Familial Colorectal Cancer Research Articles

Clinical and Genetic Characteristics of Pediatric Colorectal Cancer.

Compared to colorectal cancer (CRC) in adults, CRC in children is extremely rare. Although its incidence has increased recently, there is a lack of clinical research on the disease. Inherited cancer susceptibility syndromes (ICSS), a group of disorders in which patients are predisposed to susceptibility to a wide range of tumors as a result of pathogenic mutations in genes in their germ line, are an important cause of CRC in children. Delayed diagnosis due to atypical clinical presentation, as well as limited awareness of ICSS among doctors, contributes to poor outcomes in juvenile CRC patients. Therefore, improving clinicians' understanding of the diagnosis and treatment of the disease is crucial to enhancing children's prognosis with CRC. Clinical data and laboratory reports were collected from eight pediatric patients diagnosed with CRC at the Children's Hospital of Nanjing Medical University between 2020 and 2023. The clinical and genetic characteristics of these patients were evaluated and compared with other patients with early-onset CRC in the literature. A total of 8 children with CRC were enrolled in the study, including 5 male and 3 female children, with a median age of 140 (73-177) months. The main clinical manifestations were unexplained abdominal pain, abdominal distension, vomiting, and hematochezia. Three cases of intestinal obstruction and two cases of intestinal intussusception occurred among the patients. All eight children underwent surgical treatment, including one case of snare resection of rectal polyp, five cases of subtotal colectomy, and two cases of radical resection of CRC. One case of radical resection of CRC utilized laparoscopic and colonoscopic combined resection guided by indocyanine green (ICG) fluorescence navigation system. Postoperative combination of pathological pictures and immunohistochemical (IHC) staining results confirmed high-grade squamous intraepithelial lesion (HSIL) in Case 1, and mucinous adenocarcinoma in the remaining seven cases. Out of eight pediatric patients with CRC, except for Case 1 and Case 7, who did not undergo chemotherapy, the remaining six patients all received postoperative chemotherapy; among them, the patients in Cases 1, 6, 7, and 8 achieved complete remission, whereas the patients in Cases 2 and 4 died due to postoperative recurrence and distant metastasis, the patient in Case 3 is still undergoing chemotherapy, and the patient in Case 5 was lost to follow-up after surgery. The results of the genetic test report showed that two children had ICSS caused by mismatch gene repair system defects (deficient MMR, dMMR); in Case 3, the child's genetic test results showed heterozygous mutation of MSH2 in the MMR gene, with high microsatellite instability (MSI-H), and the results of the methylation test of the MLH1 gene were negative, which, combined with the family history of heterozygous mutation of the MSH2 gene, ruled out sporadic CRC and led to the diagnosis of Lynch syndrome (LS); Case 8 genetic testing showed two heterozygous mutations in the MMR gene PMS2 with microsatellite stabilization (MSS), and a diagnosis of constitutional mismatch repair deficiency (CMMRD) was considered. Pediatric CRC is confronted with delayed diagnosis and poor clinical prognosis, mainly due to nonspecific clinical presentation and the low index of suspicion among clinicians. Early detection and diagnosis is the fundamental guarantee to improve the prognosis of pediatric CRC patients, and pediatric surgeons enhance the understanding of pediatric CRC and standardize the surgery as much as possible.

A Haplotype GWAS in Syndromic Familial Colorectal Cancer.

A previous genome-wide association study (GWAS) in colorectal cancer (CRC) patients with gastric and/or prostate cancer in their families suggested genetic loci with a shared risk for these three cancers. A second haplotype GWAS was undertaken in the same colorectal cancer patients and different controls with the aim of confirming the result and finding novel loci. The haplotype GWAS analysis involved 685 patients with colorectal cancer cases and 1642 healthy controls from Sweden. A logistic regression model was used with a sliding window haplotype approach. Whole-genome and exome sequencing datawere used to find candidate SNPs to be tested in a nested case-control study. In the analysis of 685 colorectal cancer cases and 1642 controls, all ten candidate loci from the previous study were confirmed. Fifty candidate loci were suggested with a p-value < 5 × 10-6 and odds ratios between 1.35-6.52. Two of the 50 loci, on 13q33.3 and 16q23.3, were the same as in the previous study. Whole-genome or exome data from 122 colorectal cancer patients was used to search for candidate variants in these 50 loci. A nested case-control study was performed to test genetic variants at 11 loci in a cohort of 827 familial colorectal cancer and a sub-cohort of 293 familial CRC cases with colorectal, gastric, and/or prostate cancer within their families and 1530 healthy controls. One SNP, rs115943733 on 10q11.21, reached statistical significance (OR = 3.26, p = 0.009). Seven SNPs in 4 loci had a higher OR in the smaller cohort compared to the larger study CRC cases. The results in this GWAS gave support for suggested loci with an increased shared risk of CRC, gastric, and/or prostate cancer. Further studies are needed to confirm the shared risk to be able to use this information in cancer prevention.

