BMPR2 as a Novel Predisposition Gene for Hereditary Colorectal Polyposis.

BACKGROUND & AIMS: Colorectal cancer (CRC) is one of the most prevalent tumors worldwide, with incidence quickly increasing (particularly in the context of early-onset cases), despite important prevention efforts, mainly in the form of population-wide screening programs. Although many cases present a clear familial component, the current list of hereditary CRC genes leaves a considerable proportion of the cases unexplained. METHODS: In this work, we used whole-exome sequencing approaches on 19 unrelated patients with unexplained colonic polyposis to identify candidate CRC predisposition genes. The candidate genes were then validated in an additional series of 365 patients. CRISPR-Cas9 models were used to validate BMPR2 as a potential candidate for CRC risk. RESULTS: We found 8 individuals carrying 6 different variants in the BMPR2 gene (approximately 2% of our cohort of patients with unexplained colonic polyposis). CRISPR-Cas9 models of 3 of these variants showed that the p.(Asn442Thrfs∗32) truncating variant completely abrogated BMP pathway function in a similar way to the BMPR2 knockout. Missense variants p.(Asn565Ser), p.(Ser967Pro) had varying effects on cell proliferation levels, with the former impairing cell control inhibition via noncanonical pathways. CONCLUSIONS: Collectively, these results support loss-of-function BMPR2 variants as candidates to be involved in CRC germline predisposition.

Linked-color imaging versus high definition white-light endoscopy for evaluation of post-polypectomy scars of nonpedunculated lesions: LCI-Scar study.

BACKGROUND: Detection and treatment of recurrence after piecemeal endoscopic mucosal resection of nonpedunculated colorectal polyps are crucial for avoidance of post-colonoscopy cancer. Linked-color imaging (LCI) has demonstrated improved polyp detection but has never been assessed for evaluation of post-polypectomy scars. Our aim was to compare sensitivity and negative predictive value (NPV) between LCI and white-light endoscopy (WLE) for detection of post-polypectomy recurrence. METHODS: Patients undergoing surveillance colonoscopy after resection of lesions ≥15 mm were included in this prospective, single-center, randomized, crossover study. Each post-polypectomy scar underwent two examinations, one with LCI and the other with WLE, performed by two blinded endoscopists. Blue-light imaging (BLI) was then applied. A diagnosis of recurrence with a level of confidence was made for each modality and histopathology was the gold standard. RESULTS: 129 patients with 173 scars were included. Baseline patient, lesion, and procedural characteristics were similar in both arms. Recurrence was detected in 56/173 (32.4%), with 27/56 (48.2%) adenomas and 29/56 (51.8%) serrated lesions. LCI had greater sensitivity (96.4% [95%CI 87.8%-99.5%]) versus WLE (89.3% [95%CI 78.1%-95.9%]) and greater NPV (98.1% [95%CI 93.4%-99.8%] versus 94.6% [95%CI 88.7%-98.0%]). Paired concordance between modalities was 96.0%. In discordant cases, LCI identified four true-positive cases not detected by WLE and reclassified one false-positive of WLE. WLE reclassified two false positives of LCI without any increase in recurrence detection. CONCLUSIONS: LCI was highly accurate and had greater ability than WLE to rule out recurrence on post-polypectomy scars after resection of large polyps.

CTNND1 is involved in germline predisposition to early-onset gastric cancer by affecting cell-to-cell interactions.

BACKGROUND: CDH1 and CTNNA1 remain as the main genes for hereditary gastric cancer. However, they only explain a small fraction of gastric cancer cases with suspected inherited basis. In this study, we aimed to identify new hereditary genes for early-onset gastric cancer patients (EOGC; < 50 years old). METHODS: After germline exome sequencing in 20 EOGC patients and replication of relevant findings by gene-panel sequencing in an independent cohort of 152 patients, CTNND1 stood out as an interesting candidate gene, since its protein product (p120ctn) directly interacts with E-cadherin. We proceeded with functional characterization by generating two knockout CTNND1 cellular models by gene editing and introducing the detected genetic variants using a lentiviral delivery system. We assessed ß-catenin and E-cadherin levels, cell detachment, as well as E-cadherin localization and cell-to-cell interaction by spheroid modeling. RESULTS: Three CTNND1 germline variants [c.28_29delinsCT, p.(Ala10Leu); c.1105C > T, p.(Pro369Ser); c.1537A > G, p.(Asn513Asp)] were identified in our EOGC cohorts. Cells encoding CTNND1 variants displayed altered E-cadherin levels and intercellular interactions. In addition, the p.(Pro369Ser) variant, located in a key region in the E-cadherin/p120ctn binding domain, showed E-cadherin mislocalization. CONCLUSIONS: Defects in CTNND1 could be involved in germline predisposition to gastric cancer by altering E-cadherin and, consequently, cell-to-cell interactions. In the present study, CTNND1 germline variants explained 2% (3/172) of the cases, although further studies in larger external cohorts are needed.

