Exome sequencing in hereditary Colorectal cancer. Exome sequencing

Background: Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer, but only a limited proportion of these have mutations in known high-penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Aims: To identify germ-line mutations in colorectal cancer susceptibility genes in families with attenuated polyposis syndromes in an attempt to identify high or moderate penetrant genetic variants. To analyse for contributing gene variants in candidate genes in patients with hereditary colorectal cancer and also colorectal cancer at young age and de novo cases. Methods: Three families with attenuated polyposis and 107 patients with or without family history of colorectal cancer were divided into eleven clinical subgroups. Exome sequencing was used to identify disease-associated variants in the three families and in one family linkage analysis was also performed. Subgroups were analysed for contributing genetic variants in identified genes. Results: A high-penetrant mutation in GREM1 and also a probable causative mutation in POLE were identified. Rare truncating variants were detected in LMO7, GPLD1, EXT2, FBXL13, CLCA4, ECT2L, MMP8 and LIG4 and possible deleterious amino-acid substitutions were found in BUB1B, LMO7 and MMP8. Conclusions: High-penetrant mutations predisposing to colorectal cancer still remain to be identified. A combination of exome-sequencing and linkage analysis has proven to be useful but whole genome sequencing might be necessary to find mutations also in noncoding regions. Alterations of regions that give rise to activating mutations and up-regulation of genes can also have an effect on tumour initiation in hereditary colorectal cancer syndromes. In small families and simplex cases candidate variants of variable penetrance can be identified.