Familial Colorectal Cancer Research Articles

P188 Cumulative inflammatory burden as a risk factor for colorectal neoplasia in inflammatory bowel disease patients with primary sclerosing cholangitis: a multi-center case-control study

Abstract Background Inflammatory bowel disease (IBD) patients with concomitant primary sclerosing cholangitis (PSC-IBD) have a 25-year cumulative risk of up to 50% to develop colorectal neoplasia (CRN). Mucosal inflammation is an important driver of CRN, but it is unknown whether this also applies to PSC-IBD patients. We aimed to assess the impact of chronic mucosal inflammation per colonic segment on CRN risk in PSC-IBD patients. Methods This is a multi-center case-control study including cases with PSC-IBD and CRN and controls with PSC-IBD without CRN. Subjects were included from 8 medical centers in Canada and the Netherlands. Exclusion criteria were a CRN diagnosis prior to IBD or PSC diagnosis, familial CRC syndromes, and <2 available colonoscopy reports. Data was collected on demographics, IBD and PSC disease characteristics, CRN lesions, and endoscopy reports between 1977 and 2023. Pan-colonic and segmental (right colon, transverse colon, left colon, rectum) endoscopic cumulative inflammatory burden scores were calculated as the sum of (mean) endoscopic inflammation severity between colonoscopies x length of the surveillance interval until index procedure. The index procedure was the colonoscopy during which CRN was detected (cases) or randomly selected and matched for disease duration (controls). The primary outcome was a CRN diagnosis, secondary outcomes were CRN grade and location, time to CRN (Kaplan-Meier curve), pan-colonic cumulative inflammatory burden, cumulative inflammatory burden per colonic segment harboring CRN, and colonic surgery. Results We included 335 PSC-IBD patients (224 UC, 101 CD) with a median follow-up of 8 years (IQR: 5.0-14.0) and 6 endoscopies (IQR: 4.0-8.0). Median disease duration was 19.5 years for IBD (IQR: 11.0-26.0) and 13 years for PSC (IQR: 7.0-19.0). Advanced neoplasia (HGD or CRC) was found in 35 out of 102 cases (34%). Fifty-six (55%) cases were diagnosed with > 1 lesion, and 43 (42%) had ≥ 1 right-sided lesion. Median time to index CRN was 17 years (IQR: 8.0-24.0). Sixty-six patients underwent (sub)total colectomy or proctocolectomy, including 49 (74%) due to CRN diagnosis. There was no difference in pan-colonic cumulative inflammatory burden scores (mean scores: 4.7 (cases) and 3.7 (controls); P=0.21, 95%-CI: -2.52-.56) and segmental scores (mean scores: 4.9 (cases) and 4.1 (controls); P=0.27, 95%-CI: -2.29-.65) between cases and controls. Mortality was 13% (n=45.) Conclusion In this large multi-center cohort study, the risk for CRN-associated colectomy in PSC-IBD was high, while pan-colonic and segmental cumulative inflammatory burden scores were not associated with CRN risk.

Genetic association of circulating interleukins and risk of colorectal cancer: A bidirectional Mendelian randomization study.