Germline mutations in WNK2 could be associated with serrated polyposis syndrome.

BACKGROUND: Patients with serrated polyposis syndrome (SPS) have multiple and/or large serrated colonic polyps and higher risk for colorectal cancer. SPS inherited genetic basis is mostly unknown. We aimed to identify new germline predisposition factors for SPS by functionally evaluating a candidate gene and replicating it in additional SPS cohorts. METHODS: After a previous whole-exome sequencing in 39 SPS patients from 16 families (discovery cohort), we sequenced specific genes in an independent validation cohort of 211 unrelated SPS cases. Additional external replication was also available in 297 SPS cases. The WNK2 gene was disrupted in HT-29 cells by gene editing, and WNK2 variants were transfected using a lentiviral delivery system. Cells were analysed by immunoblots, real-time PCR and functional assays monitoring the mitogen-activated protein kinase (MAPK) pathway, cell cycle progression, survival and adhesion. RESULTS: We identified 2 rare germline variants in the WNK2 gene in the discovery cohort, 3 additional variants in the validation cohort and 10 other variants in the external cohorts. Variants c.2105C>T (p.Pro702Leu), c.4820C>T (p.Ala1607Val) and c.6157G>A (p.Val2053Ile) were functionally characterised, displaying higher levels of phospho-PAK1/2, phospho-ERK1/2, CCND1, clonogenic capacity and MMP2. CONCLUSION: After whole-exome sequencing in SPS cases with familial aggregation and replication of results in additional cohorts, we identified rare germline variants in the WNK2 gene. Functional studies suggested germline WNK2 variants affect protein function in the context of the MAPK pathway, a molecular hallmark in this disease.

Use of multi-gene panels in patients at high risk of hereditary digestive cancer: position statement of AEG, SEOM, AEGH and IMPaCT-GENÓMICA consortium. / Uso de paneles de genes en pacientes con alto riesgo de cáncer digestivo hereditario: documento de posicionamiento de la AEG, SEOM, AEGH y consorcio IMPaCT-GENÓMICA.

This position statement, sponsored by the Asociación Española de Gastroenterología, the Sociedad Española de Oncología Médica, the Asociación Española de Genética Humana and the IMPaCT-Genómica Consortium aims to establish recommendations for use of multi-gene panel testing in patients at high risk of hereditary gastrointestinal and pancreatic cancer. To rate the quality of the evidence and the levels of recommendation, we used the methodology based on the GRADE system (Grading of Recommendations Assessment, Development and Evaluation). We reached a consensus among experts using a Delphi method. The document includes recommendations on clinical scenarios where multi-gene panel testing is recommended in colorectal cancer, polyposis syndromes, gastric and pancreatic cancer, as well as the genes to be considered in each clinical scenario. Recommendations on the evaluation of mosaicisms, counseling strategies in the absence of an index subject and, finally, constitutional analysis after identification of pathogenic tumor variants are also made.

Screening uptake of colonoscopy versus fecal immunochemical testing in first-degree relatives of patients with non-syndromic colorectal cancer: A multicenter, open-label, parallel-group, randomized trial (ParCoFit study).

