Exploring the molecular profile of localized colon cancer: insights from the AIO Colopredict Plus registry

Ira Ekmekciu; Doreen Maria Zucha; Jens Christmann; Sarah Wisser; Vera Heuer; Buelent Sargin; Stephan Hollerbach; Christof Lamberti; Lothar Müller; Celine Lugnier; Berlinda Verdoodt; Robin Denz; Tobias Terzer; Inke Feder; Anke Reinacher-Schick; Andrea Tannapfel; Iris Tischoff

doi:10.3389/fonc.2024.1434791

Exploring the molecular profile of localized colon cancer: insights from the AIO Colopredict Plus registry

Front Oncol. 2024 Nov 19:14:1434791. doi: 10.3389/fonc.2024.1434791. eCollection 2024.

Authors

Ira Ekmekciu^#¹, Doreen Maria Zucha^#², Jens Christmann^#², Sarah Wisser², Vera Heuer¹, Buelent Sargin³, Stephan Hollerbach⁴, Christof Lamberti⁵, Lothar Müller⁶, Celine Lugnier¹, Berlinda Verdoodt², Robin Denz⁷, Tobias Terzer¹, Inke Feder², Anke Reinacher-Schick¹, Andrea Tannapfel², Iris Tischoff²

Affiliations

¹ Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr University, Bochum, Germany.
² Institute of Pathology, Ruhr University, Bochum, Germany.
³ Hematology and Medical Oncology, St-Marien-Hospital Lunen, Lunen, Germany.
⁴ Department of Gastroenterology, Allgemeines Krankenhaus (AKH) Celle, Celle, Germany.
⁵ Hematology and Oncology, Regiomed Hospital Group, Coburg, Germany.
⁶ Onkologie UnterEms, Leer, Germany.
⁷ Department of Medical Informatics, Biometrics and Epidemiology, Ruhr University, Bochum, Germany.

^# Contributed equally.

Abstract

Introduction: Understanding the mutational landscape of colon cancer (CC) is crucial for targeted therapy development. Microsatellite instability (MSI-H), rat sarcoma (RAS), and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations (MT) are pivotal markers. Further investigation into clinicopathological features of RAS and BRAF MT in microsatellite stable (MSS) and MSI-H tumors is warranted.

Methods: A retrospective analysis of 4883 localized CC patients (pts.) was conducted. Molecular profiling assessed MSI, KRAS, NRAS, and BRAF MT. Correlation with clinicopathological data employed ANOVA and Chi-square tests. Disease-free survival (DFS) and overall survival (OS) were analyzed adjusting for age, gender, sidedness, UICC stage, Charlson Comorbidity Index (CCI). A Cox model incorporated all variables as covariates.

Results: This analysis included 4883 pts. (2302 female/2572 male, 3865 (79.2%) MSS, 1018 (20.8%) MSI-H). MSS pts. had more All-Wild Type (WT), KRAS MT, and NRAS MT tumors vs. MSI-H pts. (42.1% vs. 21.1%; 39.8% vs. 15.4%; 3.6% vs. 0.7%; p<0.001 for each). BRAF MT tumors (95.5% BRAF V600E MT) were more prevalent in MSI-H individuals (62.8% vs. 8.1%, p<0.001). KRAS and BRAF MT tumors were more frequently right-sided, while BRAF MT tumors were associated with female gender, advanced disease stage, lymph node positivity, and poorer differentiation in the MSS subset (p<0.001). Common KRAS mutations included p.G12D (30.44%) and p.G12V (21.3%) in MSS and p.G13D (28.9%) and p.G12D (22.37%) in MSI-H. NRAS MT tumors were dominated by codon 61 mutations (51.7%). Survival analysis revealed worst prognosis in BRAF MT MSS tumors (DFS: HR 1.74 (95% CI 1.15-2.62, p=0.009; OS: HR 1.61 (95% CI 0.99-2.6), p=0.055). The 3-years DFS and 5-years OS rates were lowest in this subset (61.6% and 57.7% respectively).

Discussion: These findings highlight the complex interplay between molecular subtypes, clinicopathological features, and survival outcomes in early CC. Further research is needed to elucidate underlying mechanisms and develop personalized treatment strategies.

Keywords: BRAF; RAS; colon cancer; localized; microsatellite instability; real world data.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research was supported by the Protein Research Unit Ruhr within Europe (PURE), funded by the Ministry of Innovation, Science and Research (MIWF) of North-Rhine Westphalia, Germany (grant number: 233-1.08.03.03-031-68079) and by Roche Pharma AG from 2016-2018. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.