Colorectal cancer in Lynch syndrome families: consequences of gene germline mutations and the gut microbiota

BackgroundLynch syndrome (LS)-associated colorectal cancer (CRC) always ascribes to pathogenic germline mutations in mismatch repair (MMR) genes. However, the penetrance of CRC varies among those with the same MMR gene mutation. Thus, we hypothesized that the gut microbiota is also involved in CRC development in LS families.MethodsThis prospective, observational study was performed from December 2020 to March 2023. We enrolled 72 individuals from 9 LS families across six provinces in China and employed 16S rRNA gene amplicon sequencing to analyze the fecal microbiota components among LS-related CRC patients (AS group), their spouses (BS group), mutation carriers without CRC (CS group), and non-mutation carriers (DS group) using alpha and beta diversity indices.ResultsThere were no apparent differences in age or gender among the four groups. Alpha and beta diversity indices exhibited no significant differences between the AS and BS groups, verifying the role of germline mutations in the occurrence of CRC in LS families. Beta diversity analysis exhibited significant differences between the AS and CS groups, revealing the importance of the gut microbiota for the occurrence of CRC in LS families. A greater difference (both alpha and beta diversity indices) was shown between the AS and DS groups, demonstrating the combined impact of the gut microbiota and genetic germline mutations on the occurrence of CRC in LS families. Compared with those in the CS and DS groups, we identified ten microbial genera enriched in the AS group, and one genus (Bacteroides) decreased in the AS group. Among the elevated genera in the AS group, Agathobacter, Coprococcus and Prevotellaceae_NK3B31_group were butyrate-producing genera.ConclusionThis study found the development of CRC in the LS families can be attributed to the combined effects of gene germline mutations as well as the gut microbiota and provided novel insights into the prevention and treatment of CRC in the LS families.

New Insights into Aspirin's Anticancer Activity: The Predominant Role of Its Iron-Chelating Antioxidant Metabolites.

Epidemiological studies have suggested that following long-term, low-dose daily aspirin (LTLDA) administration for more than 5 years at 75-100 mg/day, 20-30% of patients (50-80 years old) had a lower risk of developing colorectal cancer (CRC) and about the same proportion in developing iron deficiency anemia (IDA). In cases of IDA, an increase in iron excretion is suspected, which is caused by aspirin chelating metabolites (ACMs): salicylic acid, salicyluric acid, 2,5-dihydroxybenzoic acid, and 2,3-dihydroxybenzoic acid. The ACMs constitute 70% of the administered aspirin dose and have much longer half-lives than aspirin in blood and tissues. The mechanisms of cancer risk reduction in LTLDA users is likely due to the ACM's targeting of iron involved in free radical damage, iron-containing toxins, iron proteins, and associated metabolic pathways such as ferroptosis. The ACMs from non-absorbed aspirin (about 30%) may also mitigate the toxicity of heme and nitroso-heme and other iron toxins from food, which are responsible for the cause of colorectal cancer. The mode of action of aspirin as a chelating antioxidant pro-drug of the ACMs, with continuous presence in LTLDA users, increases the prospect for prophylaxis in cancer and other diseases. It is suggested that the anticancer effects of aspirin depend primarily on the iron-chelating antioxidant activity of the ACMs. The role of aspirin in cancer and other diseases is incomplete without considering its rapid biotransformation and the longer half-life of the ACMs.

Search for germline gene variants in colorectal cancer families presenting with multiple primary colorectal cancers.

A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.

PTEN depletion reduces H3K27me3 levels to promote epithelial-to-mesenchymal transition in epithelial colorectal cancer cells.

