Genotype-Phenotype Correlations in Autosomal Dominant and Recessive APC Mutation-Negative Colorectal Adenomatous Polyposis

Dig Dis Sci. 2023 Jul;68(7):2799-2810. doi: 10.1007/s10620-023-07890-9. Epub 2023 Mar 2.


The most prevalent type of intestinal polyposis, colorectal adenomatous polyposis (CAP), is regarded as a precancerous lesion of colorectal cancer with obvious genetic characteristics. Early screening and intervention can significantly improve patients' survival and prognosis. The adenomatous polyposis coli (APC) mutation is believed to be the primary cause of CAP. There is, however, a subset of CAP with undetectable pathogenic mutations in APC, known as APC (-)/CAP. The genetic predisposition to APC (-)/CAP has largely been associated with germline mutations in some susceptible genes, including the human mutY homologue (MUTYH) gene and the Nth-like DNA glycosylase 1 (NTHL1) gene, and DNA mismatch repair (MMR) can cause autosomal recessive APC (-)/CAP. Furthermore, autosomal dominant APC (-)/CAP could occur as a result of DNA polymerase epsilon (POLE)/DNA polymerase delta 1 (POLD1), axis inhibition protein 2 (AXIN2), and dual oxidase 2 (DUOX2) mutations. The clinical phenotypes of these pathogenic mutations vary greatly depending on their genetic characteristics. Therefore, in this study, we present a comprehensive review of the association between autosomal recessive and dominant APC (-)/CAP genotypes and clinical phenotypes and conclude that APC (-)/CAP is a disease caused by multiple genes with different phenotypes and interaction exists in the pathogenic genes.

Keywords: APC mutation negative; Autosomal dominant heredity; Autosomal recessive heredity; Colorectal adenomatous polyposis; Genotype–phenotype correlation.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenomatous Polyposis Coli* / diagnosis
  • Adenomatous Polyposis Coli* / genetics
  • Adenomatous Polyposis Coli* / pathology
  • Genes, APC
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Germ-Line Mutation
  • Humans
  • Mutation
  • Phenotype