Primary and Secondary Prevention Interventions to Reduce Risk Factors Associated with Colorectal Cancer in High-Risk Groups: a Systematic Literature Review.

In the USA, colorectal cancer (CRC) is the 2nd leading cause of cancer-related deaths. Certain groups in the USA are at an increased risk of developing CRC, including those with a genetic risk and family history. The purpose of this project was to synthesize primary and secondary prevention interventions for individuals who are at high risk of CRC due to family history or genetic predisposition. This study systematically reviewed articles from PubMed, Google Scholar, and EBSCO using specific search terms to find relevant articles. Sixteen articles were identified for full-text review, which were categorized as non-drug interventions (n = 7) and drug interventions (n = 9). Non-drug interventions focused primarily on increasing screening in those with a first-degree relative (FDR) with CRC or those with Lynch syndrome (LS). Interventions that increased CRC screening often had a tailored component and were otherwise varied in study designs and intervention type. Drug interventions focused on the use of NSAIDs on patients with familial adenomatous polyposis (FAP). Studies showed very little racial and ethnic diversity. Findings suggest that tailored interventions are particularly effective in increasing CRC screening, and greater diversity of sample is needed with respect to race and ethnicity.

The CHAMP-study: the CHemopreventive effect of lithium in familial AdenoMatous Polyposis; study protocol of a phase II trial.

BACKGROUND: Familial adenomatous polyposis (FAP) is a rare autosomal dominant disease characterized by germline mutations in the Adenomatous Polyposis Coli (APC) gene, resulting in the development of numerous colorectal adenomas. As these patients have a high risk of developing colorectal cancer (CRC), guidelines suggest prophylactic colectomy during early adulthood, however, adenoma development is still observed in the remaining intestinal tract. Therefore, FAP patients would benefit from chemoprevention strategies reducing the development of adenomas. Recent work in mice reveals a chemopreventive effect of lithium on the development of adenomas by inhibiting the expansion of Apc mutated intestinal stem cells (ISCs) within the crypts of normal intestinal mucosa. Here, we aim to investigate the effect of lithium on the spread of APC mutant cells within the human intestinal epithelium. METHODS: This prospective phase II single arm trial has a duration of 18 months. FAP patients (18-35 years) with a genetically confirmed APC mutation who did not undergo colectomy will be treated with lithium carbonate orally achieving a serum level of 0.2-0.4 mmol/l between month 6 and 12. Colonoscopy with biopsies of normal intestinal mucosa will be performed at baseline and every six months. The primary endpoint is the effect of lithium on the spread of APC mutant cells within intestinal crypts over time by using APC specific marker NOTUM in situ hybridization. Secondary endpoints include change in adenoma burden, patient reported side effects and safety-outcomes. Total sample size is 12 patients and recruitment will take place in the Amsterdam UMC, location AMC in the Netherlands. DISCUSSION: The outcome of this study will function as a proof-of-concept for the development of novel chemoprevention approaches that interfere with the competition between normal and mutant ISCs. TRIAL REGISTRATION: ClinicalTrials.gov ( https://clinicaltrials.gov/ ): NCT05402891 (June 1, 2022) and the EU Clinical Trials Register: EuraCT 2022-000240-30 (January 1, 2022).

Artesunate inhibits intestinal tumorigenesis through inhibiting wnt signaling.

Artesunate (ART) is a clinically approved antimalarial drug and was revealed as a candidate of colorectal cancer chemopreventive agents in our drug screening system. Here, we aimed to understand the suppressive effects of ART on intestinal tumorigenesis. In vitro, ART reduced T-cell factor/lymphoid enhancer factor (TCF/LEF) promoter transcriptional activity. In vivo, ART inhibited intestinal polyp development. We found that ART reduces TCF1/TCF7 nuclear translocation by binding the Ras-related nuclear protein (RAN), suggesting that ART inhibits TCF/LEF transcriptional factor nuclear translocation by binding to RAN, thereby inhibiting Wnt signaling. Our results provide a novel mechanism through which artesunate inhibits intestinal tumorigenesis.

Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG).

Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.

Resveratrol and aspirin eliminate tetraploid cells for anticancer chemoprevention.

Tetraploidy constitutes a genomically metastable state that can lead to aneuploidy and genomic instability. Tetraploid cells are frequently found in preneoplastic lesions, including intestinal cancers arising due to the inactivation of the tumor suppressor adenomatous polyposis coli (APC). Using a phenotypic screen, we identified resveratrol as an agent that selectively reduces the fitness of tetraploid cells by slowing down their cell cycle progression and by stimulating the intrinsic pathway of apoptosis. Selective killing of tetraploid cells was observed for a series of additional agents that indirectly or directly stimulate AMP-activated protein kinase (AMPK) including salicylate, whose chemopreventive action has been established by epidemiological studies and clinical trials. Both resveratrol and salicylate reduced the formation of tetraploid or higher-order polyploid cells resulting from the culture of human colon carcinoma cell lines or primary mouse epithelial cells lacking tumor protein p53 (TP53, best known as p53) in the presence of antimitotic agents, as determined by cytofluorometric and videomicroscopic assays. Moreover, oral treatment with either resveratrol or aspirin, the prodrug of salicylate, repressed the accumulation of tetraploid intestinal epithelial cells in the Apc(Min/+) mouse model of colon cancer. Collectively, our results suggest that the chemopreventive action of resveratrol and aspirin involves the elimination of tetraploid cancer cell precursors.

BID mediates selective killing of APC-deficient cells in intestinal tumor suppression by nonsteroidal antiinflammatory drugs.

Colorectal tumorigenesis is driven by genetic alterations in the adenomatous polyposis coli (APC) tumor suppressor pathway and effectively inhibited by nonsteroidal antiinflammatory drugs (NSAIDs). However, how NSAIDs prevent colorectal tumorigenesis has remained obscure. We found that the extrinsic apoptotic pathway and the BH3 interacting-domain death agonist (BID) are activated in adenomas from NSAID-treated patients. Loss of BID abolishes NSAID-mediated tumor suppression, survival benefit, and apoptosis in tumor-initiating stem cells in APC(Min/+) mice. BID-mediated cross-talk between the extrinsic and intrinsic apoptotic pathways is responsible for selective killing of neoplastic cells by NSAIDs. We further demonstrate that NSAIDs induce death receptor signaling in both cancer and normal cells, but only activate BID in cells with APC deficiency and ensuing c-Myc activation. Our results suggest that NSAIDs suppress intestinal tumorigenesis through BID-mediated synthetic lethality triggered by death receptor signaling and gatekeeper mutations, and provide a rationale for developing more effective cancer prevention strategies and agents.

Current status of prophylactic surgical treatment for familial adenomatous polyposis in Japan.

PURPOSE: We conducted this study to clarify the current clinical practice of prophylactic colectomy for patients with familial adenomatous polyposis (FAP) in Japan. METHODS: This retrospective multi-center cohort study involved 23 specialized institutions for colorectal disease in Japan. We analyzed the records of 147 patients who underwent prophylactic surgical treatment between 2000 and 2012. Patients were divided into Group 1 (2000-2006) and Group 2 (2007-2012) based on their date of surgery. RESULTS: Age at the time of prophylactic surgery was 27 and 31 years in Groups 1 and 2, respectively. The proportion of attenuated FAP was significantly lower in Group 2 than in Group 1 (1.0 vs. 13 %, respectively). Pathological examination revealed an increased incidence of malignant polyps in the resected specimens from Group 2 patients (10 vs. 23 %, respectively; P = 0.034). Laparoscopic surgery was more frequent in Group 2 than in Group 1 (61 vs. 40 %, respectively). There was no surgical mortality in either group. CONCLUSION: Prophylactic surgery for FAP results in good short-term surgical outcomes in Japan. The current surgical approach is characterized by limited surgical indications for patients with attenuated FAP, delayed timing of colectomy, and the increasing standardization of laparoscopic surgery.

