Colorectal cancer (CRC) is the third most common cancer type and a major cause for cancer deaths. Retrotransposons are transposable elements (TE) able to mobilize and insert via an RNA intermediate. Although germline retrotransposition can contribute to genetic diversity, uncontrolled retrotransposition can lead to genomic instability. Retrotransposons are normally repressed by promoter methylation however, they become highly active in many cancers, such as CRC. Since retrotransposons are difficult to detect, their role in tumorigenesis has remained considerably unexplored. The main goal of this thesis project was to further understand the impact of retrotransposition in colorectal tumorigenesis utilizing whole genome sequencing (WGS) and Nanopore sequencing. In study I, we detected an active reference long interspersed element-1 (LINE-1) located in the first intron of TTC28. This active LINE-1 led to the most frequent somatic structural rearrangement in our dataset, with a total of 83 somatic retrotranspositions in 92 CRCs. In study II, we applied long-distance inverse-PCR (LDI-PCR) with Nanopore sequencing to detect retrotranspositions arising from the active LINE-1 identified in study I. We identified 25 subclonal insertions in addition to 14 insertions previously detected by WGS, indicating active retrotransposition during the tumorigenic process. In study III, we characterized somatic retrotransposon insertions in 202 colorectal tumor whole genomes. Among recurrent insertions in fragile sites and cancer genes, we identified two insertions in exon 16 of APC, suggesting that retrotransposon insertions can contribute to tumor initiation. Furthermore, the number of somatic insertions correlated with the CpG island methylator phenotype (CIMP), the genomic fraction of allelic imbalance (AI), and poor CRC survival. These findings suggest that the clinical impact of retrotransposition in CRC might be more important than previously acknowledged, although several questions remain unanswered. Future work should shed light on the timing and novel mechanisms by which retrotransposition could influence tumorigenesis. The better understanding of the role of both somatic and germline retrotransposition could provide tools for patient stratification and cancer prevention.
Original languageEnglish
  • Aaltonen, Lauri, Supervisor
  • Kilpivaara, Outi, Supervisor
  • Palin, Kimmo, Supervisor
Place of PublicationHelsinki
Print ISBNs978-951-51-6701-9
Electronic ISBNs978-951-51-6702-6
Publication statusPublished - 2020
MoE publication typeG5 Doctoral dissertation (article)

Bibliographical note

M1 - 69 s. + liitteet

Fields of Science

  • 3111 Biomedicine

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