BACKGROUND: Colonoscopy screening is underused by first-degree relatives (FDRs) of patients with non-syndromic colorectal cancer (CRC) with screening completion rates below 50%. Studies conducted in FDR referred for screening suggest that fecal immunochemical testing (FIT) was not inferior to colonoscopy in terms of diagnostic yield and tumor staging, but screening uptake of FIT has not yet been tested in this population. In this study, we investigated whether the uptake of FIT screening is superior to the uptake of colonoscopy screening in the familial-risk population, with an equivalent effect on CRC detection. METHODS AND FINDINGS: This open-label, parallel-group, randomized trial was conducted in 12 Spanish centers between February 2016 and December 2021. Eligible individuals included asymptomatic FDR of index cases <60 years, siblings or ≥2 FDR with CRC. The primary outcome was to compare screening uptake between colonoscopy and FIT. The secondary outcome was to determine the efficacy of each strategy to detect advanced colorectal neoplasia (adenoma or serrated polyps ≥10 mm, polyps with tubulovillous architecture, high-grade dysplasia, and/or CRC). Screening-naïve FDR were randomized (1:1) to one-time colonoscopy versus annual FIT during 3 consecutive years followed by a work-up colonoscopy in the case of a positive test. Randomization was performed before signing the informed consent using computer-generated allocation algorithm based on stratified block randomization. Multivariable regression analysis was performed by intention-to-screen. On December 31, 2019, when 81% of the estimated sample size was reached, the trial was terminated prematurely after an interim analysis for futility. Study outcomes were further analyzed through 2-year follow-up. The main limitation of this study was the impossibility of collecting information on eligible individuals who declined to participate. A total of 1,790 FDR of 460 index cases were evaluated for inclusion, of whom 870 were assigned to undergo one-time colonoscopy (n = 431) or FIT (n = 439). Of them, 383 (44.0%) attended the appointment and signed the informed consent: 147/431 (34.1%) FDR received colonoscopy-based screening and 158/439 (35.9%) underwent FIT-based screening (odds ratio [OR] 1.08; 95% confidence intervals [CI] [0.82, 1.44], p = 0.564). The detection rate of advanced colorectal neoplasia was significantly higher in the colonoscopy group than in the FIT group (OR 3.64, 95% CI [1.55, 8.53], p = 0.003). Study outcomes did not change throughout follow-up. CONCLUSIONS: In this study, compared to colonoscopy, FIT screening did not improve screening uptake by individuals at high risk of CRC, resulting in less detection of advanced colorectal neoplasia. Further studies are needed to assess how screening uptake could be improved in this high-risk group, including by inclusion in population-based screening programs. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT02567045).

Eflornithine plus Sulindac for Prevention of Progression in Familial Adenomatous Polyposis.

BACKGROUND: The efficacy and safety of combination therapy with eflornithine and sulindac, as compared with either drug alone, in delaying disease progression in patients with familial adenomatous polyposis are unknown. METHODS: We evaluated the efficacy and safety of the combination of eflornithine and sulindac, as compared with either drug alone, in adults with familial adenomatous polyposis. The patients were stratified on the basis of anatomical site with the highest polyp burden and surgical status; the strata were precolectomy (shortest projected time to disease progression), rectal or ileal pouch polyposis after colectomy (longest projected time), and duodenal polyposis (intermediate projected time). The patients were then randomly assigned in a 1:1:1 ratio to receive 750 mg of eflornithine, 150 mg of sulindac, or both once daily for up to 48 months. The primary end point, assessed in a time-to-event analysis, was disease progression, defined as a composite of major surgery, endoscopic excision of advanced adenomas, diagnosis of high-grade dysplasia in the rectum or pouch, or progression of duodenal disease. RESULTS: A total of 171 patients underwent randomization. Disease progression occurred in 18 of 56 patients (32%) in the eflornithine-sulindac group, 22 of 58 (38%) in the sulindac group, and 23 of 57 (40%) in the eflornithine group, with a hazard ratio of 0.71 (95% confidence interval [CI], 0.39 to 1.32) for eflornithine-sulindac as compared with sulindac (P = 0.29) and 0.66 (95% CI, 0.36 to 1.24) for eflornithine-sulindac as compared with eflornithine. Among 37 precolectomy patients, the corresponding values in the treatment groups were 2 of 12 patients (17%), 6 of 13 (46%), and 5 of 12 (42%) (hazard ratios, 0.30 [95% CI, 0.07 to 1.32] and 0.20 [95% CI, 0.03 to 1.32]); among 34 patients with rectal or ileal pouch polyposis, the values were 4 of 11 patients (36%), 2 of 11 (18%), and 5 of 12 (42%) (hazard ratios, 2.03 [95% CI, 0.43 to 9.62] and 0.84 [95% CI, 0.24 to 2.90]); and among 100 patients with duodenal polyposis, the values were 12 of 33 patients (36%), 14 of 34 (41%), and 13 of 33 (39%) (hazard ratios, 0.73 [95% CI, 0.34 to 1.52] and 0.76 [95% CI, 0.35 to 1.64]). Adverse and serious adverse events were similar across the treatment groups. CONCLUSIONS: In this trial involving patients with familial adenomatous polyposis, the incidence of disease progression was not significantly lower with the combination of eflornithine and sulindac than with either drug alone. (Funded by Cancer Prevention Pharmaceuticals; ClinicalTrials.gov number, NCT01483144; EudraCT number, 2012-000427-41.).

A Liquid Biopsy Signature for the Detection of Patients With Early-Onset Colorectal Cancer.

