Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis

Abstract

Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.

Identification of driving genes of familial adenomatous polyposis by differential gene expression analysis and weighted gene co-expression network analysis

“…Familial adenomatous polyposis (FAP) is an autosomal dominant disorder resulting from mutations in the adenomatous polyposis coli (APC) gene [ 1 , 2 ]. FAP is the most common intestinal polyposis [ 3 ], and the most prominent feature is multiple adenomatous polyposis of the digestive tract which frequently leads to obstruction, gastrointestinal bleeding as well as other complications [ 4 ]. Polyposis can also develop into colorectal cancer and directly endanger human life and health [ 5 ].…”

The enigma of glutamine synthetase and b-catenin expression in hepatocellular adenoma in familial adenomatous polyposis coli

“…However, diffuse GS expression in FAP does imply b-catenin activation pathway, as GS is encoded by GLUL , a target gene upregulated by b-catenin. In FAP, APC mutation results in disruption of b-catenin degradation with subsequent b-catenin accumulation and activation [ 5 ]. Absence of nuclear b-catenin despite biallelic APC mutation can probably be explained by lower levels of b-catenin activation than when CTNNB1 mutation is present.…”

“…Absence of nuclear b-catenin despite biallelic APC mutation can probably be explained by lower levels of b-catenin activation than when CTNNB1 mutation is present. The loss of function due to APC mutation may not be complete, leaving some residual capacity of the protein, hence also of b-catenin degradation [ 5 ]. The presence of nuclear b-catenin also does not necessarily represent CTNNB1 mutation, as has been shown in some FAP-associated hepatoblastoma [ 6 ] and in high-grade dysplastic intraductal papillary neoplasm of the bile duct (IPNB) with somatic APC mutation [ 7 ].…”