Retrotransposon insertions can initiate colorectal cancer and are associated with poor survival

• Published in: Nature communications Vol. 10; no. 1; pp. 4022 - 9
• Main Authors: Cajuso, Tatiana, Sulo, Päivi, Tanskanen, Tomas, Katainen, Riku, Taira, Aurora, Hänninen, Ulrika A., Kondelin, Johanna, Forsström, Linda, Välimäki, Niko, Aavikko, Mervi, Kaasinen, Eevi, Ristimäki, Ari, Koskensalo, Selja, Lepistö, Anna, Renkonen-Sinisalo, Laura, Seppälä, Toni, Kuopio, Teijo, Böhm, Jan, Mecklin, Jukka-Pekka, Kilpivaara, Outi, Pitkänen, Esa, Palin, Kimmo, Aaltonen, Lauri A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 49/47; 631/208/69; 692/4020; Adenomatous polyposis coli; Aged; Caco-2 Cells; Cancer; Carcinogenesis; Carcinogenesis - genetics; Carcinogens; Cell Line, Tumor; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; CpG islands; CpG Islands - genetics; DNA Methylation; Female; Gastrointestinal system; Gastrointestinal tract; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genomes; Genomic Instability; Humanities and Social Sciences; Humans; Kaplan-Meier Estimate; Long Interspersed Nucleotide Elements - genetics; Male; Medicin och hälsovetenskap; Middle Aged; multidisciplinary; Mutagenesis, Insertional; Phenotypes; Retrotransposition; Science; Science (multidisciplinary); Stability; Survival; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-11770-0

Genomic instability pathways in colorectal cancer (CRC) have been extensively studied, but the role of retrotransposition in colorectal carcinogenesis remains poorly understood. Although retrotransposons are usually repressed, they become active in several human cancers, in particular those of the gastrointestinal tract. Here we characterize retrotransposon insertions in 202 colorectal tumor whole genomes and investigate their associations with molecular and clinical characteristics. We find highly variable retrotransposon activity among tumors and identify recurrent insertions in 15 known cancer genes. In approximately 1% of the cases we identify insertions in APC , likely to be tumor-initiating events. Insertions are positively associated with the CpG island methylator phenotype and the genomic fraction of allelic imbalance. Clinically, high number of insertions is independently associated with poor disease-specific survival. Retrotransposons are usually dormant in healthy tissue, but become activated during malignancy. Here, in colorectal cancer, Cajuso et al. show that retrotransposon activity associates with clinical features of the disease.