Previous studies have reported that inflammation, especially interleukin family members, plays an important role in the development of colorectal cancer (CRC). However, because of various confounders and the lack of clinical randomized controlled trial, the causal relationship between genetically predicted level of interleukin family and CRC risk has not been fully explained. Bi-directional Mendelian randomization (MR) was conducted to investigate the causal association between interleukin family members and CRC. Several genetic variables were extracted as instrumental variables (IVs) from summary data of genome-wide association studies (GWAS) for interleukin and CRC. IVs of interleukin family were obtained from recently published GWAS studies and the summary data of CRC was from FinnGen Biobank. After a series of quality control measures and strict screening, six models were used to evaluate the causal relationship. Pleiotropy, heterogeneity test, and a variety of sensitivity analysis were also used to estimate the robustness of the model results. Genetically predicted higher circulating levels of IL-2 (odds ratio [OR]: 0.76; 95% confidence interval [CI]: 0.63-0.92; p = .0043), IL-17F(OR: 0.78; 95% CI: 0.62-1.00; p = .015), and IL-31 (OR: 0.88; 95% CI: 0.79-0.98; p = .023) were suggestively associated with decreased CRC risk. However, higher level of IL-10 (OR: 1.40; 95% CI: 1.18-1.65; p = .000094) was causally associated with increased risk of CRC. Reverse MR results indicated that the exposure of CRC was suggestively associated with higher levels of IL-36α (OR: 1.23; 95% CI: 1.01-1.49; p = .040) and IL-17RD (OR: 1.22; 95% CI, 1.00-1.48; p = .048) and lower level of IL-13 (OR: 0.78; 95% CI: 0.65-0.95; p = .013). The overall MR results did not provide evidence for causal relationships between other interleukins and CRC (p > .05). We offer suggestive evidence supporting a potential causal relationship between circulating interleukins and CRC, underscoring the significance of targeting circulating interleukins as a strategy to mitigate the incidence of CRC.

SUB1 promotes colorectal cancer metastasis by activating NF-κB signaling via UBR5-mediated ubiquitination of UBXN1.

Metastasis accounts for the major cause of colorectal cancer (CRC) related mortality due to the lack of effective treatments. In this study, we integrated the single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data and identified the transcriptional coactivator SUB1 homolog (Sac-Saccharomyces cerevisiae)/PC4 (positive cofactor 4) associated with CRC metastasis. Elevated SUB1 expression was correlated with advanced tumor stage and poor survival in CRC. In vivo and vitro assays showed that SUB1 depletion could inhibit the invasive and metastatic abilities of CRC cells. SUB1 activated NF-κB signaling and its transcriptional target genes CXCL1 and CXCL3 to drive CRC metastasis. Mechanistically, SUB1 integrated with the E3 ubiquitin-protein ligase UBR5 and increased its protein level in CRC cells. Subsequently, the increased UBR5 mainly mediated Lys11-linked polyubiquitination and degradation of NF-κB negative regulator UBXN1, thus to activate the NF-κB signaling. Overall, our study demonstrated that SUB1 promoted CRC progression by modulating UBR5/UBXN1 and activating NF-κB signaling, providing a new therapeutic strategy for treating metastatic CRC through targeting SUB1.

Intratumoral presence of the genotoxic gut bacteria pks+E. coli, Enterotoxigenic Bacteroides fragilis, and Fusobacterium nucleatum and their association with clinicopathological and molecular features of colorectal cancer

BackgroundThis study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks+Escherichia coli (pks+E.coli+), pks+E.coli- (non-E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum (F. nucleatum).MethodsWe screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR.ResultsPks+E.coli+ was associated with male sex (P < 0.01) and APC:c.835-8 A > G somatic mutation (P = 0.03). The association between pks+E.coli+ and APC:c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P = 0.02). The APC:c.835-A > G was not associated with pks+E.coli- (P = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF:c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes (Ps < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups (Ps < 0.01).ConclusionIntratumoral pks+E.coli+ but not pks+E.coli- are associated with CRCs harbouring the APC:c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures. F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.

Nonsense suppression induces read-through of a novel BMPR1A variant in a Chinese family with hereditary colorectal cancer.

