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<p>Colorectal cancer is thought to develop through the stepwise accumulation of somatic mutations. Recent years have seen the publications of several studies greatly advancing our understanding of the molecular events driving the disease. However, individual studies tend to be small and additional insights may be obtained through the combination of data from multiple sources. We performed targeted sequencing of 2172 colorectal cancers from Icelandic patients and combined these data with publicly available mutation calls from 9 515 additional tumours collected from the literature. Analysing microsatellite stable (MSS) and instable (MSI) tumours separately, we find evidence of positive selection of mutations in 112 genes that replicate across multiple studies of patients with diverse demographics. We carried out a meta-analysis of conditional selection, identifying 57 gene pairs where a mutation in one gene influences the selection of the other. We describe many associations with tumour phenotypes, including a strong association between mucinous histology and mutations in the transcription growth factor beta (TGFb) pathway, only in MSS tumours. Our study demonstrates how combining evidence from multiple sources allows for new discoveries in cancer genomics.</p>

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A meta-analysis identifies driver genes and characterizes the molecular epidemiology of colorectal cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月17日

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  • Sigurgeir Olafsson,
  • Thorri Thorarinsson,
  • Sigurjon A. Gudjonsson,
  • Mariana Bustamante,
  • Helga S. Gunnarsdottir,
  • Hildur Knutsdottir,
  • Hakon Jonsson,
  • Magnus I. Magnusson,
  • Emilia Soebech,
  • Hjaltey Runarsdottir,
  • Droplaug N. Magnusdottir,
  • Louise le Roux,
  • Jona Saemundsdottir,
  • Bjarney S. Kristinsdottir,
  • Bjarni A. Agnarson,
  • Erna M. Jonsdottir,
  • Thordur Tryggvason,
  • Magnus O. Ulfarsson,
  • Daniel F. Gudbjartsson,
  • Jon G. Jonasson,
  • Olafur Magnusson,
  • Kari Stefansson,
  • Thorunn Rafnar

摘要

Colorectal cancer is thought to develop through the stepwise accumulation of somatic mutations. Recent years have seen the publications of several studies greatly advancing our understanding of the molecular events driving the disease. However, individual studies tend to be small and additional insights may be obtained through the combination of data from multiple sources. We performed targeted sequencing of 2172 colorectal cancers from Icelandic patients and combined these data with publicly available mutation calls from 9 515 additional tumours collected from the literature. Analysing microsatellite stable (MSS) and instable (MSI) tumours separately, we find evidence of positive selection of mutations in 112 genes that replicate across multiple studies of patients with diverse demographics. We carried out a meta-analysis of conditional selection, identifying 57 gene pairs where a mutation in one gene influences the selection of the other. We describe many associations with tumour phenotypes, including a strong association between mucinous histology and mutations in the transcription growth factor beta (TGFb) pathway, only in MSS tumours. Our study demonstrates how combining evidence from multiple sources allows for new discoveries in cancer genomics.