Researchers have reported novel genetic alterations and molecular classifiers of tumor variants in patients with colorectal cancer, according to a recent study published by Nunes et al in Nature.
Background
“Since 2018, Uppsala University and BGI [Genomics] have carried out in-depth cooperation on the U-CAN cohort. This time, BGI’s advanced genomics technology and data analysis resources were applied to a large-scale colorectal cancer population. Not only were the significant predictive effects of multiple mutation events on prognosis found, but the newly constructed fine typing of expression profiles will also play an important role in guiding individualized diagnosis and treatment of colorectal cancer in the future,” explained co–senior study author Lin Cong, PhD, a specialized scientist at the Institute of Intelligent Medical Research.
Study Methods and Results
In the recent study, the researchers analyzed the whole genomes and transcriptomes of 1,063 primary colorectal cancers within a population-based cohort—with the goal of determining the functional and prognostic impact of cancer-causing somatic mutations. They noted that 94% of the patients completed the 5-year clinical follow-up.
The researchers identified 96 mutated driver genes, 9 of which were previously unknown in colorectal cancer and 24 of which were new to any type of cancer. Several specific mutation patterns unique to colorectal cancer were identified. Mutations in the WNT, EGFR, and TGF-beta pathways; the mitochondrial gene CYB, three regulatory elements, 21 copy-number variations, and the COSMIC SBS44 mutation signature were all linked to patient survival rates.
Through a timing analysis, the study found that specific genetic mutations—including APC, TP53, KRAS, BRAF, ZFP36L2, TCF7L2, FBXW7, BCL9L, and SOX9 mutations—tended to occur early in the cancer's progression. Meanwhile, other mutations like TRPS1, GNAS, and CEP170 mutations were more likely to appear during the later stages of cancer development.
Beyond identifying critical molecular changes linked to tumor invasion and metastasis, the researchers discovered disease-related mutations in the mitochondrial genome and noncoding regions, offering a comprehensive summary of mutations that could play a significant role in disease progression.
Building on these findings, the researchers developed a novel strategy to molecularly classify colorectal cancer. Through an integrated analysis that combined mutated genes with gene-expression levels, they identified five distinct colorectal cancer prognostic subtypes, each with unique molecular characteristics.
Conclusions
The researchers indicated that the study achieved one of the largest comprehensive analyses of colorectal cancer with genomes and transcriptomes to date and combined molecular features with high-quality clinical data. They hope their new classification system can help transform the way colorectal cancer is diagnosed and treated.
“In the future, a multiomics technology platform that integrates regularization, standardization, automation, informatization, intelligence, and scale will empower large-scale genomic research cooperation and facilitate the research and application of big data for large groups of people,” underscored co–lead study author Li Fuqiang, a specialized scientist at the Institute of Intelligent Medical Research.
The researchers concluded that this platform represents the potential for future advancements in genomic research and personalized medicine.
Disclosure: For full disclosures of the study authors, visit nature.com.
