An oncogenic hot L1 evades somatic repression and initiates CRC. L1 Inheritance: Inheritance of a hot FL-L1Hs source element begins the process of L1-mediated cancer (this study). In this case, the patient inherited an African-specific hot FL-L1Hs source element on Chromosome 17 (black bar with fire outline, bottom) from one of her parents. L1 Expression: The inherited FL-L1Hs source element evades somatic repression and generates transcripts (squiggle lines, bottom) in normal colon tissues (this study). L1 Insertion: A somatic L1 offspring element is integrated into the sixteenth exon of the APC gene, thereby disrupting one APC allele (light blue star on Chr 5, bottom; this study) (Miki et al. 1992). The second APC allele is disrupted by the somatic mutation p.R1450* (black star on Chr 5, bottom; this study). Thus, both gatekeeper APC alleles are disrupted and the adenoma phase is initiated. Polyp Formation: Following loss of APC function, additional important driver mutations in the PIK3CA and KRAS genes (black stars on Chr 3 and Chr 12, respectively, bottom) result in progression to adenocarcinoma (cluster of red cells, top). Adenocarcinoma: Additional driver and passenger mutations occur to further drive progression of adenocarcinoma. These changes include new somatic L1 insertions (light blue stars, bottom), SNVs and indels (black stars, bottom), and perhaps other structural variants.