Epithelial-to-mesenchymal (EMT) transition is one of the best-known examples of tumor cell plasticity. EMT enhances cancer cell metastasis, which is the main cause of colorectal cancer (CRC)-related mortality. Therefore, understanding underlying molecular mechanisms contributing to the EMT process is crucial to finding druggable targets and more effective therapeutic approaches in CRC. In this study, we demonstrated that phosphatase and tensin homolog (PTEN) knockdown (KD) induces EMT in epithelial CRC, likely through the activation of AKT. PTEN KD modulated chromatin accessibility and reprogrammed gene transcription to mediate EMT in epithelial CRC cells. Active AKT can phosphorylate enhancer of zeste homolog 2 (EZH2) on serine 21, which switches EZH2 from a transcriptional repressor to an activator. Interestingly, PTEN KD reduced the global levels of trimethylation of histone 3 at lysine 27(H3K27me3) in an EZH2-phosphorylation-dependent manner. Additionally, EZH2 phosphorylation at serine 21 reduced the interaction of EZH2 with another polycomb repressive complex 2 (PRC2) component, suppressor of zeste 12 (SUZ12), suggesting that the reduced H3K27me3 levels in PTEN KD cells were due to a disruption of the PRC2 complex. Overall, we demonstrated that PTEN KD modulates changes in gene expression to induce the EMT process in epithelial CRC cells by phosphorylating EZH2 and activates transcription factors such as activator protein 1 (AP1).

Berberine inhibits colorectal liver metastasis via modulation of TGF-β in a cecum transplant mouse model.

Hepatic metastasis is the primary cause of colorectal cancer (CRC)-induced death. Our previous results showed the anti-metastatic effects of Coptidis rhizoma using in vitro model. The present study aimed to investigate whether berberine, the main active compound of C. rhizoma, inhibits colon-liver metastasis in an animal model, and to elucidate the underlying mechanisms. Murine colon carcinoma (CT26) tumor tissue was implanted into the cecum of balb/c mice with/without oral administration of berberine (100mg/kg) for 21days, after which liver metastasis was evaluated. In addition, the pharmacological actions of berberine were explored using 5-fluorouracil-resistant human colon cancer cells (HCT116/R). The administration of berberine significantly decreased the number of tumor nodules in the liver, while significant activation of E-cadherin (an epithelial marker), and suppression of vimentin, Snail and TGF-β (mesenchymal markers) were observed in primary colon tumor tissues. Berberine treatment also notably lowered the levels of inflammatory cytokines (TGF-β, TNF- α, IL-6 and IL-1β) in the blood. In HCT116/R cells, berberine significantly inhibited migration and invasion and modulated the expression of TGF-β and representative molecules related to its pathway. The results obtained with a TGF-β inhibitor (SB431542) and a TGF-β siRNA, strongly suggest that the mechanism of action of berberine is linked to TGF-β signaling. In conclusion, berberine evidently possess an anti-colon-liver metastatic effect, and its underlying mechanisms involve the inhibition of epithelial-mesenchymal transition (EMT) through the TGF-β signaling pathway. Thus, we cautiously propose the pharmacological potential of berberine in drug research studies targeting hepatic metastasis from CRC.

Sessile Serrated Lesions: Searching for the True Prevalence and Risk Factors in China.

Growing recognition identifies sessile serrated lesions (SSL) as colorectal cancer (CRC) precursors. However, the SSL detection rate remains debatable and lacks a definitive consensus. Additionally, understanding the influencing factors in SSL development is limited. We aim to retrospectively analyze the true prevalence and risk factors of SSL in China. This retrospective study collected medical data from patients who underwent colonoscopy at the Endoscopy Center of Shanghai East Hospital affiliated with Tongji University between March 1, 2019 and February 28, 2022. Data were sourced through the electronic medical record system and included information such as age, sex, lesion location, number, and pathology. This study predominantly focused on the detection rate and the clinical and endoscopic features of SSL. Of 72 287 colonoscopies in 3 years, 3905 cases were histologically confirmed as SSL. Among them, 2290 (58.6%) were male, and 1615 (41.4%) were female. The overall SSL detection rate was 5.40%, slightly surpassing Asian/Chinese averages but lower than Western rates. Males had a higher SSL detection rate (6.1%) than females (4.6%). Univariate analysis revealed a significant association between SSL with dysplasia/adenocarcinoma (SSL-D/AD) and obesity (Body Mass Index, BMI ≥ 24), CRC family history, and hypertension. After multivariable logistic regression, only obesity (BMI ≥ 24) remained a statistically significant independent risk factor for SSL-D/AD. The SSL detection rate at our center is 5.4% and increases with age. Males have a significantly higher detection rate than females. Our findings suggest that endoscopists should consider risk factors for SSL-D/AD, such as obesity, CRC family history, and hypertension.

