Fig. 15.36 Morphologicandmolecularchangesintheadenoma-carcinomasequence.ItispostulatedthatlossofonenormalcopyofthetumorsuppressorgeneAPC occursearly.Individualsmaybebornwithonemutantallele,makingthemextremelypronetothedevelopmentofcoloncancer,orinactivationofAPCmayoccurlaterinlife.Thisisthe“firsthit”accordingtoKnudson’shypothesis.ThelossoftheintactcopyofAPC follows(“secondhit”).OthermutationsinvolvingKRAS, SMAD2, and SMAD4, andthetumorsuppressorgeneTP53, leadtotheemergenceofcarcinoma,inwhichadditionalmutationsoccur.Althoughtheremaybeapreferredtemporalsequenceforthesechanges,itistheaggregateeffectofthemutations,ratherthantheirorderofoccurrence,thatappearsmostcritical.
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The tumor suppressor gene TP53 is mutated in 70% to 80% of colon cancers but is uncommonly affected in adenomas, suggesting that TP53 mutations also occur at late stages of tumor progression. Loss of function of TP53 and other tumor suppressor genes is often caused by chromosomal deletions, highlighting chromosomal instability as a hallmark of the APC/β-catenin pathway. Alternatively, tumor suppressor genes may be silenced by methylation of CpG islands, a 5′ region of some genes that frequently includes the promoter and transcriptional start site. Expression of telomerase also increases as lesions become more advanced.
The microsatellite instability pathway. In patients with DNA mismatch repair deficiency (due to loss of mismatch repair genes, as discussed earlier), mutations accumulate in microsatellite repeats, a condition referred to as microsatellite instability. These mutations generally are silent, because microsatellites typically are located in noncoding regions, but other microsatellite sequences are located in the coding or promoter regions of genes involved in regulation of cell growth, such as those encoding the type II TGF-β receptor and the proapoptotic protein BAX (Fig. 15.37 ). Because TGF-β inhibits colonic epithelial cell proliferation, type II TGF-β receptor mutants can contribute to uncontrolled cell growth, while loss of BAX may enhance the survival of genetically abnormal clones.
CpG island hyper methylation phenotype (CIMP). In a subset of colon cancers with microsatellite instability, there are no mutations in DNA mismatch repair enzymes. These tumors demonstrate the CpG island hypermethylation phenotype (CIMP). In these tumors, the MLH1 promoter region is typically hypermethylated, thereby reducing MLH1 expression and repair function. Activating mutations in the BRAF oncogene are common in these cancers. In contrast, KRAS and TP53 are not typically mutated. Thus, the combination of microsatellite instability, BRAF mutation, and methylation of specific targets, such as MLH1, is the signature of this pathway of carcinogenesis.
Overall, adenocarcinomas are distributed approximately equally over the entire length of the colon. Tumors in the proximal colon often grow as polypoid, exophytic masses that extend along one wall of the large-caliber cecum and ascending colon; these tumors rarely cause obstruction (
Fig. 15.38A ). By contrast, carcinomas in the distal colon tend to be annular lesions that produce “napkin ring” constrictions and luminal narrowing (