From APC to the genetics of hereditary and familial colon cancer syndromes

Abstract

Hereditary colorectal cancer (CRC) syndromes attributable to high penetrance mutations represent 9-26% of young-onset CRC cases. The clinical significance of many of these mutations is understood well enough to be used in diagnostics and as an aid in patient care. However, despite the advances made in the field, a significant proportion of familial and early-onset cases remains molecularly uncharacterized and extensive work is still needed to fully understand the genetic nature of CRC susceptibility. With the emergence of next-generation sequencing and associated methods, several predisposition loci have been unraveled, but validation is incomplete. Individuals with cancer-predisposing mutations are currently enrolled in life-long surveillance, but with the development of new treatments, such as cancer vaccinations, this might change in the not so distant future for at least some individuals. For individuals without a known cause for their disease susceptibility, prevention and therapy options are less precise. Herein, we review the progress achieved in the last three decades with a focus on how CRC predisposition genes were discovered. Furthermore, we discuss the clinical implications of these discoveries and anticipate what to expect in the next decade.

Figure 1

CRC syndromes. Division between syndromes is traditionally based on the number of and histopathology of intestinal polyps and mode of inheritance. The most common germline mutant genes for each syndrome are given. Ratios indicate estimates of prevalence of each syndrome based on literature (201–213).

Figure 2

Timeline of CRC and polyposis susceptibility gene discoveries in the Sanger sequencing and NGS eras. Timeline assignment is based on the discovery of the gene as a CRC or polyposis susceptibility gene (the gene itself may have been identified before). Established susceptibility genes are colored and putative are indicated with a gray box.

Figure 3

Key biological pathways associated with hereditary CRC syndromes. Genes with known germline mutations are shown in purple font. (A) Fidelity of DNA replication depends primarily on DNA polymerases ε and δ for correct base pairing and proofreading exonuclease activity. Any persisting base–base mispairs or insertion–deletion loops both on the leading and lagging strands are subsequently targeted by MMR proteins. MSH2:MSH3/6 dimers recognize the error. Interaction with MLH1:PMS2 triggers downstream repair events initiated by removal of the erroneous DNA by exonuclease 1 (Exo1). (B) Oxidation, alkylation, and deamination of DNA bases are repaired by base excision repair (BER) pathway. Eleven DNA glycosylases recognize and remove the damaged/mispaired bases; these are divided into monofunctional (e.g. MUTYH) and bifunctional (e.g. NTHL1, OGG1) glycosylases based on the presence of additional endonuclease activity. Their function is exemplified by repair of oxidative 8-oxoguanine (oxoG) and 5-hydroxycytosine (5-OHC) lesions. (C) Wnt signaling regulates cell development and stemness and is commonly hyperactivated in cancer. In the absence of secreted Wnt ligands, a cytoplasmic destruction complex directs β-catenin for proteasomal degradation and RNF43/ZNRF3 ubiquitin ligases downregulate Frizzled receptors. Upon receptor binding of Wnts, β-catenin is released and translocates to the nucleus, where it binds TCF/LEF transcription factors and displaces the Groucho repressor to activate target gene transcription. Binding of R-spondins (Rspo) to LGR5 inhibits RNF43/ZNRF3, enhancing Wnt signaling. (D) TGF-β signaling restricts proliferation of colonic epithelial cells. Bone morphogenetic proteins (BMPs) are TGF-β superfamily ligands that trigger receptor dimerization and activation via trans-phosphorylation, resulting in SMAD-dependent target gene transcription. Also, non-SMAD signaling pathways, including the PI3K–AKT–mTOR pathway, can be activated. Growth factor signaling via receptor tyrosine kinases (RTK) activates PI3K to generate phosphoinositide-3,4,5-triphosphate (PIP₃), resulting in AKT-mediated derepression of mTOR complex 1 (mTORC1). mTOR integrates nutrient and growth factor signals, promoting cell growth upon activation. PTEN lipid phosphatase antagonizes this pathway by converting PIP₃ back to PIP₂. Conversely, low glucose conditions trigger the STK11-dependent activation of AMPK, suppressing mTORC1. See references (214–220) for further details.