Nitrosyl-heme and heme iron intake from processed meats and risk of colorectal cancer in the EPIC-Spain cohort

The International Agency for Research on Cancer classified processed meats (PMs) as “carcinogenic” and red meat as “probably carcinogenic” for humans(1). The possible relationship between colorectal cancer (CRC) risk and processed meats (PMs), along with the specific compound contributing to this association have not been established yet. Nitrosyl-heme and heme iron have been proposed as potential-related compounds. The aim of this study was to assess the association of nitrosyl-heme and heme iron intake with CRC risk among participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) Spain study.This prospective study included 38,262 subjects (61.5% females) from the EPIC-Spain study. Food consumption was assessed by a validated diet history questionnaire(2). Dietary intake of nitrosylheme and heme iron was estimated by matching PMs intake and composition data based on laboratory analyses conducted using a High Performance Liquid Chromatography method(3). In brief, the daily intake of nitrosyl-heme and heme iron was determined by multiplying the intake of each PM (in grams/day) by its corresponding content of nitrosyl-heme and heme iron, and then summing up the estimated intakes from all PMs. The proportional hazards models were used to examine the association between sex-specific tertiles of nitrosyl-heme and heme iron intake and CRC risk and 95% confidence intervals (CIs) were computed using Cox regression. Age served as the time scale, stratified by age and centre with adjustments for sex, energy intake, body mass index (BMI), waist circumference, education, smoking, physical activity in MET-h/week, lifetime alcohol consumption, dietary fibre, calcium intake, and family CRC history. Homogeneity of location subtype risk was also assessed. Interactions with smoking, BMI, physical activity, and alcohol were examined and sensitivity analyses were also conducted excluding the first three years of follow-up.During a mean follow-up of 16.7 years, 577 CRC were identified. We found no overall association between nitrosyl-heme (T3 vs T1; HR: 0.98 (95% CI: 0.79-1.21)) or heme iron intakes (T3 vs T1; HR: 0.88 (95% CI: 0.70-1.10)) with CRC risk, nor according to tumour subtypes. However, we found a non-statistically significant positive association between nitrosyl-heme intake and proximal colon, HR = 1.03; 95% CI, (0.65-1.61) and rectum cancer, HR = 1.04; 95% CI, (0.70-1.56).Our study found no evidence supporting a link between nitrosyl-heme or heme iron intake and CRC risk in Spanish subjects from the EPIC cohort. As these results are novel and preliminary, more heterogeneous studies are necessary to provide more convincing evidence on their role in colorectal carcinogenesis.

Impact of metallic nanoparticles on gut microbiota modulation in colorectal cancer: A review.

Colorectal cancer (CRC) is the third most prevalent cancer. Ongoing research aims to uncover the causes of CRC, with a growing focus on the role of gut microbiota (GM) in carcinogenesis. The GM influences CRC development, progression, treatment efficacy, and therapeutic toxicities. For example, Fusobacterium nucleatum and Escherichia coli can regulate microbial gene expression through the incorporation of human small noncode RNA and potentially contribute to cancer progression. Metallic nanoparticles (MNPs) have both negative and positive impacts on GM, depending on their type. Several studies state that titanium dioxide may increase the diversity, richness, and abundance of probiotics bacteria, whereas other studies demonstrate dose-dependent GM dysbiosis. The MNPs offer cytotoxicity through the modulation of MAPK signaling pathways, NF-kB signaling pathways, PI3K/Akt signaling pathways, extrinsic signaling pathways, intrinsic apoptosis, and cell cycle arrest at G1, G2, or M phase. MNPs enhance drug delivery, enable targeted therapy, and may restore GM. However, there is a need to conduct well-designed clinical trials to assess the toxicity, safety, and effectiveness of MNPs-based CRC therapies.