[Colon Polypectomy - And Then?]. / Polypektomie am Kolon - und dann?

Colorectal cancer (CRC) is the most frequent gastrointestinal tumour. Most CRC appear to arise from adenomas of the colon in a period of 10 or 15 years. The ultimately progression of benign adenomas to malignant CRC is known as the adenoma-carcinoma sequence. In addition, the description of the "serrated pathway" has shifted the focus of interest also towards to sessile serrated adenomas and traditional serrated adenomas in the development of CRC. It has been proven that the screening colonoscopy might prevent CRC by early detection of adenomatous polyps as precursors for colorectal cancer and polypectomy. Thus, disease-associated mortality of CRC could be reduced. Colonoscopy, the gold standard in CRC diagnosis, is recommended to men and women from the age of 55. On the one hand, there are requirements to the endoscopists. On the other hand there are also essential requirements to pathologists' findings. After polypectomy a risk stratification for aftercare based on endoscopic and histological findings is necessary. Endoscopic follow-up of high-risk patients (≥ 3 tubular adenomas, ≥ 1 adenoma ≥ 1 cm, tubulovillous or villous adenoma, ≥ 1 adenoma with high-grade intraepithelial neoplasia, ≥ 10 adenoma no matter what size or histological findings) should be done sooner (< 3 years). In contrast, colonoscopy in low-risk patients (1 or 2 [tubular] adenomas, size < 1 cm) should be performed later rather than sooner (> 5 years). Colonoscopic surveys under 12 months should be done only in exceptional and very serious situations. Pharmaceutical chemoprevention of adenomas or CRC are still part of clinical trails. More data are necessary.

[Chemoprevention for Familial Adenomatous Polyposis].

Colorectal cancer (CRC) is the second most common cancer in Japan. Primary cancer prevention is especially desired for hereditary CRC patients, owing to the high incidence of cancer in these patients. Prophylactic total proctocolectomy is generally accepted for young FAP patients; however, this procedure may reduce their QOL. If we could obtain effective chemopreventive drugs for FAP patients, prophylactic surgery could be postponed until the patients are older, or be avoided altogether. Thus, such drugs would bring large benefits to FAP patients. In this review, the history of chemopreventive drug development for FAP and the future prospects of chemopreventive drugs are described.

[Colorectal neo- and dysplasia in acromegaly].

Colorectal disorders can be not only an independent disease, but also manifestation of acromegaly--a neuroendocrine disease which is characterized by chronic pathological hypersecretion of the growth hormone (GH) and the increased concentration of insulino-like growth factor type 1 (IGF-1). In clinical recommendations on diagnosis and treatment of acromegaly, colonic polyps are marked as one of most pathognomonic manifestations of acromegaly. Prevalence of coloni polyps in acromegalic is 2,5-3 times higher than in the general population. Moreover, frequency of diverticula and dolichocolon is increased in patients with acromegaly compared with general population (in 3,6 and 12 times, accordingly). Colorectal cancer incidence with a tendency to more aggressive current is also increased (by 4,4 times). When these colonic diseases is diagnosed, especially in patients of young age, it is necessary to define the IGF-1 blood level as the first stage of acromegaly identification. If diagnosis of acromegaly is confirmed, gastroenterologist with endocrinologist together should direct treatment on correction of intestinal pathology as well as on achievement of the biochemical control over acromegaly.

Yogurt Prevents Colorectal Tumorigenesis in ApcMin/+ Mice.

