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. 2023;90(3):166-175.
doi: 10.1159/000526117. Epub 2022 Oct 6.

Prevalence of Molecular Alterations in a Swiss Cohort of 512 Colorectal Carcinoma Patients by Targeted Next-Generation Sequencing Analysis in Routine Diagnostics

Simon Haefliger  1 , Katharina Marston  2 , Ilaria Alborelli  2 , Edouard-Jean Stauffer  3 , Mathias Gugger  3 , Philip M Jermann  2 , Sylvia Hoeller  2 , Luigi Tornillo  2 , Luigi M Terracciano  2 , Michel Bihl  2 , Matthias S Matter  2
Affiliations

Prevalence of Molecular Alterations in a Swiss Cohort of 512 Colorectal Carcinoma Patients by Targeted Next-Generation Sequencing Analysis in Routine Diagnostics

Simon Haefliger et al. Pathobiology. 2023.

Abstract

Introduction: Colorectal carcinoma (CRC) is among the most common carcinomas in women and men. In the advanced stage, patients are treated based on the RAS status. Recent studies indicate that in the future, in addition to KRAS and NRAS, alterations in other genes, such as PIK3CA or TP53, will be considered for therapy. Therefore, it is important to know the mutational landscape of routinely diagnosed CRC.

Method: We report the molecular profile of 512 Swiss CRC patients analyzed by targeted next-generation sequencing as part of routine diagnostics at our institute.

Results: Pathogenic and likely pathogenic variants were found in 462 (90%) CRC patients. Variants were detected in TP53 (54.3%), KRAS (48.2%), PIK3CA (15.6%), BRAF (13.5%), SMAD4 (10.5%), FBXW7 (7.8%), NRAS (3.5%), PTEN (2.7%), ERBB2 (1.6%), AKT1 (1.5%), and CTNNB1 (0.9%). The remaining pathogenic alterations were found in the genes ATM(n= 1), MAP2K1(n= 1), and IDH2(n= 1).

Discussion/conclusions: Our analysis revealed the prevalence of potential predictive markers in a large cohort of CRC patients obtained during routine diagnostic analysis. Furthermore, our study is the first of this size to uncover the molecular landscape of CRC in Switzerland.

Keywords: BRAF; Biomarkers; Cetuximab; Chromosome instability; Colon cancer; EGFR; KRAS; Microsatellite instability; Panitumumab.

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Conflict of interest statement

Matthias S. Matter has served as a consultant for Novartis and Glaxo Smith Cline and received speaker's honoraria from Thermo Fisher and Merck, all outside the current work. The other authors, namely, Simon Haefliger, Katharina Marston, Ilaria Alborelli, Philip M. Jermann, Edouard-Jean Stauffer, Mathias Gugger, Sylvia Hoeller, Luigi Tornillo, Luigi M. Terracciano, and Michel Bihl have no conflicts of interest to declare.

Figures

Fig. 1
Fig. 1
Overview of clinical and molecular features. Each column represents a patient with clinical features annotated on top of the oncoPrint (gender, tumor origin, tumor side, MS status). Mutational frequency is shown per gene. Molecular alterations are separated in missense, nonsense, frameshifts, inframe indels, and splice site variants. Columns are sorted by gender, origin, side, and MS status.
Fig. 2
Fig. 2
Gene alterations associated with clinical features. Plots show log2 odds ratios (OR, x-axis) against −log2-adjusted p values (y-axis) obtained using Fisher's exact test (adjusted for multiple hypothesis testing using the FDR method). Mutational frequency of specific genes is significantly associated with MSI status (left panel) or tumor localization (right panel), as shown when above the dotted line (−log2 (p value) = 4.33, adjusted p value = 0.05).
Fig. 3
Fig. 3
Comparison of number of detected mutations between primary and metastatic CRC as well as treated and untreated CRC. a Plots show comparison between primary and metastatic CRC after grouping according to microsatellite status. b Plots show comparison between chemotherapeutically treated and untreated (N/A) CRC. Fisher's exact test was used for comparison.
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