BMPR1A-mediated signaling transduction plays an essential role in intestinal growth. Variations of BMPR1A lead to a rare autosomal dominant inherited juvenile polyposis syndrome (JPS) with high probability of developing into colorectal cancer (CRC). Nonsense and frameshift variations, generating premature termination codons (PTCs), are the most pathogenic variants in the BMPR1A gene. This study aimed to investigate the molecular genetic etiology in a Chinese family with three generations of CRC. Pathogenic variants of 18 known CRC susceptibility genes were examined in a Chinese CRC family through multigene panel testing using the next-generation sequencing platform. The candidate gene variant was validated in the family members by Sanger sequencing. Potential biological functions of the gene variant were further investigated in the RKO colon cancer cell line. A novel nonsense variant (c.1114A>T, p.Lys372*) of BMPR1A was identified in the CRC family. This variant generated a PTC at the kinase domain and caused nonsense-mediated mRNA decay. Read-through inducing reagents G418 and PTC124 partially restored BMPR1A expression and its following signaling pathway. The identification of the novel BMPR1A variant enriched the genotype-phenotype spectrum of BMPR1A. Meanwhile, our finding also provided support for future PTC-targeting therapy for BMPR1A-mediated JPS and CRC.

Direct letters to relatives at risk of hereditary cancer—study protocol for a multi-center randomized controlled trial of healthcare-assisted versus family-mediated risk disclosure at Swedish cancer genetics clinics (DIRECT-study)

Background The results of germline genetic testing for hereditary cancer are of importance not only to the patients under investigation but also to their genetic at-risk relatives. Standard care is to encourage the proband (first family member under investigation) to pass on this risk information to the relatives. Previous research suggests that with family-mediated disclosure, only about a third of at-risk relatives contact health care to receive genetic counselling. In some studies, complementing family-mediated risk disclosure with healthcare-assisted risk disclosure almost doubles the uptake of genetic counselling in at-risk relatives. In this study, we evaluate healthcare-assisted direct letters to relatives at risk of hereditary cancer syndromes in a randomized controlled trial.MethodsProbands are recruited from Swedish outpatient cancer genetics clinics to this two-arm randomized controlled trial. The study recruits probands with either a pathogenic variant in a cancer susceptibility gene (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2) or probands with familial breast and colorectal cancer based on clinical and pedigree criteria. In both arms, probands receive standard care, i.e., are encouraged and supported to pass on information to relatives. In the intervention arm, the proband is also offered to have direct letters sent to the at-risk relatives. The primary outcome measure is the proportion of at-risk relatives contacting a Swedish cancer genetics clinic within 12 months of the proband receiving the test results.DiscussionThis paper describes the protocol of a randomized controlled clinical trial evaluating a healthcare-assisted approach to risk disclosure by offering the probands to send direct letters to their at-risk relatives. The results of this study should be informative in the future development of risk disclosure practices in cancer genetics clinics.Trial registrationClinicalTrials.gov. Identifier NCT04197856 (pre-trial registration on December 13, 2019).Also registered at the website “RCC Cancerstudier i Sverige” as study #86719.

XAF1 promotes colorectal cancer metastasis via VCP-RNF114-JUP axis.

Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment.

Inherited BRCA1 and RNF43 pathogenic variants in a familial colorectal cancer type X family

AbstractGenetic susceptibility to familial colorectal cancer (CRC), including for individuals classified as Familial Colorectal Cancer Type X (FCCTX), remains poorly understood. We describe a multi-generation CRC-affected family segregating pathogenic variants in both BRCA1, a gene associated with breast and ovarian cancer and RNF43, a gene associated with Serrated Polyposis Syndrome (SPS). A single family out of 105 families meeting the criteria for FCCTX (Amsterdam I family history criteria with mismatch repair (MMR)-proficient CRCs) recruited to the Australasian Colorectal Cancer Family Registry (ACCFR; 1998–2008) that underwent whole exome sequencing (WES), was selected for further testing. CRC and polyp tissue from four carriers were molecularly characterized including a single CRC that underwent WES to determine tumor mutational signatures and loss of heterozygosity (LOH) events. Ten carriers of a germline pathogenic variant BRCA1:c.2681_2682delAA p.Lys894ThrfsTer8 and eight carriers of a germline pathogenic variant RNF43:c.988 C &gt; T p.Arg330Ter were identified in this family. Seven members carried both variants, four of which developed CRC. A single carrier of the RNF43 variant met the 2019 World Health Organization (WHO2019) criteria for SPS, developing a BRAF p.V600 wildtype CRC. Loss of the wildtype allele for both BRCA1 and RNF43 variants was observed in three CRC tumors while a LOH event across chromosome 17q encompassing both genes was observed in a CRC. Tumor mutational signature analysis identified the homologous recombination deficiency (HRD)-associated COSMIC signatures SBS3 and ID6 in a CRC for a carrier of both variants. Our findings show digenic inheritance of pathogenic variants in BRCA1 and RNF43 segregating with CRC in a FCCTX family. LOH and evidence of BRCA1-associated HRD supports the importance of both these tumor suppressor genes in CRC tumorigenesis.

