BACKGROUND: Wnt/β-catenin signalling impairment accounts for 85% of colorectal cancers (CRCs), including sporadic and familial adenomatous polyposis (FAP) settings. An altered PI3K/mTOR pathway and gut microbiota also contribute to CRC carcinogenesis. We studied the interplay between the two pathways and the microbiota composition within each step of CRC carcinogenesis.
METHODS: Proteins and target genes of both pathways were analysed by RT-qPCR and IHC in tissues from healthy faecal immunochemical test positive (FIT+, n = 17), FAP (n = 17) and CRC (n = 15) subjects. CRC-related mutations were analysed through NGS and Sanger. Oral, faecal and mucosal microbiota was profiled by 16 S rRNA-sequencing.
RESULTS: We found simultaneous hyperactivation of Wnt/β-catenin and PI3K/mTOR pathways in FAP-lesions compared to CRCs. Wnt/β-catenin molecular markers positively correlated with Clostridium_sensu_stricto_1 and negatively with Bacteroides in FAP faecal microbiota. Alistipes, Lachnospiraceae, and Ruminococcaceae were enriched in FAP stools and adenomas, the latter also showing an overabundance of Lachnoclostridium, which positively correlated with cMYC. In impaired-mTOR-mutated CRC tissues, p-S6R correlated with Fusobacterium and Dialister, the latter also confirmed in the faecal-ecosystem.
CONCLUSIONS: Our study reveals an interplay between Wnt/β-catenin and PI3K/mTOR, whose derangement correlates with specific microbiota signatures in FAP and CRC patients, and identifies new potential biomarkers and targets to improve CRC prevention, early adenoma detection and treatment.

OBJECTIVE: Desmoid tumours (DT) are an important cause of morbidity and mortality in patients with familial adenomatous polyposis (FAP). DT development might be related to the type and approach of colectomy. We aimed to compare DT development after colectomy with ileorectal anastomosis (IRA) and proctocolectomy with ileal pouch-anal anastomosis (IPAA).
METHODS: We performed an international historical cohort study in FAP patients who underwent IRA or IPAA between 1961 and 2020. The primary outcome was the incidence of abdominal DT (either mesenteric, retroperitoneal or abdominal wall). Patients with a DT diagnosis before or at colectomy were excluded. Time to DT was considered censored at an eventual secondary proctectomy after IRA. We used multivariable Cox regression modelling to adjust for potential confounders.
RESULTS: We analysed data from 852 patients: 514 after IRA and 338 after IPAA (median follow-up 21 and 16 years, respectively). DTs were diagnosed in 64 IRA patients (12%) and 66 IPAA patients (20%). The cumulative DT incidence at 5 and 10 years was 7.5% and 9.3% after open IRA and 4.7% and 10.9% after laparoscopic IRA. These estimates were 13.6% and 15.4% after open IPAA and 8.4% and 10.0% after laparoscopic IPAA. The post-operative risk was significantly higher after IPAA (p < 0.01) in multivariable analysis, while approach did not significantly influence the risk.
CONCLUSIONS: The risk of developing an abdominal DT was found to be significantly higher after IPAA than after IRA. Postoperative DT risk should be taken into account when choosing between IRA and IPAA in FAP.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) develop early colorectal adenomas and if left untreated, progression to cancer is an inevitable event. Prophylactic surgery does not prevent further development of cancer in the rectal remnant, rectal cuff in patients with ileal pouch anal anastomosis (IPAA) and even on the ileal mucosa of the pouch body. The aim of this review is to assess long-term rates of cancer and adenoma development in patients with FAP after prophylactic surgery and to summarise current recommendations for endoscopic management and surveillance of these patients.
METHODS: A systematic literature search of studies from January 1946 through to June 2023 was conducted using the PRISMA checklist. The electronic database PubMed was searched.
RESULTS: Fifty-four papers involving 5010 patients were reviewed. Cancer rate in the rectal remnant was 8.8-16.7% in the western population and 37% in the eastern population. The cumulative risk of cancer 30 years after surgery was 24%. Mortality due to cancer in the rectal remnant is 1.1-11.1% with a 5-year survival rate of 55%. The adenoma rate after primary IPAA was 9.4-85% with a cumulative risk of 85% 20 years after surgery and a cumulative risk of 12% for advanced adenomas 10 years after surgery. Cumulative risk for adenomas after ileorectal anastomosis (IRA) was 85% after 5 and 100% after 10 years. Adenomas developed more frequently after stapled (33.9-57%) compared to hand-sewn (0-33%) anastomosis. We identified reports of 45 cancers in patients after IPAA of which 30 were in the pouch body and 15 in the rectal cuff or at the anastomosis.
CONCLUSIONS: There was a significant incidence of cancer and adenomas in the rectal remnant and ileal pouch of FAP patients during the long-term follow-up. Regular endoscopic surveillance is recommended, not only in IRA patients, but also in pouch patients after proctocolectomy.

