The Institute of Intelligent Medical Research (IIMR) of BGI Genomics, in collaboration with Sweden’s Uppsala University, have uncovered 33 novel mutated driver genes in colorectal cancer (CRC). The researchers analyzed the whole genomes and transcriptomes of 1,063 primary colorectal cancers within a population-based cohort, with 94% of the patients completing a five-year clinical follow-up. Their analysis identified 96 mutated driver genes, nine of which were previously unknown in CRC, and 24 that were new to any form of cancer.
The findings are published in the journal Nature in an article entitled “Prognostic genome and transcriptome signatures in colorectal cancers.”
“Colorectal cancer is caused by a sequence of somatic genomic alterations affecting driver genes in core cancer pathways,” the researchers wrote. “Here, to understand the functional and prognostic impact of cancer-causing somatic mutations, we analysed the whole genomes and transcriptomes of 1,063 primary colorectal cancers in a population-based cohort with long-term follow-up. From the 96 mutated driver genes, 9 were not previously implicated in colorectal cancer and 24 had not been linked to any cancer. Two distinct patterns of pathway co-mutations were observed, timing analyses identified nine early and three late driver gene mutations, and several signatures of colorectal-cancer-specific mutational processes were identified.”
Several specific mutation patterns that are unique to CRC were identified. Mutations in specific pathways (WNT, EGFR, TGFβ), a mitochondrial gene (CYB), three regulatory elements, 21 copy-number variations (alterations in the number of copies of a particular gene), and a specific mutation signature (COSMIC SBS44) were linked to patient survival rates.
Building on these findings, the researchers developed a new strategy to molecularly classify colorectal cancer. Through an integrated analysis that combined mutated genes with gene expression levels, they identified five distinct CRC prognostic subtypes (CRPSs), each with unique molecular characteristics. This new classification system is poised to revolutionize the way CRC is diagnosed and treated.
Through timing analysis, the study uncovered that specific genetic alterations, such as those in APC, TP53, KRAS, BRAF, ZFP36L2, TCF7L2, FBXW7, BCL9L, and SOX9, tend to occur early in the cancer’s progression. Meanwhile, other mutations, particularly in TRPS1, GNAS, and CEP170, are more likely to appear during the later stages of cancer development.
Beyond identifying critical molecular changes linked to tumor invasion and metastasis, the study uncovered disease-related mutations in the mitochondrial genome and non-coding regions, offering a comprehensive summary of mutations that play a significant role in disease progression.
The discovery of the mutations and expression subtypes can guide future efforts to individualized colorectal cancer therapy.