The association of smoking and alcohol in colorectal cancer in black patients - Case-control study.

Studies have focused on smoking and alcohol as risk factors for colorectal cancer (CRC). Caucasians and other populations have been studied worldwide, and both smoking and alcohol have been validated as causes of CRC. However, there are limited data on the black population; studies that have been performed in Africa have not specifically focused on these two risk factors but rather in combination with other risks. To determine how smoking and alcohol affect the incidence of CRC in the African black population. Steve Biko Academic Hospital's gastrointestinal clinic. Subjects used for the study included black African patients above 18 years who had undergone a colonoscopy for suspected CRC between 2016 and 2018. Cases used were confirmed CRC on histology; controls were negative on histology. A minimum of 68 cases and 136 controls were needed for this study according to sample calculation. Hundred and ten cases and 220 controls were obtained in the final analysis. Data were collected between June 2019 and March 2020. Smoking (odds ratio [OR] = 1.795, p = 0.049) was a significant risk factor for CRC among black patients who presented at the gastrointestinal clinic. Age > 50 years (OR = 3.742, p < 0.001), family history (OR = 12.457, p < 0.001), and the combination of smoking and alcohol (OR = 5.927, p = 0.008) were significant risk factors. Interestingly, alcohol alone was protective (OR = 0.205, p < 0.001). Both smoking and a combination of alcohol and smoking are significant risk factors in the development of CRC in the black African population. Smoking, as in most population groups, is a risk factor for CRC. The observed protective role of alcohol needs to be confirmed in larger studies representing the African population.

S507 The Impact of the COVID-19 Pandemic on an Established Hereditary Colon Cancer Registry

S507 The Impact of the COVID-19 Pandemic on an Established Hereditary Colon Cancer Registry

Abstract B152: Joint Associations of Neighborhood Socioeconomic Status and Education on the Incidence of Colorectal Cancer: The Multiethnic Cohort Study

Abstract Background: Colorectal cancer (CRC) is the 3rd most diagnosed cancer worldwide. When considered separately, both neighborhood- and individual-level SES exposures have been associated with CRC incidence. However, the joint associations of neighborhood- and individual-level SES on CRC incidence have not been examined. Methods: In a prospective study of 153,725 Multiethnic Cohort (MEC) participants (24,764 African American, 44,447 Japanese American, 34,974 Latino, 11,511 Native Hawaiian, and 38,029 White participants) recruited from predominantly Los Angeles County, California (CA), and Hawaii (HI), we examined the joint association of neighborhood SES (nSES) and individual-level education with CRC incidence (CA: 2,519, HI: 2,210 cases). Education, other demographics, and health behaviors were self-reported in the baseline questionnaire (1993-1996). CRC diagnosis was determined via linkages with state cancer registries. nSES was derived using a composite score based on 1990 US Census block group data and assigned to geocoded baseline addresses. Our joint SES measure included four categories: high nSES (quintiles 4-5) and high education (&amp;gt; high school), high nSES and low education (≤ high school), low nSES (quintiles 1-3) and high education, and low nSES and low education. State-specific hazards ratios (HR) for CRC incidence were estimated for joint SES categories. Cox regression adjusted for age at cohort entry, CRC family history, polyp history, obesity, diabetes, diet, alcohol, smoking, physical activity, and NSAID, multivitamin, and hormone therapy use. Subgroup analyses were conducted by sex, race, and ethnicity. Results: For HI MEC participants, compared to individuals with high nSES and high education, risk for CRC was highest among those with low nSES and low education (HR=1.27; 95% CI:1.11-1.45) followed by high nSES and low education (HR=1.25; 95% CI:1.12-1.41), and low nSES and high education (HR=1.17; 95% CI: 1.03-1.31). This pattern of association was observed across sex but differed across race and ethnicity (p-heterogeneity=0.04). The overall pattern of association was observed among White participants in HI. However, for Japanese American individuals in HI, compared to those with high nSES and high education, risk for CRC was highest for low nSES and high education (HR=1.29; 95% CI:1.09-1.53) and high nSES and low education (HR= 1.28; 95% CI; 1.10-1.50). For Native Hawaiian individuals, compared to those with high nSES and high education, CRC risk was highest for those with low nSES and low education (HR=1.70; 95% CI: 1.20-2.42). Associations were not statistically significant between the joint SES measure and CRC risk in CA (HRs: 0.92-0.97). Conclusion: Among MEC participants in HI, CRC risk varied with the joint measure of nSES and education across racial and ethnic groups. These findings emphasize the importance of considering the joint associations of neighborhood- and individual-level SES in understanding racial and ethnic disparities in CRC. Citation Format: Catherine Walsh, Meera Sangaramoorthy, Songyi Park, Sung-shim (Lani) Park, Gertraud Maskarinec, Lynne Wilkens, Christopher Haiman, Anna Wu, Salma Shariff-Marco, Loic Le Marchand, Iona Cheng. Joint Associations of Neighborhood Socioeconomic Status and Education on the Incidence of Colorectal Cancer: The Multiethnic Cohort Study [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr B152.