BACKGROUND & AIMS: Early-onset colorectal cancer (EOCRC) is a distinct clinical and molecular entity with poor survival outcomes compared with late-onset CRC. Although the incidence of EOCRC is rising, current CRC screening strategies have several limitations in diagnostic performance for EOCRC. In view of this clinical challenge, novel and robust biomarkers for detection of EOCRC are necessary. The aim of this study was to develop a circulating micro RNA (miRNA) signature for the diagnosis of patients with EOCRC. METHODS: A systematic discovery approach by analyzing a large, publicly available, noncoding RNA expression profiling dataset (GSE115513) was used. A panel of miRNAs was identified, which was subsequently validated in blood samples from patients with EOCRC in 2 independent cohorts (n = 149) compared with controls (n = 110) and pre/postoperative plasma specimens (n = 22) using quantitative reverse-transcription polymerase chain reaction assays. RESULTS: In the discovery phase, 4 miRNAs were found to be expressed in blood samples. A combination signature of these 4 miRNAs (miR-193a-5p, miR-210, miR-513a-5p, and miR-628-3p) yielded an area under the curve of 0.92 (95% confidence interval, 0.85-0.96) for identification of EOCRC in the training cohort. The miRNA panel performance was then confirmed in an independent validation cohort (area under the curve, 0.88; 95% confidence interval, 0.82-0.93). Moreover, the miRNA panel robustly identified patients with early-stage EOCRC (P < .001). The decreased expression of miRNAs in postsurgery plasma specimens indicated their tumor specificity. CONCLUSIONS: Our novel miRNA signature for the diagnosis of EOCRC has the potential to identify patients with EOCRC with high accuracy for clinical application in the noninvasive diagnosis of EOCRC.

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

Motorized Spiral Enteroscopy Is Effective in Patients with Prior Abdominal Surgery.

BACKGROUND: Motorized Spiral Enteroscopy (MSE) reduces procedure time and increases insertion depth into the small bowel; however, there is scarce evidence on factors affecting MSE efficacy. AIMS: To evaluate diagnostic yield and adverse events of MSE including patients with prior major abdominal surgery. METHODS: A prospective observational study was conducted on patients undergoing MSE from June 2019 to December 2021. Demographic characteristics, procedure time, depth of maximum insertion (DMI), technical success, diagnostic yield, and adverse events were collected. RESULTS: Seventy-four anterograde (54.4%) and 62 retrograde (45.6%) enteroscopies were performed in 117 patients (64 males, median age 67 years). Fifty patients (42.7%) had prior major abdominal surgery. Technical success was 91.9% for anterograde and 90.3% for retrograde route. Diagnostic yield was 71.6% and 61.3%, respectively. The median DMI was 415 cm (264-585) for anterograde and 120 cm (37-225) for retrograde enteroscopy. In patients with prior major abdominal surgery, MSE showed significantly longer small bowel insertion time (38 vs 29 min, p = 0.004), with similar diagnostic yield (61 vs 71.4%, p = 0.201) and DMI (315 vs 204 cm, p = 0.226). The overall adverse event rate was 10.3% (SAE 1.5%), with no differences related to prior abdominal surgery (p = 0.598). Patients with prior surgeries directly involving the gastrointestinal tract showed lower DMI (189 vs 374 cm, p = 0.019) with equal exploration time (37.5 vs 38 min, p = 0.642) compared to those with other abdominal surgeries. CONCLUSIONS: MSE is effective and safe in patients with major abdominal surgery, although longer procedure times were observed. A lower depth of insertion was detected in patients with gastrointestinal surgery.

Telomere Length as a New Risk Marker of Early-Onset Colorectal Cancer.

Early-onset colorectal cancer (EOCRC; age younger than 50 years) incidence has been steadily increasing in recent decades worldwide. The need for new biomarkers for EOCRC prevention strategies is undeniable. In this study, we aimed to explore whether an aging factor, such as telomere length (TL), could be a useful tool in EOCRC screening. The absolute leukocyte TL from 87 microsatellite stable EOCRC patients and 109 healthy controls (HC) with the same range of age, was quantified by Real Time Quantitative PCR (RT-qPCR). Then, leukocyte whole-exome sequencing (WES) was performed to study the status of the genes involved in TL maintenance (hTERT, TERC, DKC1, TERF1, TERF2, TERF2IP, TINF2, ACD, and POT1) in 70 sporadic EOCRC cases from the original cohort. We observed that TL was significantly shorter in EOCRC patients than in healthy individuals (EOCRC mean: 122 kb vs. HC mean: 296 kb; p < 0.001), suggesting that telomeric shortening could be associated with EOCRC susceptibility. In addition, we found a significant association between several SNPs of hTERT (rs79662648), POT1 (rs76436625, rs10263573, rs3815221, rs7794637, rs7784168, rs4383910, and rs7782354), TERF2 (rs251796 and rs344152214), and TERF2IP (rs7205764) genes and the risk of developing EOCRC. We consider that the measurement of germline TL and the status analysis of telomere maintenance related genes polymorphisms at early ages could be non-invasive methods that could facilitate the early identification of individuals at risk of developing EOCRC.