SCOPE: Yogurt consumption is related to a decreased risk of colorectal cancer (CRC), but whether such association is causal remains unclear. Patients with familial adenomatous polyposis (FAP) are at increased risk of CRC development. Here, the study investigates the efficacy of yogurt for intestinal polyposis chemoprevention in ApcMin/+ mice, a preclinical model for human FAP. METHODS AND RESULTS: A 10-week yogurt supplementation (15 g kg-1) in ApcMin/+ mice significantly reduces the intestinal polyp number (6.50 ± 0.97 versus 1.80 ± 0.49; p < 0.001) compared to controls. 16S rRNA gene-based microbiota analysis suggests that yogurt supplementation may greatly modulate the gut microbiome composition, especially in the relative abundance of Lactobacillus and Bifidobacterium. Importantly, the fecal concentration of d-lactate (d-Lac, 0.39 ± 0.04 µmol g-1 versus 8.14 ± 0.62 µmol g-1; p < 0.001) is boosted by yogurt, while oral administration with d-Lac (125 or 250 mg kg-1) reduces the polyp number by 71.43% or 77.14% (p < 0.001), respectively. The study also observes that d-Lac does not affect cell viability and anchorage-independence in CRC cells, but it greatly suppresses epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cell transformation in preneoplastic cells. Mechanistically, it demonstrates that d-Lac may attenuate epithelial cell transformation by targeting PI3K/AKT/ß-catenin axis. CONCLUSION: Yogurt protects against intestinal polyposis in ApcMin/+ mice, and d-Lac may partially account for the chemopreventive effects above.

Chemoprevention of intestinal adenomatous polyposis by acetyl-11-keto-beta-boswellic acid in APC(Min/+) mice.

Acetyl-11-keto-beta-boswellic acid (AKBA) is a derivative of boswellic acid, which is an active component of the gum resin of Boswellia serrata. AKBA has been used as an adjuvant medication for treatment of inflammatory diseases. In this study, we aimed to evaluate the efficacy of AKBA as a chemopreventive agent against intestinal adenomatous polyposis in the adenomatous polyposis coli multiple intestinal neoplasia (APC(Min/+) ) mouse model. APC(Min/+) mice were administered AKBA by p.o. gavage for 8 consecutive weeks. The mice were sacrificed and the number, size and histopathology of intestinal polyps were examined by light microscopy. AKBA decreased polyp numbers by 48.9% in the small intestine and 60.4% in the colon. An even greater AKBA effect was observed in preventing the malignant progression of these polyps. The number of large (>3 cm) colonic polyposis was reduced by 77.8%. Histopathologic analysis demonstrated a significant reduction in the number of dysplastic cells and in the degree of dysplasia in each polyp after AKBA treatment. There was no evidence of high grade dysplasia or intramucosal carcinoma in any of the polyps examined within the treated group. More interestingly, interdigitated normal appearing intestinal villi were observed in the polyps of the treated group. During the course of the study, AKBA was well tolerated by the mice with no obvious signs of toxicity. Results from immunohistochemical staining, Western blotting and enzyme-linked immunosorbent assay indicated that the chemopreventive effect of AKBA was attributed to a collection of activities including antiproliferation, apoptosis induction, antiangiogenesis and anti-inflammation. AKBA was found to exert its chemopreventive action through the inhibition of the Wnt/ß-catenin and NF-κB/cyclooxygenase-2 signaling pathways. Our findings suggest that AKBA could be a promising regimen in chemoprevention against intestinal tumorigenesis.

Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of ß-catenin.