Impact of Various Risk Factors on the Positive Fecal Immunochemical Test for Colorectal Cancer in the Iranian Population.

Background: Colorectal cancer (CRC) is the most prevalent cancer with high mortality worldwide. We aimed to evaluate the incidence of CRC based on the positive fecal immunochemical test (FIT) result in the Iranian population. Methods: The present study was conducted on the health assessment data recorded in the SINA (Integrated Health Information System) in 2018 and 2019 from individuals who had participated in the national program, including asymptomatic people aged 50-69 years or had risk factors of CRC such as family or past personal history of CRC as well as symptomatic individuals, for the early detection and prevention of CRC in Mashhad, Iran. Results: The study participants included 140,463 eligible individuals, of whom 8258 (5.88%) and 145 (2.21%) were positive for FIT and diagnosed with colon cancer, respectively. Unfortunately, only 654 people had undergone colonoscopy. Our results indicated that age, fast food intake (≥two units per day), family history of CRC in first or second-degree relatives, some gastrointestinal diseases such as inflammatory bowel disease (IBD) and CRC, as well as bleeding per anus, constipation, abdominal cramp, and losing body weight were associated with increased risk of positive FIT. However, some other factors, including having a hard job, physical activity, and Iranian nationality (compared to non-Iranians), were associated with a low risk of positive FIT screening tests for CRC. Conclusion: A high number of high-risk persons in Mashhad were positive for the FIT test in 2018-2019, and many of them were diagnosed with CRC, according to the colonoscopy results. Therefore, screening is highly recommended as the first step in the early detection of CRC.

In silico whole-transcriptome analysis reveals a potential hsa_circ_0000375-miR-424-5p-TPM2/SRPX/SRGAP1 regulatory network related to liver metastasis of colorectal cancer

Liver metastasis is the main lethal cause of colorectal cancer (CRC). The knowledge of role and mechanism of circular RNA (circRNA) in liver metastasis of CRC is still inadequate. In this study, whole-transcriptome analysis was performed using three datasets (GSE147597, GSE147602 and GSE147603). A total of 14 potential circRNAs were identified, after which their structural patterns and binding miRNAs were obtained. Next, 45 differentially expressed miRNAs (DEmiRNAs) between CRC without and with liver metastasis were acquired, consisting 38 upregulated and 7 downregulated miRNAs. After conducting intersection analysis, expression validation and correlation analysis, miR-761 and miR-424-5p were selected as the most potential miRNAs linked to liver metastasis of CRC. Subsequently, the target genes of miR-761 or miR-424-5p were predicted and differentially expressed genes (DEGs) between CRC without and with liver metastasis were obtained. 257 genes that were commonly appeared in predicted genes and DEGs were significantly enriched in “epithelial-to-mesenchymal transition” and “signaling by Robo receptor”. Among these enriched genes, only TPM2, SRPX and SRGAP1 were significantly negatively correlated with miR-424-5p and were positively linked to hsa_circ_0000375 in CRC without or with liver metastasis. Collectively, the current findings elucidated a potential hsa_circ_0000375-miR-424-5p-TPM2/SRPX/SRGAP1 network contributing to liver metastasis of CRC.