Serological levels of IGF-1 and IGFBP-3 in patients with Barrett's esophagus and esophageal adenocarcinoma: Longitudinal study. / Niveles séricos de IGF-1 e IGFBP-3 en pacientes con esófago de Barrett y adenocarcinoma de esófago. Estudio longitudinal.

BACKGROUND: Barrett's esophagus (BE) is an entity with a known histological progression to malignancy. The insulin-like growth factor (IGF) system is involved in the carcinogenesis through obesity-related mechanisms that include IGF and it has been associated with several types of cancer. OBJECTIVES: To evaluate the serological levels of IGF-1 and IGFBP-3 in patients with BE and esophageal adenocarcinoma. PATIENTS AND METHODS: Prospective study of patients with BE and esophageal adenocarcinoma who underwent upper endoscopy between September 2012 and December 2015. A baseline determination of IGF-1 and IGFBP-3 was performed. We included a control group of patients without BE. RESULTS: One hundred sixteen patients were included: 36 controls, 62 with BE (42 without dysplasia and 20 with dysplasia) and 18 with adenocarcinoma. IGF-1 and IGF-1/IGFBP-3 molar ratio showed a progression to high levels in BE and adenocarcinoma than in controls (IGF-1: 135.55±66.07ng/ml, 148.33±81.5ng/ml, 108.19±46.69ng/ml, respectively; P=.049) (molar ratio: 0.23±0.91, 0.29±0.11, 0.19±0.06, respectively; P=.001), without differences between the histological types of BE. Fifty-four out of the 65 patients with BE were followed up (median of 58.50 months, range 12-113) and 11 of them (20.4%) presented progression to low-grade dysplasia (n=8) or high-grade dysplasia/adenocarcinoma (n=3), without differences in the IGF system compared with patients without progression. CONCLUSIONS: Patients with BE and esophageal adenocarcinoma have changes in the IGF system although the serological levels of IGF-1 and IGFBP-3 do not correlate with histological progression of BE.

Linked Colour imaging for the detection of polyps in patients with Lynch syndrome: a multicentre, parallel randomised controlled trial.

OBJECTIVE: Despite regular colonoscopy surveillance, colorectal cancers still occur in patients with Lynch syndrome. Thus, detection of all relevant precancerous lesions remains very important. The present study investigates Linked Colour imaging (LCI), an image-enhancing technique, as compared with high-definition white light endoscopy (HD-WLE) for the detection of polyps in this patient group. DESIGN: This prospective, randomised controlled trial was performed by 22 experienced endoscopists from eight centres in six countries. Consecutive Lynch syndrome patients ≥18 years undergoing surveillance colonoscopy were randomised (1:1) and stratified by centre for inspection with either LCI or HD-WLE. Primary outcome was the polyp detection rate (PDR). RESULTS: Between January 2018 and March 2020, 357 patients were randomised and 332 patients analysed (160 LCI, 172 HD-WLE; 6 excluded due to incomplete colonoscopies and 19 due to insufficient bowel cleanliness). No significant difference was observed in PDR with LCI (44.4%; 95% CI 36.5% to 52.4%) compared with HD-WLE (36.0%; 95% CI 28.9% to 43.7%) (p=0.12). Of the secondary outcome parameters, more adenomas were found on a patient (adenoma detection rate 36.3%; vs 25.6%; p=0.04) and a colonoscopy basis (mean adenomas per colonoscopy 0.65 vs 0.42; p=0.04). The median withdrawal time was not statistically different between LCI and HD-WLE (12 vs 11 min; p=0.16). CONCLUSION: LCI did not improve the PDR compared with HD-WLE in patients with Lynch syndrome undergoing surveillance. The relevance of findings more adenomas by LCI has to be examined further. TRIAL REGISTRATION NUMBER: NCT03344289.

A Liquid Biopsy Assay for Noninvasive Identification of Lymph Node Metastases in T1 Colorectal Cancer.

