General Surgery
Tjun Tang, Elizabeth O'Riordan, Stewart Walsh in Cracking the Intercollegiate General Surgery FRCS Viva, 2020
What is the genetic basis of colon cancer?APC (adenomatous polyposis coli) gene mutations Occur early in 60% of all adenomas and carcinomasK-ras mutations (induce cell growth) Occur later in large adenomas and carcinomasp53 mutation (involved in DNA repair and induction of apoptosis) Later, in invasive colonic cancersAccompanied by invasion
Colon cancer: pathology and natural history
A. R. Genazzani in Hormone Replacement Therapy and Cancer, 2020
The APC gene has an open reading frame of 8538 base pairs (bp)14 and comprises 15 coding exons, with exon 15 alone containing 6571 bp, making it the largest known human exon. The gene encodes a 2843–residue protein with a molecular weight of 310 kDa14 and wide tissue expression, including stomach, liver, esophagus, kidney, brain and eye. In Figure 4 the principal regions of the APC protein with their functions are schematically reported. This protein, which has a cytoplasmic localization, can be subdivided into two major regions: the carboxy terminal (75%) and the amino terminal (25%), the latter of which contains proline-free blocks with heptad repeats of hydrophobic residues. This pattern is characteristic of α-helical coils and implies protein-protein interactions. In fact, the amino terminus is critical for homo-oligomerization (Figure 4). Most APC gene mutations result in the production of a protein that is truncated at some point beyond residue 171. Thus, the potential for continued oligomerization should generally be preserved in truncated proteins, permitting the formation of inactivating complexes, explaining the dominant negative effect of the mutant protein.
Gastrointestinal cancer
Peter Hoskin, Peter Ostler in Clinical Oncology, 2020
Familial adenomatous polyposis (FAP) accounts for 1% of bowel cancers. It is a rare, dominantly inherited condition, i.e. there is a 50% chance of inheriting the mutated APC tumour-suppressor gene from an affected parent. The APC gene is located on chromosome 5q21. It has a prevalence of 1 in 10,000 births. There are characteristic physical signs to indicate a gene carrier, e.g. congenital hypertrophy of the retinal pigment epithelium (CHRPE), osteomas of the jaw, prepuberty epidermoid cysts. Affected individuals develop multiple (>100) benign polyps from a very young age (puberty). Inevitably, over the subsequent years, one or more of these polyps will transform into a cancer, usually during the third and fourth decades, 20–30 years before the general population. The risk for colorectal cancer is estimated at 90% by age 45 years. Prophylactic surgical excision of the colon and rectum is advised in young adults. Upper gastrointestinal malignancy (usually duodenal) will also develop in 5% and benign desmoid tumours in 10%. The latter can arise within the abdomen and may prove fatal owing to relentless local spread. Gardener syndrome is similar to familial polyposis coli but characterized by skeletal and cutaneous abnormalities, e.g. osteomas of the mandible and skull, sebaceous cysts and dermoid cysts.
Expression Levels of WNT Signaling Pathway Genes During Early Tooth Development
Published in Organogenesis, 2023
Yuhan Song, Fujie Song, Xuan Xiao, Zhifeng Song, Shangfeng Liu
Adenomatous polyposis coli (APC) gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in cell migration and adhesion, transcriptional activation, and apoptosis.61 Mutations in Apc may cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy.62 Besides, other diseases such as Gardner syndrome, which is characterized by the presence of multiple intracolonic polyps and extracolonic tumors, can also be caused by Apc mutation. Our previous study found that patients with Gardner syndrome also had multiple impacted and supernumerary teeth.16 We found that Apc was expressed at E14.5-P7 and there are up to 2037 different mutation forms in Apc, suggesting that Apc played an important role in all stages of early tooth development.
Chromosome 6p amplification detected in blood cell-free DNA in advanced intraocular retinoblastoma
Published in Ophthalmic Genetics, 2022
Shreya Sirivolu, Liya Xu, Mikako Warren, Rishvanth K. Prabakar, Rachana Shah, Peter Kuhn, James Hicks, Jesse L. Berry
In addition to being the first RB case with SCNA detection in blood, interestingly this patient did not have a germline RB1 mutation but did have a germline adenomatous polyposis coli (APC) gene mutation. APC encodes a tumor-suppressor protein that has a role in processes such as cell migration and adhesion, transcriptional activation, and apoptosis. Mutations in the APC gene are responsible for familial adenomatous polyposis (FAP), which has a role in a majority of sporadic colorectal cancers (24). In the pediatric population, mutations in APC have also been associated with increased risk of hepatoblastoma (25). This specific APC mutation, c.3920T>A, increases the risk for colorectal cancers by leading to a hypermutable region of the gene resulting in increased cancer predisposition (26,27). A study investigating the association between APC c.3920T>A and non-colorectal cancers reported that this variant was detected in 11.8% of cancer patients compared to 4.7% of healthy subjects (28). Males had significantly increased carrier prevalence in lung, urologic, pancreatic, and skin cancers and females had significantly higher carrier prevalence in breast and skin cancer (28). An association between APC and RB1 variants has not been previously described in RB patients. It remains to be determined whether this germline APC mutation had a contributory role in the unusually high tumor fraction detected in the blood in this patient.
Recent updates on Wnt signaling modulators: a patent review (2014-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Vishalgiri G. Goswami, Bhumika D. Patel
Aberrant hyperactivation of Wnt signaling is observed in CRC. APC is widely accepted as tumor-suppressor gene in CRC. Mutation or inactivation of this gene is a key early event in colorectal tumorigenesis. APC truncation is a major driver of colorectal cancer. This indicates the role of APC-mediated canonical signaling pathway in colorectal cancer. APC mutation often occurs in the mutation cluster region (MCR) which accounts for 10% of the entire coding region in the APC gene. Consistent with this hypothesis, more than 80% of colorectal patients show APC mutation [26,27]. A study concluded that 28 out of 43 somatic mutations in colorectal cancer cells occur in the MCR, which inhibits β-catenin ubiquitination, degradation, and ultimately leads to unrestricted transcription of cell proliferation genes. β-catenin mutation also plays a key role in colorectal cancer. Approximately 10% of CRCs carry mutations in the GSK3β phosphorylation site located in the N-terminus of β-catenin [28]. Alexander A. et al. described that majority of β-catenin gene CTNNB1 mutation in CRC is homozygous and restricted to mutation at codons 41 and 45 [29]. The same finding was also proved by Laura et al. where the authors suggested that CTNNB1 mutation is common in MSI-H (high-level microsatellite instability) colorectal carcinoma [30]. These types of specific mutations prove that the right level of β-catenin stabilization is essential for carcinogenesis. This finding suggests an important role of β-catenin in targeting colorectal cancer.
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