Translation, cultural adaptation, and psychometric testing of the Supportive care needs survey for partners and caregivers for Swedish family members of persons diagnosed with colorectal cancer

BackgroundColorectal cancer is the third most common cancer diagnosis globally and is increasing in both incidence and prevalence. Despite evidence showing that family members of persons diagnosed with cancer have supportive care needs, no validated questionnaire measuring the needs of family members of persons diagnosed with CRC exists in Swedish. Thus, the objective of the present study was to translate, culturally adapt, and evaluate the psychometric properties the Supportive Care Needs Survey – Partners and Caregivers 45.MethodsThe translation and cultural adaptation followed a systematic yet iterative process. Firstly, the questionnaire was translated using a forward–backward approach. Secondly, face and content validity and comprehensibility were evaluated by two expert panels of colorectal cancer specialist nurses and family members, respectively. Lastly, the psychometric properties, validity, and reliability of the translated questionnaire were evaluated among 45 Swedish family members of persons diagnosed with colorectal cancer.ResultsThe face, content, and construct validity of the translated questionnaire were evaluated as satisfying. Moreover, psychometric evaluations showed high data quality and satisfactory internal consistency. However, the results also revealed unsolved issues regarding relevance, targeting, and internal consistency, as well as a probable scaling failure.ConclusionThe translated and adapted questionnaire can be used to identify family members unmet needs of support throughout the colorectal cancer trajectory. The questionnaire showed promising validity and reliability in the target population. However, it needs to be further evaluated in a larger sample, preferably involving factor analysis and stability over time.

Long-term benefits and harms of early colorectal cancer screening in German individuals with familial cancer risk.

Individuals with a family history of colorectal cancer (CRC) may benefit from early screening with colonoscopy or immunologic fecal occult blood testing (iFOBT). We systematically evaluated the benefit-harm trade-offs of various screening strategies differing by screening test (colonoscopy or iFOBT), interval (iFOBT: annual/biennial; colonoscopy: 10-yearly) and age at start (30, 35, 40, 45, 50 and 55 years) and end of screening (65, 70 and 75 years) offered to individuals identified with familial CRC risk in Germany. A Markov-state-transition model was developed and used to estimate health benefits (CRC-related deaths avoided, life-years gained [LYG]), potential harms (eg, associated with additional colonoscopies) and incremental harm-benefit ratios (IHBR) for each strategy. Both benefits and harms increased with earlier start and shorter intervals of screening. When screening started before age 50, 32-36 CRC-related deaths per 1000 persons were avoided with colonoscopy and 29-34 with iFOBT screening, compared to 29-31 (colonoscopy) and 28-30 (iFOBT) CRC-related deaths per 1000 persons when starting age 50 or older, respectively. For iFOBT screening, the IHBRs expressed as additional colonoscopies per LYG were one (biennial, age 45-65 vs no screening), four (biennial, age 35-65), six (biennial, age 30-70) and 34 (annual, age 30-54; biennial, age 55-75). Corresponding IHBRs for 10-yearly colonoscopy were four (age 55-65), 10 (age 45-65), 15 (age 35-65) and 29 (age 30-70). Offering screening with colonoscopy or iFOBT to individuals with familial CRC risk before age 50 is expected to be beneficial. Depending on the accepted IHBR threshold, 10-yearly colonoscopy or alternatively biennial iFOBT from age 30 to 70 should be recommended for this target group.

S2365 Unusual Suspect: Hereditary Colon Cancer Due to BRIP-1 Germline Mutation

S2365 Unusual Suspect: Hereditary Colon Cancer Due to BRIP-1 Germline Mutation

Astragaloside IV inhibits AOM/DSS-induced colitis-associated tumorigenesis via activation of PPARγ signaling in mice