BACKGROUND & AIMS: We recently reported use of tissue-based transcriptomic biomarkers (microRNA [miRNA] or messenger RNA [mRNA]) for identification of lymph node metastasis (LNM) in patients with invasive submucosal colorectal cancers (T1 CRC). In this study, we translated our tissue-based biomarkers into a blood-based liquid biopsy assay for noninvasive detection of LNM in patients with high-risk T1 CRC. METHODS: We analyzed 330 specimens from patients with high-risk T1 CRC, which included 188 serum samples from 2 clinical cohorts-a training cohort (N = 46) and a validation cohort (N = 142)-and matched formalin-fixed paraffin-embedded samples (N = 142). We performed quantitative reverse-transcription polymerase chain reaction, followed by logistic regression analysis, to develop an integrated transcriptomic panel and establish a risk-stratification model combined with clinical risk factors. RESULTS: We used comprehensive expression profiling of a training cohort of LNM-positive and LMN-negative serum specimens to identify an optimized transcriptomic panel of 4 miRNAs (miR-181b, miR-193b, miR-195, and miR-411) and 5 mRNAs (AMT, forkhead box A1 [FOXA1], polymeric immunoglobulin receptor [PIGR], matrix metalloproteinase 1 [MMP1], and matrix metalloproteinase 9 [MMP9]), which robustly identified patients with LNM (area under the curve [AUC], 0.86; 95% confidence interval [CI], 0.72-0.94). We validated panel performance in an independent validation cohort (AUC, 0.82; 95% CI, 0.74-0.88). Our risk-stratification model was more accurate than the panel and an independent predictor for identification of LNM (AUC, 0.90; univariate: odds ratio [OR], 37.17; 95% CI, 4.48-308.35; P < .001; multivariate: OR, 17.28; 95% CI, 1.82-164.07; P = .013). The model limited potential overtreatment to only 18% of all patients, which is dramatically superior to pathologic features that are currently used (92%). CONCLUSIONS: A novel risk-stratification model for noninvasive identification of T1 CRC has the potential to avoid unnecessary operations for patients classified as high-risk by conventional risk-classification criteria.

Familial component of early-onset colorectal cancer: opportunity for prevention.

BACKGROUND: Individuals with a non-syndromic family history of colorectal cancer are known to have an increased risk. There is an opportunity to prevent early-onset colorectal cancer (age less than 50 years) (EOCRC) in this population. The aim was to explore the proportion of EOCRC that is preventable due to family history of colorectal cancer. METHODS: This was a retrospective multicentre European study of patients with non-hereditary EOCRC. The impact of the European Society of Gastrointestinal Endoscopy (ESGE), U.S. Multi-Society Task Force (USMSTF), and National Comprehensive Cancer Network (NCCN) guidelines on prevention and early diagnosis was compared. Colorectal cancer was defined as potentially preventable if surveillance colonoscopy would have been performed at least 5 years before the age of diagnosis of colorectal cancer, and diagnosed early if colonoscopy was undertaken between 1 and 4 years before the diagnosis. RESULTS: Some 903 patients with EOCRC were included. Criteria for familial colorectal cancer risk in ESGE, USMSTF, and NCCN guidelines were met in 6.3, 9.4, and 30.4 per cent of patients respectively. Based on ESGE, USMSTF, and NCCN guidelines, colorectal cancer could potentially have been prevented in 41, 55, and 30.3 per cent of patients, and diagnosed earlier in 11, 14, and 21.1 per cent respectively. In ESGE guidelines, if surveillance had started 10 years before the youngest relative, there would be a significant increase in prevention (41 versus 55 per cent; P = 0.010). CONCLUSION: ESGE, USMSTF, and NCCN criteria for familial colorectal cancer were met in 6.3, 9.4, and 30.4 per cent of patients with EOCRC respectively. In these patients, early detection and/or prevention could be achieved in 52, 70, and 51.4 per cent respectively. Early and accurate identification of familial colorectal cancer risk and increase in the uptake of early colonoscopy are key to decreasing familial EOCRC.

Prevalence of adenomatous polyposis in a fecal immunochemical test-based colorectal cancer screening program and risk of advanced neoplasia during follow-up.

BACKGROUND : Current guidelines recommend genetic counseling and intensive colonoscopy surveillance for patients with ≥ 10 colorectal adenomas based on scarce data. We investigated the prevalence of this condition in a fecal immunochemical test (FIT)-based colorectal (CRC) screening program, and the incidence of metachronous lesions during follow-up. METHODS: We retrospectively included all FIT-positive participants with ≥ 10 adenomas at index colonoscopy between 2010 and 2018. Surveillance colonoscopies were collected until 2019. Patients with inherited syndromes, serrated polyposis syndrome, total colectomy, or lacking surveillance data were excluded. The cumulative incidence of CRC and advanced neoplasia were analyzed by Kaplan-Meier analysis. Risk factors for metachronous advanced neoplasia were investigated by multivariable logistic regression analysis. RESULTS: 215 of 9582 participants (2.2 %) had ≥ 10 adenomas. Germline genetic testing was performed in 92 % of patients with ≥ 20 adenomas, identifying two inherited syndromes (3.3 %). The 3-year cumulative incidence of CRC and advanced neoplasia were 1 % and 16 %, respectively. In 39 patients (24.2 %), no polyps were found on first surveillance colonoscopy. The presence of an advanced adenoma was independently associated with a higher risk of advanced neoplasia at first surveillance colonoscopy (odds ratio 3.91, 95 %CI 1.12-13.62; P = 0.03). Beyond the first surveillance colonoscopy, the risk of metachronous advanced neoplasia was lower. CONCLUSIONS: The prevalence of ≥ 10 adenomas in a FIT-based CRC screening program was 2.2 %; a small proportion of inherited syndromes were detected, even amongst those with ≥ 20 adenomas. A low rate of post-colonoscopy CRC was observed and the risk of advanced neoplasia beyond the first surveillance colonoscopy tended to progressively decrease throughout successive follow-ups.