Combining Colonoscopy With Fecal Immunochemical Test Can Improve Current Familial Colorectal Cancer Colonoscopy Surveillance: A Modelling Study

The authors assessed whether familial colorectal cancer (FCRC) surveillance in individuals without hereditary CRC can be optimized METHODS: The Adenoma and Serrated Pathway to Colorectal Cancer (ASCCA)-FCRC model simulates CRC development in individuals with a family history of CRC at 2-fold and 4-fold increased CRC risk compared with the general population. The authors simulated a strategy without surveillance, the current Dutch guideline (5-yearly colonoscopy between ages 45 and 75 years), and the following 3 sets of alternative strategies: colonoscopy surveillance, surveillance combining colonoscopy and fecal immunochemical testing (FIT), and FIT-based surveillance. Each set included a range of strategies differing in age range and test interval. The optimal strategy was defined as the strategy with highest quality-adjusted life-years (QALYs) satisfying all of the following criteria: in the (near-)efficiency area of the cost-effectiveness frontier and compared with current surveillance; noninferior effectiveness; no substantial increase in colonoscopy burden; and not more expensive. The optimal strategy was 10-yearly colonoscopy with 2-yearly FIT between colonoscopies from ages 40 to 80 years for both 2-fold and 4-fold increased CRC risk. At 2-fold risk, this strategy prevented 0.8 more CRC deaths, gained 15.8 more QALYs at 731 fewer colonoscopies, and saved €98,000 over the lifetime of 1000 individuals compared with current surveillance. At 4-fold risk, figures were 2.1 more CRC deaths prevented, 37.0 more QALYs gained at 567 fewer colonoscopies, and €127,000 lower costs. Current surveillance was not (near-)efficient. FIT could play an important role in FCRC surveillance. Surveillance with 10-yearly colonoscopy and 2-yearly FIT between colonoscopies from ages 40 to 80 years increased QALYs and reduced colonoscopy burden and costs compared with current FCRC surveillance.

The RP11-417E7.1/THBS2 signaling pathway promotes colorectal cancer metastasis by activating the Wnt/β-catenin pathway and facilitating exosome-mediated M2 macrophage polarization

BackgroundMetastasis is the major cause of colorectal cancer (CRC) mortality. Emerging evidence suggests that long noncoding RNAs (lncRNAs) drive cancer metastasis and that their regulatory pathways could be targeted for preventing metastasis. However, the underlying mechanisms of lncRNAs in CRC metastasis remain poorly understood.MethodsMicroarray analysis was used to screen for differentially expressed lncRNAs. Transwell assays, fibronectin cell adhesion assays, and mouse metastasis models were utilized to evaluate the metastatic capacities of CRC in vitro and in vivo. Chromatin isolation by RNA purification, chromatin immunoprecipitation and chromosome conformation capture were applied to investigate the underlying mechanism involved. qRT‒PCR and transmission electron microscopy were performed to confirm macrophage polarization and the presence of cancer-derived exosomes.ResultsThe lncRNA RP11-417E7.1 was screened and identified as a novel metastasis-associated lncRNA that was correlated with a poor prognosis. RP11-417E7.1 enhances the metastatic capacity of CRC cells in vivo and in vitro. Mechanistically, RP11-417E7.1 binding with High mobility group A1 (HMGA1) promotes neighboring thrombospondin 2 (THBS2) transcription via chromatin loop formation between its promoter and enhancer, which activates the Wnt/β-catenin signaling pathway and facilitates CRC metastasis. Furthermore, exosomes derived from CRC cells transport THBS2 into macrophages, thereby inducing the M2 polarization of macrophages to sustain the prometastatic microenvironment. Notably, netropsin, a DNA-binding drug, suppresses chromatin loop formation mediated by RP11-417E7.1 at the THBS2 locus and significantly inhibits CRC metastasis in vitro and in vivo.ConclusionsThis study revealed the novel prometastatic function and mechanism of the lncRNA RP11-417E7.1, which provides a potential prognostic indicator and therapeutic target in CRC.