BackgroundColitis-associated colorectal cancer (CAC) is a severe complication of inflammatory bowel disease (IBD), resulting from long-term inflammation in the intestines. The primary cause of CAC is the imbalance of oxidative metabolism in intestinal cells, triggered by excessive reactive oxygen (ROS) and nitrogen (NO) species production due to prolonged intestinal inflammation. This imbalance leads to genomic instability caused by DNA damage, eventually resulting in the development of intestinal cancer. Previous studies have demonstrated that astragaloside IV is effective in treating dextran sulfate sodium salt (DSS)-induced colitis, but there is currently no relevant research on its efficacy in treating CAC. MethodsTo investigate the effect of astragaloside IV against CAC and the underlying mechanism, C57 mice were treated with (20, 40, 80 mg/kg) astragaloside IV while CAC was induced by intraperitoneal injection of 10 mg/kg azoxymethane (AOM) and ad libitum consumption of 2% dextran sulfate sodium salt (DSS). We re-verified the activating effects of astragaloside IV on PPARγ signaling in IEC-6 cells, which were reversed by GW9662 (the PPARγ inhibitor). ResultsOur results showed that astragaloside IV significantly improved AOM/DSS-induced CAC mice by inhibiting colonic shortening, preventing intestinal mucosal damage, reducing the number of tumors and, the expression of Ki67 protein. In addition, astragaloside IV could activate PPARγ signaling, which not only promoted the expression of Nrf2 and HO-1, restored the level of SOD, CAT and GSH, but also inhibited the expression of iNOS and reduced the production of NO in the intestine and IEC-6 cells. And this effect could be reversed by GW9662 in vitro. Astragaloside IV thus decreased the level of ROS and NO in the intestinal tract of mice, as well as reduced the damage of DNA, and therefore inhibited the occurrence of CAC. ConclusionAstragaloside IV can activate PPARγ signaling in intestinal epithelial cells and reduces DNA damage caused by intestinal inflammation, thereby inhibiting colon tumourigenesis. The novelty of this study is to use PPARγ as the target to inhibit DNA damage to prevent the occurrence of CAC.

Investigation of the enhanced antitumour potency of CD46-specific chimeric antigen receptor-T cells in human colorectal cancer liver metastases after combination with nanotherapeutics

Liver metastasis is the major cause of colorectal cancer (CRC)-related death, and 1/4 CRC patients present liver metastases at first diagnosis. Despite significant improvements in metastatic CRC, the long-term outcome remains poor. Chimeric antigen receptor (CAR)-T cell therapy represents a powerful strategy with superior efficacy for personalized cancer. Herein, CRC and adjacent non-tumor tissues from patients with liver metastasis were subjected to mass spectrometry (MS) analysis to identify differentially expressed proteins. CD46 was upregulated in CRC tissues, particularly for CRC liver metastasis (CRLM), and critically associated with poor prognosis in different cohorts. Consistently, CD46 promoted aggressive behaviors and liver metastasis ability of CRC cells, indicating that CD46 was a prognostic factor in patients with CRLM. Mechanistically, CD46 transformed T cells into Tregs by binding to the Lcp1, thus protecting CRC cells from immune surveillance. CD46-CAR T cells were constructed and significantly regressed tumors in NCG mice bearing CD46-overexpressed CRC cells, along with little cytotoxicity to CD46-low-expressed cells. Meanwhile, CD46-CAR T cells showed robust antitumor activity in an established PDX xenograft model, which was enhanced by RANTES/IL15 cytokines. Moreover, folic acid-modified magnesium silicate hollow nanospheres containing cytokines IL-2, IL15, and CCL5 (FA_IL/CCL) were designed and exhibited excellent biodegradable and biocompatible properties. FA_IL/CCL efficiently potentiated the immune efficacy of CD46-CAR T cells by suppressing the proliferation and liver metastasis in CD46 high-expressed CRC PDX mice. Collectively, our findings highlight that CD46-CAR T cell therapy may provide a potential in the treatment of human CRLM, nanotherapeutics will potentiate the immune efficacy with good biosafety.

