutic opportunity for fibroblast-rich gastric cancers.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229-263. doi:10.3322/caac.21834
2. Huang J, Lucero-Prisno DE 3rd, Zhang L, et al. Updated epidemiology of gastrointestinal cancers in East Asia.Nat Rev Gastroenterol Hepatol. 2023;20(5):271-287. doi:10.1038/s41575-022-00726-3
3. Sundar R, Nakayama I, Markar SR, et al. Gastric cancer. Lancet. 2025;405(10494):2087-2102. doi:10.1016/S0140-6736(25)00052-2
4. Guan WL, He Y, Xu RH. Gastric cancer treatment: recent progress and future perspectives.J Hematol Oncol. 2023;16(1):57. Published 2023 May 27. doi:10.1186/s13045-023-01451-3
5. Lei ZN, Teng QX, Tian Q, et al. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther. 2022;7(1):358. Published 2022 Oct 8. doi:10.1038/s41392-022-01190-w
6. Hemler ME. Tetraspanin proteins promote multiple cancer stages. Nat Rev Cancer. 2014;14(1):49-60. doi:10.1038/nrc3640
7. Heo K, Lee S. TSPAN8 as a Novel Emerging Therapeutic Target in Cancer for Monoclonal Antibody Therapy. Biomolecules. 2020;10(3):388. Published 2020 Mar 3. doi:10.3390/biom10030388

Event

UEG Week Barcelona 2026

Topics

Oesophagus Stomach & H. Pylori Mechanisms & Personalised Medicine Digestive Oncology

Submission format

Abstract

Session

Translational advances in upper gastrointestinal tract malignancies

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

More Like This:

BRIDGING THE GAP IN COLORECTAL CANCER DETECTION BIOMARKER DISCOVERY: INTEGRATING SYSTEMATIC EVIDENCE AND MACHINE LEARNING TO IDENTIFY A 5-GENE PLASMA SIGNATURE FOR ENHANCING NON-INVASIVE ASSESSMENT

Luis Lima

COMPARATIVE WHOLE TRANSCRIPTOME ANALYSIS OF PAIRED GASTRIC CANCER AND ADJACENT NON-NEOPLASTIC MUCOSA REVEALS MOLECULAR SIGNATURES OF GASTRIC CARCINOGENESIS

Juozas Kupcinskas

TSPAN8 FACILITATES CANCER-ASSOCIATED FIBROBLAST-INDUCED GASTRIC CANCER PROGRESSION VIA WNT SIGNALING

Qinglin Zhang

FAMILIAL COLORECTAL CANCER HISTORY IS ASSOCIATED WITH A DISTINCT IMMUNE–GENOMIC PHENOTYPE IN MICROSATELLITE-STABLE RECTAL CANCER: A PROSPECTIVE MULTICENTRE COHORT STUDY

Marco Scarpa

Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

Evelien Dekker

Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

UEG Presentation

New

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

FAMILIAL COLORECTAL CANCER HISTORY IS ASSOCIATED WITH A DISTINCT IMMUNE–GENOMIC PHENOTYPE IN MICROSATELLITE-STABLE RECTAL CANCER: A PROSPECTIVE MULTICENTRE COHORT STUDY

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FAMILIAL COLORECTAL CANCER HISTORY IS ASSOCIATED WITH A DISTINCT IMMUNE–GENOMIC PHENOTYPE IN MICROSATELLITE-STABLE RECTAL CANCER: A PROSPECTIVE MULTICENTRE COHORT STUDY

Silvia Negro 1, Melania Scarpa 2, Francesca Galuppini 3, Sara Vedovato 4, Roberta Salmaso 3, Andromachi Kotsafti 2, Valerio Pellegrini 5, Luca Maria Saadeh 4, Antonio Rosato 2, Gaya Spolverato 1, Imerio Angriman 1, Cesare Ruffolo 4, Quoc Riccardo Bao 4, Anna Matteazzi 4, Lorenzo Dell'Atti 6, Dario Gregori 3, Ignazio CASTAGLIUOLO 3, Matteo Fassan 7, Angelo Paolo Dei Tos 3, Marco Scarpa 1

Affiliations

1 DISCOG, University of Padova, Padova, Italy

2 Veneto Institute of Oncology IOV-IRCCS, Padova, Italy

3 University of Padova, Padova, Italy

4 Azienda Ospedale Università di Padova, Padova, Italy

5 AULSS 2 Marca Trevigiana, Treviso, Italy

6 Azienda Unità Sanitaria Locale - IRCCS Reggio Emilia, Reggio Emilia, Italy

7 University of Padova, Treviso, Italy

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Abstract

Introduction

Most rectal cancers are microsatellite-stable (MSS) and poorly responsive to immunotherapy [1], yet the biological determinants of this immune resistance remain incompletely understood. The tumor immune microenvironment is directly involved in the therapy response but, little is known about the role of the surrounding rectal mucosa immune environment [2]. We investigated whether familial aggregation of colorectal cancer identifies a distinct MSS rectal cancer subtype.