The two faces of Blastocystis spp.: is it the cause of colorectal cancer (CRC) or a consequence of it?

IntroductionOver the last few years, there has been an increase in the prevalence of &lt;i&gt;Blastocystis&lt;/i&gt; spp. in colorectal cancer (CRC) patients. Moreover, various in vitro and in vivo studies have highlighted that intestinal colonisation of &lt;i&gt;Blastocystis&lt;/i&gt; spp. has an influence on host immune responses leading to cellular apoptosis and membrane permeability. It has been suggested that &lt;i&gt;Blastocystis&lt;/i&gt; spp. is an important risk factor for the worsening of CRC.AimTo present evidence concerning the association between CRC and &lt;i&gt;Blastocystis&lt;/i&gt; spp.Material and methodsA review of the literature was performed by searching Science Direct, PubMed, Scopus and Google Scholar databases up to December, 2023.Results and discussionOut of all in vitro and in vivo studies selected for this review, the majority of them have confirmed a significantly higher prevalence of &lt;i&gt;Blastocystis&lt;/i&gt; spp. in colorectal cancer patients in comparison to the control groups. Several in vitro human colorectal carcinoma cell line studies have shown significant cytopathic and immunological effects of &lt;i&gt;Blastocystis&lt;/i&gt; spp. Additionally, in vivo experimental animal model studies have shown that &lt;i&gt;Blastocystis&lt;/i&gt; spp. infection significantly contributed to large intestinal polyp (colorectal adenoma) formation and the progression of colorectal carcinogenesis.ConclusionsThese studies strongly support suggestions that &lt;i&gt;Blastocystis&lt;/i&gt; spp. could be an important factor to existing CRC development by influencing the host immune response and increasing oxidative damage.

Hereditary Colorectal Cancer: From Diagnosis to Surgical Options

AbstractHereditary colorectal cancer (CRC) syndromes account for up to 5% of CRC. Patients have an increased risk of CRC and extracolonic cancers, both of which develop at an early age. The main polyposis syndromes include familial adenomatous polyposis, MYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and PTEN hamartoma syndrome. The non-polyposis syndromes include Lynch syndrome and familial colorectal cancer type X. Each of the syndromes have distinct but sometimes overlapping phenotypes. Clinical evaluation and ultimately the underlying germline genetic pathogenic variants define the syndromes. Each syndrome has polyp, CRC, and extracolonic risks and management is based on early and timely surveillance with therapeutic and often extended prophylactic surgery. Surgical intervention strategies are individualized, considering not only the earlier onset of malignancies and heightened risks for metachronous cancers but also the patient's needs and quality of life. This article reviews the different diagnostic approaches to hereditary CRC and highlights subsequent disease-specific management and surgical decision-making strategies.

Exploring the genetic and epigenetic underpinnings of early-onset cancers: Variant prioritization for long read whole genome sequencing from family cancer pedigrees.

Despite significant advances in our understanding of genetic cancer susceptibility, known inherited cancer predisposition syndromes explain at most 20% of early-onset cancers. As early-onset cancer prevalence continues to increase, the need to assess previously inaccessible areas of the human genome, harnessing a trio or quad family-based architecture for variant filtration, may reveal further insights into cancer susceptibility. To assess a broader spectrum of variation than can be ascertained by multi-gene panel sequencing, or even whole genome sequencing with short reads, we employed long read whole genome sequencing using an Oxford Nanopore Technology (ONT) PromethION of 3 families containing an early-onset cancer proband using a trio or quad family architecture. Analysis included 2 early-onset colorectal cancer family trios and one quad consisting of two siblings with testicular cancer, all with unaffected parents. Structural variants (SVs), epigenetic profiles and single nucleotide variants (SNVs) were determined for each individual, and a filtering strategy was employed to refine and prioritize candidate variants based on the family architecture. The family architecture enabled us to focus on inapposite variants while filtering variants shared with the unaffected parents, significantly decreasing background variation that can hamper identification of potentially disease causing differences. Candidate d e novo and compound heterozygous variants were identified in this way. Gene expression, in matched neoplastic and pre-neoplastic lesions, was assessed for one trio. Our study demonstrates the feasibility of a streamlined analysis of genomic variants from long read ONT whole genome sequencing and a way to prioritize key variants for further evaluation of pathogenicity, while revealing what may be missing from panel based analyses.