The "diagnose and leave in" strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial.

BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %-98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %-93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

Combination of Sulindac and Eflornithine Delays the Need for Lower Gastrointestinal Surgery in Patients With Familial Adenomatous Polyposis: Post Hoc Analysis of a Randomized Clinical Trial.

BACKGROUND: Colectomy and proctocolectomy are the initial standard of care for patients with familial adenomatous polyposis. Pharmacotherapy to prevent the progression of polyposis and surgeries in the lower GI tract would be beneficial to patients with this disease. OBJECTIVE: This analysis aimed to evaluate the impact of eflornithine-sulindac combination versus monotherapy in delaying time to disease progression in the lower GI tract of patients with familial adenomatous polyposis. DESIGN: This is a post hoc analysis of a randomized phase 3 trial. SETTING: This study was conducted in 21 hospitals in 7 countries treating patients with familial adenomatous polyposis. PATIENTS: Adults with familial adenomatous polyposis were randomly assigned 1:1:1 into 3 arms. INTERVENTIONS: Patients received either eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. MAIN OUTCOME MEASURES: Efficacy was evaluated as the time from randomization to predefined primary disease progression end points. RESULTS: A total of 158 patients were included in the study. Disease progression was observed in 2 of 54 (3.7%), 9 of 53 (17.0%), and 10 of 51 (19.6%) patients with at least partial lower GI tract in the combination, sulindac, and eflornithine arms, corresponding to risk reductions of 80% (p = 0.02) and 83% (p = 0.01) between combination and sulindac or eflornithine. When endoscopic excision of adenomas ≥10 mm in size was censored, the need for major surgery was observed in 0 of 54, 7 of 53 (13.2%), and 8 of 51 (15.7%) patients in the combination, sulindac, and eflornithine arms, corresponding to risk reductions approaching 100% between combination and sulindac (p = 0.005) or combination and eflornithine (p = 0.003). LIMITATIONS: This was a post hoc analysis, the sample size was small, and there were fewer than expected events. CONCLUSIONS: Eflornithine-sulindac combination therapy was superior to either drug alone in delaying or preventing the need for lower GI tract surgery in patients with familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/B658. REGISTRATION: ClinicalTrials.gov, NCT01483144; EU Clinical Trials Register, EudraCT 2012-000427-41. LA COMBINACIN DE SULINDAC Y EFLORNITINA RETRASA LA NECESIDAD DE CIRUGA DEL TUBO DIGESTIVO BAJO EN PACIENTES CON PAF ANLISIS POSTHOC DE UN ENSAYO CLNICO ALEATORIZADO: ANTECEDENTES:La colectomía y la proctocolectomía son el estándar inicial de atención para los pacientes con poliposis adenomatosa familiar. La farmacoterapia para prevenir la progresión de la poliposis y las cirugías en el tracto gastrointestinal inferior sería beneficiosa para los pacientes con esta enfermedad.OBJETIVO:Este análisis tuvo como objetivo evaluar el impacto de la combinación de eflornitina-sulindac versus la monoterapia en el retraso del tiempo hasta la progresión de la enfermedad en el tracto gastrointestinal inferior de pacientes con poliposis adenomatosa familiar.DISEÑO:Este es un análisis posthoc de un ensayo de fase 3 aleatorizado.ENTORNO CLINICO:Veintiún hospitales en 7 países que tratan a pacientes con poliposis adenomatosa familiar.PACIENTES:Adultos con poliposis adenomatosa familiar fueron aleatorizados 1: 1: 1 en 3 brazos.INTERVENCIONES:Los pacientes recibieron eflornitina (750 mg), sulindac (150 mg) o ambos una vez al día durante un máximo de 48 meses.PRINCIPALES MEDIDAS DE VALORACION:La eficacia se evaluó como el tiempo desde la aleatorización hasta los criterios de valoración primarios predefinidos de progresión de la enfermedad.RESULTADOS:Los resultados se informan para la población de estudio excluyendo a los pacientes que se habían sometido a ileostomías permanentes (n = 158). Se observó progresión de la enfermedad en 2/54 (3,7%), 9/53 (17,0%) y 10/51 (19,6%) pacientes con al menos tracto gastrointestinal inferior parcial en los brazos de combinación, sulindac y eflornitina, respectivamente, correspondientes al riesgo de reducciones del 80% (p = 0,02) y del 83% (p = 0,01) entre la combinación y el sulindaco o la eflornitina, respectivamente. Cuando se censuró la escisión endoscópica de adenomas ≥10 mm de tamaño, se observó la necesidad de cirugía mayor en 0/54, 7/53 (13,2%) y 8/51 (15,7%) pacientes en la combinación, sulindac y eflornitina, respectivamente, correspondientes a reducciones de riesgo cercanas al 100% entre combinación y sulindac (p = 0,005) o combinación y eflornitina (p = 0,003).LIMITACIONES:Este fue un análisis posthoc, el tamaño de la muestra fue pequeño y hubo menos eventos de los esperados.CONCLUSIONES:La terapia de combinación de eflornitina-sulindac fue superior a cualquier fármaco solo para retrasar o prevenir la necesidad de cirugía del tracto gastrointestinal inferior en pacientes con poliposis adenomatosa familiar. Consulte Video Resumen en http://links.lww.com/DCR/B658.

