Figure 1.

Mutagenesis of APC by a somatic L1 insertion. (A) A schematic of the L1 insertion in APC. The top diagram shows the location of the APC gene (vertical red bar) in band q22.2 of Chromosome 5. The diagram below depicts the 1387-bp somatic L1 insertion (dark and light green) in exon 16 of APC with the associated hallmarks of retrotransposition, including a flanking 14-bp TSD (orange), poly(A) tail (T in reverse order; red) and evidence for twin priming (two green boxes separated by an 18-bp deletion at the inversion point). (B) The two diagrams show the inactivating mutations that were discovered in both alleles of APC in the tumor. The top allele is inactivated by the L1 insertion at codon 1396 (multicolored bar; p.F1396L1) and has the reference codon at position 1450 (gray circle). The bottom allele is inactivated by the p.R1450* stop codon (red circle) and does not have an L1 insertion (gray circle). (C) The diagram shows the sites that are affected by these mutations within the APC protein. Also depicted is the L1 insertion identified by Miki et al. (1992) (red square; p.P1526L1). All three of these mutations occur within or near the somatic mutation cluster region (black bar) (Miyoshi et al. 1992) and are similar to other inactivating APC mutations in CRC (see Discussion). This image is adapted from the output of the Protein Painter tool (http://explore.pediatriccancergenomeproject.org/proteinPainter). The APC protein is 2843 amino acids long and consists of the following domains: Suppressor APC (red; involved in nuclear export and other functions); Armadillo/beta-catenin-like repeats (orange; mediate protein–protein interactions); APC cysteine-rich regions (yellow; bind beta-catenin); SAMP (green; binds axin); APC basic (blue; interacts with microtubules); and MAPRE1-binding (aka EB1-binding; purple; binds the microtubule-associating protein MAPRE1).