A preliminary enrichment analysis of tumor genes in patients suffering from rectal cancer with and without CNS metastasis.

e16381 Background: Colorectal cancers have been touted as the third most common cancer and the third leading cause of cancer death worldwide. Of these, rectal cancers often have a more favorable outcome, and are generally responsive to chemotherapy and radiation, due to metastasis limited to local tissues via lymphatics. However, in recent years, cases of rectal cancer with distant metastasis to the CNS have been noted at an urban community hospital serving a primarily Hispanic population in central New Jersey. Methods: We used genetic data from 51 patients at our local cancer center over 5 years to delineate risk factors associated with CNS metastasis. Of these patients, two had CNS metastasis with available tumor genetic information. We performed a gene enrichment analysis to determine phenotypic terms and molecular pathways associated with each gene set using Enrichr. Results: Of 51 patients, genetic data was available on 20, of which 18 had rectal cancer without CNS metastasis. Mutations involving 23 genes were found in this cohort, analysis of which found enrichment of the terms “Lynch Syndrome” and “Constitutional mismatch repair deficiency syndrome”, which are classically implicated in CRCs. In addition, enrichment of the terms “rectal cancer childhood”, “colorectal cancer childhood”, and “Familial colorectal cancer” were found. Of the two patients who had metastasis to the CNS, mutations involving 14 genes were found. Interestingly, both patients had mutations involving KRAS. Analysis of these genes found enrichment of the terms “pilomyxoid astrocytoma”, “giant cell glioblastoma” and “gliosarcoma”. Interestingly, common to both cohorts were the classic CRC-associated genes KRAS, APC and TP53, further solidifying their role in general CRCs. Conclusions: While this study is ongoing, preliminary data suggest that genetic analysis of tumors in patients with rectal cancer can determine whether a patient is susceptible to CNS metastasis. Given the heterogeneity of these cancers, further studies involving tumor and germ-line genetic analysis, which follow patients longitudinally may benefit in predicting which tumors are prone to CNS metastasis before they metastasize.

A GWAS in Swedish colorectal cancer families with gastric and prostate cancer.

e15644 Background: We have previously suggested a syndrome with increased risk for colorectal- and other cancers, primarily gastric- and prostate cancer. The data favoured this syndrome inherited as a complex disease. Therefore, we conducted a Genome Wide Association Study (GWAS) on colorectal cancer patients, who’s relatives had prostate-, and/or gastric cancer. Methods: The GWAS analysis consisted of 685 cases of colorectal cancer and 4780 healthy controls from Sweden. A sliding window haplotype analysis was conducted using a logistic regression model.Thereafter, we performed sequencing to find candidate variants, finally to be tested in a nested case-control study. Results: Candidate loci/genes on ten chromosomal regions were suggested with odds ratios (ORs) between 1.71-3.62 and p-values &lt; 5x10-8 in the analysis. The regions suggested were 1q32.2, 3q29, 4q35.1, 4p15.31, 4q26, 8p23.1, 13q33.3, 13q13.3, 16q23.3 and 22q11.21. All regions, except one on 1q32.2, had protein coding genes, many already shown to be involved in cancer, such as ZDHHC19, SYNPO2, PCYT1A, MYO16, TXNRD2, COMT, and CDH13. Sequencing of 122 colorectal cancer patients with gastric- and prostate cancer in their families identified 10 candidate variants from six of the loci in the haplotype regions to finally be tested in a nested case-control study of similar colorectal cancer cases and controls. Conclusions: There was some support for an increased risk of colorectal-, gastric-, and/or prostate cancer in all the six loci tested. [Table: see text]