Aims & Methods

This study was a sub-analysis of data from two multicentric observational cohort studies, IMMUNOREACT 1 (clinicaltrials.gov NCT04915326) and 2 (clinicaltrials.gov NCT04917263), that included 374 MSS rectal cancer patients, classified as sporadic (FH⁻) or familial (FH⁺), with a predefined subgroup of patients with an affected first-degree relative (FDR⁺). Immune, transcriptomic, and genomic profiling were performed on tumour-adjacent normal mucosa and tumour tissue.Sections were stained with monoclonal antibodies targeting CD3, CD4, CD8, CD8β, T-bet, FoxP3, PD-L1, CD80, MSH6, and PMS2. Epithelial cells with antigen-presenting features (pan-cytokeratin⁺, CD80⁺, CD86⁺, HLA-ABC⁺) and T-cell subsets — including activated CD8⁺ T cells (CD8⁺CD28⁺ and CD8⁺CD38⁺), inhibitory T cells (CD3⁺CTLA-4⁺), activated CD4⁺ T cells (CD4⁺CD25⁺), and regulatory T cells (CD4⁺CD25⁺FoxP3⁺) — were quantified by flow cytometry. Gene expression profiling was performed using the PanCancer IO 360™ panel (NanoString Technologies). Targeted next‐generation sequencing (NGS) for solid tumours was performed using the Archer® VariantPlex® Solid Tumor Panel, enabling detection of single-nucleotide variants and copy number variations in cancer-associated genes.

Results

Among 374 patients, 25% were FH⁺ and 17% FDR⁺. In nCRT-naïve disease, FDR⁺ cases showed higher epithelial CD80⁺ cell density in normal mucosa. After nCRT, FH⁺ patients exhibited increased activated CD8⁺CD28⁺ T cells and reduced epithelial HLA-ABC expression, while FDR⁺ cases showed lower CD3⁺ T-cell density. Transcriptomic analyses suggested a relatively quiescent familial mucosal phenotype, characterised by attenuation of DNA damage repair, proliferative, metabolic, angiogenic, and immune pathways. The impact of mutational ratio differed by familial background: in FH⁻ disease, a higher mutational ratio was associated with improved disease-free survival and with immune features, including CD8⁺ T-cell density and epithelial CD80 expression, whereas in FH⁺ cancer, it was not associated with outcome and appeared uncoupled from these immune parameters.

Conclusion

In conclusion, our findings suggest that MSS rectal cancers arising in patients with familial CRC aggregation, particularly those with an affected first-degree relative, may represent a distinct biological subgroup characterized by altered epithelial–immune coordination and impaired coupling between therapy-induced genomic stress and immune surveillance. If validated in larger and independent cohorts, these observations could have implications beyond risk stratification alone. Family history may help refine biological subclassification within MSS rectal cancer and inform the design of trials evaluating immunotherapy-based strategies in this traditionally immune-resistant disease. More broadly, these data provide a rationale for mechanistic studies aimed at clarifying the basis of altered coordination between genomic perturbation and antitumour immunity in familial MSS rectal cancer.

References

1. Cercek A, Lumish M, Sinopoli J, Weiss J, Shia J, Lamendola-Essel M, et al. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer. New England Journal of Medicine. 2022 Jun 23;386(25):2363–76. doi:10.1056/NEJMoa2201445
2. Marchiori C, Scarpa M, Kotsafti A, Morgan S, Fassan M, Guzzardo V, et al. Epithelial CD80 promotes immune surveillance of colonic preneoplastic lesions and its expression is increased by oxidative stress through STAT3 in colon cancer cells. Journal of Experimental & Clinical Cancer Research. 2019 Dec 9;38(1):190. doi:10.1186/s13046-019-1205-0

Event

UEG Week Barcelona 2026

Topics

IBD Pancreas Gut Microbiota Endoscopy Digestive Oncology Colorectal

Submission format

Abstract

Session

Hot topics in clinical GI research

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

Evelien Dekker

Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

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Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

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Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

Evelien Dekker 1

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1 AMC, Amsterdam, Netherlands

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Abstract

Event

Postgraduate Teaching Programme Barcelona 2026

Topics

Mechanisms & Personalised Medicine Surgery Digestive Oncology Colorectal

Session

Advanced colorectal cancer: Previously deadly, now chronic disease

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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Marco Scarpa

Summary: Advanced colorectal cancer: Previously deadly, now chronic disease

Evelien Dekker

Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

UEG Presentation

New

Share via Email Share on Facebook Share on X Share on LinkedIn Share on Bluesky

Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

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Panel discussion: Advanced colorectal cancer: Previously deadly, now chronic disease

Summary

AI Generated

Summary is not available for this content yet.

Download PDF

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Abstract

Event

Postgraduate Teaching Programme Barcelona 2026

Topics

Mechanisms & Personalised Medicine Surgery Digestive Oncology Colorectal

Session

Advanced colorectal cancer: Previously deadly, now chronic disease

Citation

2026: United European Gastroenterology Journal 2026; 14 (S1)

Published

2026

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