Integration of multi-omics data uncovers novel germline susceptibility candidates in early-onset colorectal cancer

Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This study aimed to identify novel hereditary CRC susceptibility genes by integrating germline and tumour whole-exome sequencing (WES) with transcriptomic profiling across a cohort of early-onset CRC (EOCRC) patients. Tumours were categorised using Consensus Molecular Subtypes (CMS) classification and analysed for mutational signature and burden. We used a novel 'All vs One' multi-omic integration approach to identify loss-of-function rare germline variants with concordant gene expression alterations in tumour tissue. Five candidate genes (ADCY4, NOXO1, CDHR2, ARHGAP10, EEF2K) were prioritised based on this approach and potential biological relevance in CRC. These findings highlight the molecular heterogeneity of EOCRC and demonstrate the utility of multi-omic approaches in refining germline variant interpretation. Integrating tumour transcriptomics enhances gene discovery efforts and supports a more comprehensive understanding of CRC heritability in younger individuals.

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Publication Details

Journal
European Journal of Human Genetics
Published
2026-01-15
DOI
https://doi.org/10.1038/s41431-025-02004-7
Primary Topic
Genetic factors in colorectal cancer
Type
article
Field-Weighted Citation Impact
0.00

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article

Integration of multi-omics data uncovers novel germline susceptibility candidates in early-onset colorectal cancer

María J. Ladra-González, Andrés Dacal, Jorge Amigo, Ana Álvarez-Castro et al.
European Journal of Human Genetics
Genetic factors in colorectal cancer
article

Integration of multi-omics data uncovers novel germline susceptibility candidates in early-onset colorectal cancer

María J. Ladra-González, Andrés Dacal, Jorge Amigo, Ana Álvarez-Castro, José Manuel Cameselle-Teijeiro, Joaquín Cubiella, Sergi Castellví-Bel, Silvia Carlés, Ceres Fernandez-Rozadilla, Anael López-Novo, Miriam Cuatrecasas, Clara Ruiz-Ponte, Ángel Carracedo, María Victoria Álvarez-Sánchez, Fernando Fernández-López
article en

Abstract

Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This study aimed to identify novel hereditary CRC susceptibility genes by integrating germline and tumour whole-exome sequencing (WES) with transcriptomic profiling across a cohort of early-onset CRC (EOCRC) patients. Tumours were categorised using Consensus Molecular Subtypes (CMS) classification and analysed for mutational signature and burden. We used a novel 'All vs One' multi-omic integration approach to identify loss-of-function rare germline variants with concordant gene expression alterations in tumour tissue. Five candidate genes (ADCY4, NOXO1, CDHR2, ARHGAP10, EEF2K) were prioritised based on this approach and potential biological relevance in CRC. These findings highlight the molecular heterogeneity of EOCRC and demonstrate the utility of multi-omic approaches in refining germline variant interpretation. Integrating tumour transcriptomics enhances gene discovery efforts and supports a more comprehensive understanding of CRC heritability in younger individuals.

European Journal of Human Genetics
Universidade de Santiago de Compostela (ES), Complejo Hospitalario Universitario de Santiago (ES), Center for Research in Molecular Medicine and Chronic Diseases (ES), Fundación Pública Galega de Medicina Xenómica (ES), Hospital Universitario Lucus Augusti (ES), Instituto de Investigación Sanitaria de Santiago (ES), Complejo Hospitalario de Pontevedra (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Instituto de Investigación de Enfermedades Raras (ES), Complejo Hospitalario de Ourense (ES)
European Commission, Xunta de Galicia, National Institutes of Health, Instituto de Salud Carlos III, European Regional Development Fund, Servicio Gallego de Salud, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, NIH Office of the Director, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Common Fund
Openalex Percentile: Top 88%
Genetic factors in colorectal cancer
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