BACKGROUND: Patients with familial adenomatous polyposis (FAP) experience psychological and social challenges concerning future events such as marriage and childbirth alongside the medical risks of colorectal cancer (CRC) and FAP-related disease. We retrospectively investigated the rate of marriage and childbirth postoperatively in Japanese patients with FAP.
METHODS: We included 161 patients who had colorectal surgery and reported marital status from a national survey of 35 Japanese institutions. Participants were classified according to marital status: married before colectomy (80 patients), married after colectomy (13 patients), and unmarried (68 patients).
RESULTS: The marriage rate for all 161 patients (57.8%, standardized ratio 0.95, 95% confidence interval [CI] 0.76-1.14) was comparable to that in the general Japanese population (57.1%). The marriage rate among the 81 patients who were unmarried before colectomy was low (16.0%); however, the standardized marital ratio (0.75, 95% CI 0.34-1.15) was not significantly lower than that of the general population. In multivariable logistic regression, younger age (born after 1980, odds ratio [OR] 0.12, p < 0.001) and genetic testing (OR 4.06, p = 0.001) were associated with postoperative marriage. Seventy-one percent of patients with FAP who married after colectomy became pregnant and achieved delivery.
CONCLUSIONS: The marriage rate of patients with FAP was comparable to that of the general population whereas the rate after colectomy was low among patients with FAP. However, in patients with FAP, colorectal surgery itself may not lead to negative consequences in terms of fecundity.

Familial adenomatous polyposis (FAP) is a rare disease characterized by the development of adenomatous polyps in the colon and rectum already in adolescence. If left untreated, patients develop colorectal cancer (CRC) with a 100% probability. To date, the gold standard of FAP management is surgery, which is associated with morbidity and mortality. A chemopreventive agent capable of delaying, preventing and reversing the development of CRC has been sought. Several classes of drugs have been used but to date no chemopreventive drug has been found for the management of this disease. In recent years, the importance of estrogen receptors in FAP and CRC, particularly the β subtype, has emerged. Indeed, the expression of the latter is strongly reduced in adenomatous polyps and CRC and is inversely correlated with the aggressiveness of the disease. Since phytoestrogens have a high affinity for this receptor, they have been suggested for use as chemopreventive agents in FAP and CRC. A combination of phytoestrogens and insoluble fibres has proved particularly effective. In this review, the various mechanisms of action of phytoestrogens were analyzed and the effectiveness of using phytoestrogens as an effective chemopreventive strategy was discussed.

Familial adenomatous polyposis (FAP) patients face an almost certain 100% risk of developing colorectal cancer, necessitating prophylactic colectomy to prevent disease progression. A crucial goal is to hinder this progression. In a recent clinical trial involving 14 FAP patients, half received 60 g of black raspberry (BRB) powder orally and BRB suppositories at bedtime, while the other half received only BRB suppositories at bedtime over 9 months. This intervention led to a notable reduction in rectal polyps for 11 patients, although 3 showed no response. In this study, we delved into the metabolic changes induced by BRBs in the same patient cohort. Employing mass spectrometry-based non-targeted metabolomics, we analyzed pre- and post-BRB urinary and plasma samples from the 11 responders. The results showed significant alterations in 23 urinary and 6 plasma metabolites, influencing various pathways including polyamine, glutathione metabolism, the tricarboxylic acid cycle, inositol metabolism, and benzoate production. BRBs notably elevated levels of several metabolites associated with these pathways, suggesting a potential mechanism through which BRBs facilitate rectal polyp regression in FAP patients by modulating multiple metabolic pathways. Notably, metabolites derived from BRB polyphenols were significantly increased post-BRB intervention, emphasizing the potential therapeutic value of BRBs in FAP management.

