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

作者：Anael López-Novo, Jorge Amigo, Andrés Dacal, David Remedios-Espino, Joaquín Cubiella, María Victoria Álvarez-Sánchez, María J. Ladra-González, Fernando Fernández-López, Ana Álvarez-Castro, Silvia Carlés, José Manuel Cameselle-Teijeiro, Míriam Cuatrecasas, Francesc Balaguer, Sergi Castellví-Bel, Ceres Fernandez-Rozadilla, Ángel Carracedo, Clara Ruiz-Ponte · 发表于：European Journal of Human Genetics · 年份：2026 · DOI：10.1038/s41431-025-02004-7 · 研究领域：Genetic factors in colorectal cancer、Colorectal Cancer Treatments and Studies、Cancer Genomics and Diagnostics

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.