BACKGROUND & AIMS: Mutational inactivation of adenomatous polyposis coli (APC) is an early event in colorectal cancer (CRC) progression that affects the stability and increases the activity of ß-catenin, a mediator of Wnt signaling. Progression of CRC also involves inactivation of signaling via transforming growth factor ß and bone morphogenetic protein (BMP), which are tumor suppressors. However, the interactions between these pathways are not clear. We investigated the effects of loss of the transcription factor Smad4 on levels of ß-catenin messenger RNA (mRNA) and Wnt signaling. METHODS: We used microarray analysis to associate levels of Smad4 and ß-catenin mRNA in colorectal tumor samples from 250 patients. We performed oligonucleotide-mediated knockdown of Smad4 in human embryonic kidney (HEK293T) and in HCT116 colon cancer cells and transgenically expressed Smad4 in SW480 colon cancer cells. We analyzed adenomas from (APC(Δ1638/+)) and (APC(Δ1638/+)) × (K19Cre(ERT2)Smad4(lox/lox)) mice by using laser capture microdissection. RESULTS: In human CRC samples, reduced levels of Smad4 correlated with increased levels of ß-catenin mRNA. In Smad4-depleted cell lines, levels of ß-catenin mRNA and Wnt signaling increased. Inhibition of BMP or depletion of Smad4 in HEK293T cells increased binding of RNA polymerase II to the ß-catenin gene. Expression of Smad4 in SW480 cells reduced Wnt signaling and levels of ß-catenin mRNA. In mice with heterozygous disruption of Apc(APC(Δ1638/+)), Smad4-deficient intestinal adenomas had increased levels of ß-catenin mRNA and expression of Wnt target genes compared with adenomas from APC(Δ1638/+) mice that expressed Smad4. CONCLUSIONS: Transcription of ß-catenin is inhibited by BMP signaling to Smad4. These findings provide important information about the interaction among transforming growth factor ß, BMP, and Wnt signaling pathways in progression of CRC.

Helicobacter pylori is a risk factor for colonic neoplasms.

OBJECTIVES: It has been suggested that Helicobacter pylori (H. pylori) constitutes a risk for the development of adenomatous polyps and adenocarcinoma of the colon. Our aim was to study the association between H. pylori-positive gastritis and the occurrence of any colonic neoplasm. METHODS: From a computerized database of surgical pathology reports, we selected 156,000 subjects who underwent colonoscopy and esophago-gastro-duodenoscopy with biopsy results from both procedures. RESULTS: Compared with normal gastric mucosa, H. pylori gastritis occurred more frequently among patients with hyperplastic polyps (OR=1.24, 95% CI: 1.18-1.30), adenomatous polyps (1.52, 1.46-1.57), advanced adenomas (1.80, 1.69-1.92), villous adenomas or adenomas with high-grade dysplasia (1.97, 1.82-2.14), and adenocarcinomas (2.35, 1.98-2.80). Similarly, the strength of the association between H. pylori-positive gastritis and colonic neoplasm increased with size and number of the adenomas. The association between H. pylori gastritis and the occurrence of colonic neoplasm was similar for different locations of the large bowel. Other gastric conditions etiologically associated with H. pylori, such as intestinal metaplasia, adenoma, lymphoma, and adenocarcinoma, were also significantly associated with an increased risk of colonic neoplasm. CONCLUSIONS: Various forms of gastritis related to H. pylori infection confer an increased risk for colonic neoplasm. In the past, when H. pylori infection was more prevalent, its attributable risk to the occurrence of colorectal neoplasm may have been quite substantial.

Genetics, inheritance and strategies for prevention in populations at high risk of colorectal cancer (CRC).