Low Incidence of Colorectal Advanced Neoplasia During Surveillance in Individuals with a Family History of Colorectal Cancer

BackgroundFamily history of colorectal cancer (CRC) is used to stratify individuals into risk categories which determine timing of initial screening and ongoing CRC surveillance. Evidence for long-term CRC risk following a normal index colonoscopy in family history populations is limited.AimsTo assess the incidence of advanced neoplasia and associated risk factors in a population undergoing surveillance colonoscopies due to family history of CRC.MethodsSurveillance colonoscopy findings were examined in 425 individuals with a family history of CRC, a normal index colonoscopy and a minimum of 10 years of follow-up colonoscopies. Advanced neoplasia risk was determined for three CRC family history categories (near-average, medium and high-risk), accounting for demographics and time after the first colonoscopy.ResultsThe median follow-up was 13.5 years (IQR 11.5–16.0), with an incidence of advanced neoplasia of 14.35% (61/425). The number of affected relatives and age of CRC diagnosis in the youngest relative did not predict the risk of advanced neoplasia (p > 0.05), with no significant differences in advanced neoplasia incidence between the family history categories (p = 0.16). Patients ≥ 60 years showed a fourfold (HR 4.14, 95% CI 1.33–12.89) higher advanced neoplasia risk during surveillance than those < 40 years at index colonoscopy. With each subsequent negative colonoscopy, the risk of advanced neoplasia at ongoing surveillance was reduced.ConclusionsThe incidence of advanced neoplasia was low (14.35%), regardless of the family history risk category, with older age being the main risk for advanced neoplasia. Delaying onset of colonoscopy or lengthening surveillance intervals could be a more efficient use of resources in this population.

A Challenging Case: Colorectal Cancer During Pregnancy

Introduction: Colorectal cancer (CRC) occurring in younger women can lead to an increased incidence of colorectal cancer during pregnancy. The estimated frequency of malignancy during pregnancy with colorectal cancer specifically estimated at 1 in 13,000 pregnancies. However, the exact causes of colorectal cancer during pregnancy are not yet fully understood. Diagnosing and managing colorectal cancer during pregnancy pose significant challenges because the symptoms can be masked by the normal signs and symptoms of pregnancy. Case Pesentation: A 42-year-old pregnant patient, Mrs. L, presented with abdominal pain, a history of dark-colored bowel movements, and a lump on the left side of her neck that had been present for a year. She had also experienced a weight loss of 5 kg both before and during pregnancy, and there was no previous history of malignancy. The patient underwent various diagnostic procedures, including pregnancy ultrasound, abdominal ultrasound, and colonoscopy biopsy. Based on the comprehensive evaluation of the patient's medical history, physical examination, and supporting tests, she was diagnosed with stage IV rectal adenocarcinoma with metastases to the liver, kidney, and lymph nodes. The patient was in her second pregnancy (G2P1Ab0) at 27-29 weeks of gestation. Conclusion: Colorectal cancer during pregnancy poses diagnostic and therapeutic challenges, as the signs and symptoms are often attributed to the normal progression of pregnancy, resulting in delayed diagnosis at an advanced stage. Early detection, evaluation, and monitoring of nonspecific symptoms are crucial, and a multidisciplinary approach is necessary for the management of colorectal cancer during pregnancy.

Immune microenvironment profiling of normal appearing colorectal mucosa biopsied over repeat patient visits reproducibly separates lynch syndrome patients based on their history of colon cancer.

Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC), increasing lifetime risk of CRC by up to 70%. Despite this higher lifetime risk, disease penetrance in LS patients is highly variable and most LS patients undergoing CRC surveillance will not develop CRC. Therefore, biomarkers that can correctly and consistently predict CRC risk in LS patients are needed to both optimize LS patient surveillance and help identify better prevention strategies that reduce risk of CRC development in the subset of high-risk LS patients. Normal-appearing colorectal tissue biopsies were obtained during repeat surveillance colonoscopies of LS patients with and without a history of CRC, healthy controls (HC), and patients with a history of sporadic CRC. Biopsies were cultured in an ex-vivo explant system and their supernatants were assayed via multiplexed ELISA to profile the local immune signaling microenvironment. High quality cytokines were identified using the rxCOV fidelity metric. These cytokines were used to perform elastic-net penalized logistic regression-based biomarker selection by computing a new measure - overall selection probability - that quantifies the ability of each marker to discriminate between patient cohorts being compared. Our study demonstrated that cytokine based local immune microenvironment profiling was reproducible over repeat visits and sensitive to patient LS-status and CRC history. Furthermore, we identified sets of cytokines whose differential expression was predictive of LS-status in patients when compared to sporadic CRC patients and in identifying those LS patients with or without a history of CRC. Enrichment analysis based on these biomarkers revealed an LS and CRC status dependent constitutive inflammatory state of the normal appearing colonic mucosa. This prospective pilot study demonstrated that immune profiling of normal appearing colonic mucosa discriminates LS patients with a prior history of CRC from those without it, as well as patients with a history of sporadic CRC from HC. Importantly, it suggests the existence of immune signatures specific to LS-status and CRC history. We anticipate that our findings have the potential to assess CRC risk in individuals with LS and help in preemptively mitigating it by optimizing surveillance and identifying candidate prevention targets. Further studies are required to validate our findings in an independent cohort of LS patients over multiple visits.

Understanding the Hereditary Factors in Cancer- Recent Insights and Developments: An Updated Review

Background: Although cancer (Ca) etiology can be multifactorial, it is nearly universally intertwined with genetic mutations that instigate tumor genesis or progression. This updated review aims at describing if this dispute remains meaningful based on a thorough literature survey. Methodology: This updated review was conducted over the last 2.5 decades using 3 (three) search engines: Web of Science (WoS), Pubmed and Science direct that encompassed all associated information and hypothetical considerations, globally, utilizing information from 1998 through 2022. All such, concepts, logically deducted explanations and scientifically assumed points if Ca remains hereditary is the main focus of this review. Results/ Findings: This appraisal on cancer, though yielded some instances of hereditariness in origin, mostly remains of genetic origin. Reportedly, cancers can be passed down from one family member to another through genes, and, may cause by genetic mutation present in eggs or sperms cell during fertilization which are actually considered as hereditary cancer, like breast, colon, and prostate cancer, as well as less common cancers, viz., pancreatic and ovarian cancer. Therefore, understanding the hereditary factors of Ca is critical not only for assessing the genetic contribution to cancer, but also for designing preventive and therapeutic strategies. It allows identifying people who are at a higher risk due to family history and/or genetic makeup, allow early detection through improved surveillance and, more importantly, for tailored therapeutic modality. By addressing recent advancement, this review will provide an overview on the hereditary factors of cancers and/or raising awareness on significant role of development in Ca genetics. The Journal of Ad-din Women's Medical College; Vol. 11 (2), July 2023; p 48-57

PLA2G12A as a Novel Biomarker for Colorectal Cancer with Prognostic Relevance

Metastasis is the leading cause of colorectal cancer (CRC)-related deaths. Therefore, the identification of accurate biomarkers predictive of metastasis is needed to better stratify high-risk patients to provide preferred management and reduce mortality. In this study, we identified 13 new genes that modified circulating tumor cell numbers using a genome-wide genetic screen in a whole animal CRC model. Candidate genes were subsequently evaluated at the gene expression level in both an internal human CRC cohort of 153 patients and an independent cohort from the TCGA including 592 patients. Interestingly, the expression of one candidate, PLA2G12A, significantly correlated with both the time to recurrence and overall survival in our CRC cohort, with its low expression being an indicator of a poor clinical outcome. By examining the TCGA cohort, we also found that low expression of PLA2G12A was significantly enriched in epithelial–mesenchymal transition signatures. Finally, the candidate functionality was validated in vitro using three different colon cancer cell lines, revealing that PLA2G12A deficiency increases cell proliferation, migration, and invasion. Overall, our study identifies PLA2G12A as a prognostic biomarker of early-stage CRC, providing evidence that its deficiency promotes tumor growth and dissemination.