Journal Article

DKFZ-2025-02997

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Genomic characterization of colorectal tumors: insights into significantly mutated genes, pathways, and survival outcomes.

Harrison, T. A. ; Zaidi, S. H. ; Yin, H. ; Steinfelder, R. S. ; Qu, C. ; Aglago, E. K. ; Berndt, S. I. ; Boardman, L. A. ; Brenner, H.DKFZ* ; Buchanan, D. D.Extern* ; Campbell, P. T. ; Cao, Y. ; Chan, A. T. ; Chanock, S. J. ; Doheny, K. F. ; Drew, D. A. ; Figueiredo, J. C. ; French, A. J. ; Gallinger, S. ; Georgeson, P. ; Giannakis, M. ; Goode, E. L. ; Gruber, S. B. ; Gsur, A. ; Gunter, M. J. ; Harlid, S. ; Hoffmeister, M.DKFZ* ; Huang, W.-Y. ; Hullar, M. A. ; Huyghe, J. R. ; Jenkins, M. A. ; Lin, Y. ; Moreno, V. ; Murphy, N. ; Newcomb, P. A. ; Newton, C. C. ; Nowak, J. A. ; Obón-Santacana, M. ; Ogino, S. ; Shelford, T. ; Song, M. ; Thomas, C. E. ; Toland, A. E. ; Ugai, T. ; Um, C. Y. ; Van Guelpen, B. ; Trinh, Q. M. ; Sun, W. ; Hudson, T. J. ; Hsu, L. ; Peters, U. ; Phipps, A. I.

2025
BioMed Central London

Abstract: Identifying significantly mutated genes in tumors aids in understanding disease etiology and survival and may aid in the discovery of new drug targets. We aimed to detect and characterize mutated genes from a large, well-characterized group of colorectal cancers.In tumor and paired normal samples from 6,111 colorectal patients, we sequenced 199 genes identified from whole exome sequencing of over 1,100 tumors. Analyses focused on non-silent mutations. We classified significantly mutated genes after stratification by hypermutation status, and estimated associations of mutated genes/pathways with disease-specific (DS)-survival using Cox regression, adjusting for age, sex, mutation burden, hypermutation status, and study while accounting for multiple comparisons (n = 4,874).We identified 57 genes that were significantly mutated in colorectal cancer, including 9 that were not previously reported. Among individual genes, only BRAF p.V600E mutations were significantly associated with poorer survival after correction for multiple testing (HR 1.96, P = 2.07 × 10- 10), with a more pronounced association among those with non-hypermutated tumors (HR 2.24, P = 1.79 × 10- 12). We also observed statistically significant associations with survival for four mutated pathways: TP53/ATM (HR 1.24, P = 7.96 × 10- 4), RTK/RAS (HR 1.33, P = 3.81 × 10- 6), TGF-beta (HR 1.25, P = 1.85 × 10- 3), and WNT (HR 0.81, P = 2.52 × 10- 03).We identified 9 significantly mutated genes, some of which are known drug targets. Among individual genes, only the BRAF p.V600E mutation was significantly associated with DS-survival, suggesting a limited survival impact from mutations driving colorectal cancer development.

Keyword(s): Colorectal neoplasm ; Somatic mutations ; Survival ; Targeted sequencing

Note: Division of Preventive Oncology, German Cancer Research Center (DKFZ) / epub

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Contributing Institute(s):

1. C070 Klinische Epidemiologie der Krebsfrüherkennung (C070)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2025

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