Hereditary forms of colorectal cancer account for less than 5 % of colorectal cancer but attract disproportionate attention because they offer an opportunity for effective surgical prophylaxis, influence the health of the wider family and give insight into the critical pathways of carcinogenesis. Familial Adenomatous Polyposis (FAP) due to loss of the APC gene and Lynch syndrome or Hereditary Non-Polyposis Colon Cancer (HNPCC) due to breakdown in MisMatch Repair are the principal syndromes of broader interest and both have been the subject of chemoprevention trials. There has been a longstanding interest in non-steroidal anti inflammatories in FAP where trials have shown regression of polyps with the "pro drug"sulindac and the selective COX2 inhibitors though impact on long-term cancer risk is not confirmed. The CAPP1 trial focused on two interventions in a factorial design, aspirin and resistant starch or fermentable fibre. Resistant starch is not absorbed in the small intestine and undergoes colonic fermentation to short-chain fatty acids including butyrate which have anti-cancer effects. Polyposis registry clinicians across Europe recruited adolescents with FAP to receive aspirin (600 mg as 2 tablets/d) and/or 30 g as 2 sachets/d in a 1:1 blend of potato starch and high amylose maize starch [Hylon VII]) with placebo control for at least a year or until surgery before age 21. Fifty-nine percent (133/227) of recruits had a baseline and at least one other endoscopy. After a median of 17 months , the primary endpoint of a risk of an increased polyp number in the rectum and sigmoid colon was not significantly reduced in either treatment group with relative risks of 0.77 (aspirin; 95 % CI, 0.54-1.10;) and 1.05 (RS; 95 % CI, 0.73-1.49. The diameter of the largest polyp detected tended to be smaller in the aspirin arm. The planned subgroup analyses of patients who elected to continue on study for more than one year found a significant reduction in the size of the largest polyp in the aspirin versus non-aspirin group (p = 0.02), Mean crypt length decreased significantly over time on study in the two combined RS groups, compared with the two combined non-RS groups (p < 0.0001 for interaction), in a model of the interaction between intervention and time. In CAPP2, 1009 Lynch syndrome gene carriers were recruited from 43 international centres. 937 commenced intervention: 600 mg enteric coated aspirin and/or 30grams of the resistant starch Novelose in a 2 by 2 factorial placebo controlled design. After a mean of 29 months, intervention, there was no evidence that either agent influenced development of colonic neoplasia. However, the design included double blind follow-up for at least 10 years. After a mean of 55.7 months, and despite regular colonoscopy and polyp removal, 48 recruits developed CRC. Of these, 18 received aspirin and 30 received AP; the HR for CRC for aspirin was 0.63 (CI 0.35-1.13, p = 0.12). Five of the 48 people who developed CRC each had two primary colon cancers. Poisson regression analysis to allow for multiple primary events indicated a protective effect: IRR 0.56 (CI 0.32-0.99, p = 0.05). For those who took aspirin (or AP) for a minimum of 2 years (per protocol) the HR was 0.41 (CI 0.19-0.86 p = 0.02) and the IRR, 0.37 (CI 0.18-0.78 p = 0.008). Combined analysis of all LS cancers including CRC revealed a similar effect. On intention to treat analysis, the HR was 0.65 (CI 0.42-1.00, p = 0.05 and IRR was 0.59 (CI 0.39-0.90 p = 0.01), while the Per Protocol analysis HR was 0.45 (CI 0.26-0.79 p = 0.005,) and IRR was 0.42 (CI 0.25-0.72, p = 0.001). Adverse events in the aspirin and placebo groups were similar with 11 significant gastrointestinal bleeds or ulcers in the aspirin group and 9 in the placebo group. The evidence is now sufficient to recommend aspirin to all Lynch syndrome gene carriers. CAPP3 will recruit 3000 gene carriers into a dose inferiority study to test the relative benefits of 100mg, 300 or 600mg daily doses.

Azithromycin induces read-through of the nonsense Apc allele and prevents intestinal tumorigenesis in C3B6F1 ApcMin/+ mice.

Therapeutic strategies that promote read-through of a mutant gene have proved effective for certain non-neoplastic diseases. However, the efficacy of this approach is unproven regarding neoplastic diseases with germline nonsense mutations, including familial adenomatous polyposis. Here we examined the cancer-preventive efficacy of the macrolide antibiotic azithromycin, with a reported read-through effect, on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice harboring a nonsense Apc mutation resulting in a truncated Apc protein. Mice were given drinking water lacking azithromycin or containing 0.0125-0.2 mg/mL azithromycin from 3 weeks of age. The small intestine and cecum were analyzed for pathological changes and alterations of intestinal flora. Azithromycin suppressed the number of tumors and the proportion of adenocarcinomas, with the most effective drinking-water concentration being 0.0125 mg/mL. Furthermore, azithromycin recovered the cellular level of full-length Apc, resulting in downregulation of ß-catenin and cyclin D1. Conversely, the effect of azithromycin on the diversity of the intestinal microbiota depended on the drinking-water concentration. These results suggest that the balance between azithromycin-mediate read-through of mutant Apc mRNA and antibacterial effects influences intestinal tumorigenesis. Thus, azithromycin is a potential anticancer agent for familial adenomatous polyposis patients harboring nonsense mutations.