Background and study aims Some patients with familial adenomatous polyposis (FAP) and extensive duodenal polyposis or cancer require total duodenectomy. Regular postoperative endoscopic surveillance of the remaining jejunum and stomach is recommended, but little is known about the outcomes after this surgery. Patients and methods Patients with FAP who underwent either pancreatoduodenectomy (PD) or pancreas-preserving total duodenectomy (PPTD) were identified at two expert centers. Data about postoperative endoscopic surveillance outcomes were collected, as well as survival outcomes. Results Overall, 119 patients (50% female) underwent duodenectomy (86 PD and 33 PPTD); 100 for benign duodenal polyposis and 19 for duodenal or ampullary cancer. Details of postoperative endoscopic surveillance were available for 88 patients (74%). During a median follow-up of 106 months, 36 patients (41%) were diagnosed with jejunal adenomas after duodenectomy, with a significantly higher proportion in patients who underwent PPTD compared with patients who underwent PD (log-rank, P < 0.01). Two patients developed jejunal cancer (2%). Twenty-six patients (30%) were diagnosed with a total of 66 gastric adenomas, of which 61% were located in the fundus/body and 39% in the antrum. Five patients (6%) developed gastric cancer after a median of 15 years (range 6-23 years), all but one within carpeting fundic gland polyposis. Patients who underwent surgery for cancer had worse survival than patients with benign disease and all but one patient with postoperative gastric/jejunal cancer died. Conclusions After duodenectomy in FAP, a considerable risk of developing adenomas and cancer in the stomach and jejunum exists with poor cancer prognosis, highlighting the need for close postoperative endoscopic surveillance.

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder affecting patients with germline mutations of the adenomatous polyposis coli (APC) tumor suppressor gene. The surgical treatment of colorectal disease in FAP, which has the goal of colorectal cancer prevention, varies based on both patient and disease factors but can include the following: total colectomy with ileorectal anastomosis, proctocolectomy with stapled or hand-sewn ileal pouch-anal anastomosis, or total proctocolectomy with end ileostomy. The operative options and extent of resection, as well as the use of endoscopy and chemoprevention for the management of polyposis, will be discussed in detail in this article. In addition, commonly debated management decisions related to the treatment of patients with FAP, including the timing of prophylactic colorectal resections for patients with FAP and management of the polyp burden in the rectum, will be discussed. Finally, genotype considerations and the impact of desmoid disease on operative decisions in the setting of FAP will also be reviewed.

Serrated polyposis syndrome (SPS) presents with multiple sessile serrated lesions (SSL) in the large intestine and confers increased colorectal cancer (CRC) risk. However, the etiology of SPS is not known. SSL-derived organoids have not been previously studied but may help provide insights into SPS pathogenesis and identify novel biomarkers and chemopreventive strategies. This study examined effects of EGFR and COX pathway inhibition in organoid cultures derived from uninvolved colon and polyps of SPS patients. We also compared with organoids representing the hereditary gastrointestinal syndromes, Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS). Eighteen total organoid colon cultures were generated from uninvolved colon and polyps in SPS, FAP, LS, and non-syndromic screening colonoscopy patients. BRAF and KRAS mutation status was determined for each culture. Erlotinib (EGFR inhibitor) and sulindac (COX inhibitor) were applied individually and in combination. A 44-target gene custom mRNA panel (including WNT and COX pathway genes) and a 798-gene microRNA gene panel were used to quantitate organoid RNA expression by NanoString analysis. Erlotinib treatment significantly decreased levels of mRNAs associated with WNT and MAPK kinase signaling in organoids from uninvolved colon from all four patient categories and from all SSL and adenomatous polyps. Sulindac did not change the mRNA profile in any culture. Our findings suggest that EGFR inhibitors may contribute to the chemopreventive treatment of SSLs. These findings may also facilitate clinical trial design using these agents in SPS patients. Differentially expressed genes identified in our study (MYC, FOSL1, EGR1, IL33, LGR5 and FOXQ1) may be used to identify other new molecular targets for chemoprevention of SSLs.

Cancer prevention in hereditary gastrointestinal predisposition syndromes relies primarily on intensive screening (e.g., colonoscopy) or prophylactic surgery (e.g., colectomy). The use of chemopreventive agents as an adjunct to these measures has long been studied both in the general population and in hereditary cancer patients, in whom the risk of malignancy, and therefore the potential risk reduction, is considerably greater. However, to date only few compounds have been found to be effective, safe, and tolerable for widespread use. Furthermore, many of the studies involving these rare syndromes suffer from small sample sizes, heterogeneous patient cohorts, short follow-up duration, and lack of standardized endpoints, creating challenges to draw generalizable conclusion regarding efficacy. The following review summarizes the current data on various chemopreventive compounds used in Lynch syndrome and familial adenomatous polyposis in addition to several agents that are currently being investigated.