Flat colorectal cancers are genetically determined and progress to invasion without going through a polypoid stage.
Growing evidence suggests that flat colorectal cancers (CRC) account for 10% to 20% of all CRCs and that these are frequently associated with more advanced pathologies. However, controversy exists as to the origin and progression of flat CRCs compared with the more common polypoid-type morphology. We report using the azoxymethane mouse model for human CRC that KK/HIJ and I/LNJ mice develop different frequencies of flat and polypoid tumors; 83% of colon tumors in I/LNJ mice are flat compared with only 19% in KK/HIJ mice, indicating a strong genetic predisposition to the development of specific CRC morphologies. Like polypoid tumors, all flat tumors show a significant increase in the level of nuclear beta-catenin (CATNNB1), supported by similar frequencies of mutations in the phosphorylation domain-coding region (codons 32-41) of Catnnb1. However, in contrast to previous reports, tumors bearing higher "oncogenic potential" do not cluster in codon 41 of Catnnb1. There are no differences between flat and polypoid tumors in the frequency of mutations in codons 12 and 13 of Kras or codon 624 of Braf. Similarly, there are no differences between tumor morphologies in their location along the proximal-to-distal colonic axis or in the relative quantity of intratumor stromal myofibroblasts as marked by the expression of alpha-smooth muscle actin. Using a combination of serial colonoscopic and histologic analyses, we definitively show that flat CRCs do not develop de novo but progress through a flat adenomatous stage to invasive carcinoma without transit through an intermediary polypoid stage.
Uronis
Joshua M
JM
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Herfarth
Hans H
HH
Rubinas
Tara C
TC
Bissahoyo
Anika C
AC
Hanlon
Kathleen
K
Threadgill
David W
DW
D000818:Animals; D001397:Azoxymethane; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D004724:Endoscopy; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics*; D011123:Polyploidy; D051176:beta Catenin / Q000235:genetics
D051176:beta Catenin; D001397:Azoxymethane