Theoretical basis validation and oxidative stress markers for cancer prevention clinical trials of aspirin.

Aspirin, a nonsteroidal anti-inflammatory drug, has been proven effective in a clinical trial of carcinogenesis blockade. However, various modes of action have been reported for these effects. Thus, in this study, we aimed to present reasonable mode of actions as a proof of concept for human trials, especially trials for patients with familial adenomatous polyposis (FAP). Aspirin treatment at 1000 ppm inhibited intestinal tumorigenesis in FAP model Min mice. As a mode of action, aspirin regulated ß-catenin signaling, inflammation, and oxidative stress both in vivo and in vitro. Furthermore, we examined novel markers predictive of aspirin treatment based on liquid biopsy. Here, we demonstrated that aspirin reduced the levels of reactive carbonyl species in the serum of Min mice. These data are expected to be of use for proof of concept of aspirin human trials and implied for the prediction of aspirin efficacy.

Chemoprevention of familial adenomatous polyposis by bromo-noscapine (EM011) in the Apc(Min/+) mouse model.

Germline mutation of the tumor suppressor gene, adenomatous polyposis coli (APC), is responsible for familial adenomatous polyposis (FAP) with nearly 100% risk for colon cancer at an early age. Although FAP is involved in only 1% of all colon cancer cases, over 80% of sporadic cancers harbor somatic mutations of APC. We show here that bromo-noscapine (EM011), a rationally designed synthetic derivative of a natural nontoxic tubulin-binding alkaloid-noscapine, that reduces the dynamics of microtubules, causes a reversible G(2) /M arrest in wild type murine embryonic fibroblasts (MEFs), but an aberrant exit from a brief mitotic block, followed by apoptosis in MEFs after APC deletion with small interfering RNA. Furthermore, both ß-catenin levels and activity fell to half the original levels with a concomitant reduction of cell proliferation-inducing cyclin D1, c-Myc, and induction of cytostatic protein p21 before caspase-3 activation. Additionally, we show a statistically significant reduction in the number of newly emerging intestinal polyps (to 35% compared with untreated mice) as well as the mean size of polyps (to 42% compared with untreated mice) in EM011-treated Apc(Min/+) mice as compared to their sham-treated control littermates. The remaining polyps in the EM011 treated group of Apc(Min/+) mice showed evidence of elevated apoptosis as revealed by immunohistochemistry. We failed to detect any evidence of histopathological and hematological toxicities following EM011 treatment. Taken together, our data are persuasive that a clinical trial of EM011 is possible for the prevention/amelioration of polyposis in FAP patients.

High-risk consumers' perceptions of preimplantation genetic diagnosis for hereditary cancers: a systematic review and meta-analysis.

Individuals carrying deleterious germline mutations placing them at increased risk for hereditary cancer syndromes (high-risk consumers) often have a great deal of fear and concern over transmitting mutations to their offspring, particularly conditions which are autosomal dominant. Preimplantation genetic diagnosis (PGD) is a procedure that can detect certain germline cancer predisposing mutations present in embryos. The objective of this review was to assess high-risk consumers' knowledge and perceptions of PGD for hereditary cancers. A systematic literature review was conducted through PubMed, Wiley Interscience, PsychInfo, and Cochrane Library databases to identify all articles assessing consumer knowledge and attitudes of PGD for hereditary cancer syndromes. We assessed heterogeneity and the robustness of findings through additional analyses according to study location, hereditary cancer type, and sample size. Thirteen articles remained eligible after the application of specific criteria. Results show a general low level of knowledge about PGD for hereditary cancers, moderate rates of acceptability among high-risk groups, and high levels of need for information about PGD. Individuals in specific risk groups such as those with a personal or family history of hereditary breast and ovarian cancer (HBOC) syndrome or familial adenomatous polyposis (FAP) may benefit from educational information from healthcare professionals about the use of PGD.