miRNome Profiling and Functional Analysis Reveal Involvement of hsa-miR-1246 in Colon Adenoma-Carcinoma Transition by Targeting AXIN2 and CFTR.

Regulatory changes occurring early in colorectal cancer development remain poorly investigated. Since the majority of cases develop from polyps in the adenoma-carcinoma transition, a search of early molecular features, such as aberrations in miRNA expression occurring prior to cancer development, would enable identification of potentially causal, rather than consequential, candidates in the progression of polyp to cancer. In the current study, by employing small RNA-seq profiling of colon biopsy samples, we described differentially expressed miRNAs and their isoforms in the adenoma-carcinoma transition. Analysis of healthy-adenoma-carcinoma sequence in an independent validation group enabled us to identify early deregulated miRNAs including hsa-miR-1246 and hsa-miR-215-5p, the expressions of which are, respectively, gradually increasing and decreasing. Loss-of-function experiments revealed that inhibition of hsa-miR-1246 lead to reduced cell viability, colony formation, and migration rate, thereby indicating an oncogenic effect of this miRNA in vitro. Subsequent western blot and luciferase reporter assay provided evidence of hsa-miR-1246 being involved in the regulation of target AXIN2 and CFTR genes' expression. To conclude, the present study revealed possible involvement of hsa-miR-1246 in early colorectal cancer development and regulation of tumor suppressors AXIN2 and CFTR.

Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer.

BACKGROUND & AIMS: A significant proportion of colorectal cancer (CRC) cases have familial aggregation but little is known about the genetic factors that contribute to these cases. We performed an exhaustive functional characterization of genetic variants associated with familial CRC. METHODS: We performed whole-exome sequencing analyses of 75 patients from 40 families with a history of CRC (including early-onset cases) of an unknown germline basis (discovery cohort). We also sequenced specific genes in DNA from an external replication cohort of 473 families, including 488 patients with colorectal tumors that had normal expression of mismatch repair proteins (validation cohort). We disrupted the Fas-associated factor 1 gene (FAF1) in DLD-1 CRC cells using CRISPR/Cas9 gene editing; some cells were transfected with plasmids that express FAF1 missense variants. Cells were analyzed by immunoblots, quantitative real-time polymerase chain reaction, and functional assays monitoring apoptosis, proliferation, and assays for Wnt signaling or nuclear factor (NF)-kappa-B activity. RESULTS: We identified predicted pathogenic variant in the FAF1 gene (c.1111G>A; p.Asp371Asn) in the discovery cohort; it was present in 4 patients of the same family. We identified a second variant in FAF1 in the validation cohort (c.254G>C; p.Arg85Pro). Both variants encoded unstable FAF1 proteins. Expression of these variants in CRC cells caused them to become resistant to apoptosis, accumulate beta-catenin in the cytoplasm, and translocate NF-kappa-B to the nucleus. CONCLUSIONS: In whole-exome sequencing analyses of patients from families with a history of CRC, we identified variants in FAF1 that associate with development of CRC. These variants encode unstable forms of FAF1 that increase resistance of CRC cells to apoptosis and increase activity of beta-catenin and NF-kappa-B.