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Showing papers by "Francesc Balaguer published in 2020"


Journal ArticleDOI
TL;DR: This Review outlines these epigenetic aberrations in CRC and their potential as diagnostic, prognostic and predictive biomarkers and therapeutic targets, as well as the role of non-coding RNAs as epigenetic regulators.
Abstract: Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, evolves as a result of the stepwise accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium, leading to the development of colorectal adenomas and invasive adenocarcinomas. Although genetic alterations have a major role in a subset of CRCs, the pathophysiological contribution of epigenetic aberrations in this malignancy has attracted considerable attention. Data from the past couple of decades has unequivocally illustrated that epigenetic marks are important molecular hallmarks of cancer, as they occur very early in disease pathogenesis, involve virtually all key cancer-associated pathways and, most importantly, can be exploited as clinically relevant disease biomarkers for diagnosis, prognostication and prediction of treatment response. In this Review, we summarize the current knowledge on the best-studied epigenetic modifications in CRC, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators. We focus on the emerging potential for the bench-to-bedside translation of some of these epigenetic alterations into clinical practice and discuss the burgeoning evidence supporting the potential of emerging epigenetic therapies in CRC as we usher in the era of precision medicine.

345 citations


Journal ArticleDOI
Mev Dominguez-Valentin1, Julian R. Sampson2, Toni T. Seppälä3, Sanne W. ten Broeke4, John-Paul Plazzer5, Sigve Nakken1, Christoph Engel6, Stefan Aretz7, Mark A. Jenkins8, Lone Sunde9, Lone Sunde10, Inge Bernstein11, Gabriel Capellá, Francesc Balaguer12, Huw D. Thomas13, D. Gareth Evans14, D. Gareth Evans15, John Burn16, Marc S. Greenblatt17, Eivind Hovig1, Wouter H. de Vos tot Nederveen Cappel, Rolf H. Sijmons18, Lucio Bertario19, Maria Grazia Tibiletti, Giulia Martina Cavestro20, Annika Lindblom21, Adriana Della Valle, Francisco López-Köstner, Nathan Gluck22, Lior H. Katz23, Karl Heinimann24, Carlos A. Vaccaro25, Reinhard Büttner26, Heike Görgens27, Elke Holinski-Feder28, Monika Morak28, Stefanie Holzapfel7, Robert Hüneburg29, Magnus von Knebel Doeberitz30, Magnus von Knebel Doeberitz31, Markus Loeffler6, Nils Rahner32, Hans K. Schackert27, Verena Steinke-Lange28, Wolff Schmiegel33, Deepak Vangala33, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo3, Laura Renkonen-Sinisalo34, John L. Hopper8, Aung Ko Win8, Robert W. Haile35, Noralane M. Lindor36, Steven Gallinger37, Loic Le Marchand38, Polly A. Newcomb39, Jane C. Figueiredo40, Stephen N. Thibodeau36, Karin Wadt, Christina Therkildsen41, Henrik Okkels11, Zohreh Ketabi41, Leticia Moreira12, Ariadna Sánchez12, Miquel Serra-Burriel12, Marta Pineda, Matilde Navarro, Ignacio Blanco, Kate Green14, Fiona Lalloo14, Emma J Crosbie15, James Hill14, Oliver G. Denton2, Ian M. Frayling2, Einar Andreas Rødland1, Hans F. A. Vasen42, Miriam Mints43, Florencia Neffa, Patricia Esperon, Karin Alvarez, Revital Kariv22, Guy Rosner22, Tamara Alejandra Piñero25, María Laura Gonzalez25, Pablo Kalfayan25, Douglas Tjandra8, Ingrid Winship8, Ingrid Winship5, Finlay A. Macrae8, Finlay A. Macrae5, Gabriela Möslein, Jukka-Pekka Mecklin44, Maartje Nielsen4, Pål Møller1, Pål Møller45 
TL;DR: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

334 citations


Journal ArticleDOI
01 Jan 2020-Gut
TL;DR: Risk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol.
Abstract: Background and aims Serrated polyposis syndrome (SPS) is associated with an increased risk of colorectal cancer (CRC). International guidelines recommend surveillance intervals of 1–2 years. However, yearly surveillance likely leads to overtreatment for many. We prospectively assessed a surveillance protocol aiming to safely reduce the burden of colonoscopies. Methods Between 2013 and 2018, we enrolled SPS patients from nine Dutch and Spanish hospitals. Patients were surveilled using a protocol appointing either a 1-year or 2-year interval after each surveillance colonoscopy, based on polyp burden. Primary endpoint was the 5-year cumulative incidence of CRC and advanced neoplasia (AN) during surveillance. Results We followed 271 SPS patients for a median of 3.6 years. During surveillance, two patients developed CRC (cumulative 5-year incidence 1.3%[95% CI 0% to 3.2%]). The 5-year AN incidence was 44% (95% CI 37% to 52%), and was lower for patients with SPS type III (26%) than for patients diagnosed with type I (53%) or type I and III (59%, p Conclusion Risk stratification substantially reduced colonoscopy burden while achieving CRC incidence similar to previous studies. AN incidence is considerable in SPS patients, but extension of surveillance intervals was not associated with increased AN in those identified as low-risk by the protocol. We identified SPS type III patients as low-risk group that might benefit from even less frequent surveillance. Trial registration number The study was registered on http://www.trialregister.nl; trial-ID NTR4609.

42 citations




Journal ArticleDOI
TL;DR: Although both techniques seem to be similar in detecting patients with advanced colorectal neoplasms, CCE is more sensitive for the detection of any neoplastic lesion than CTC.
Abstract: Colon capsule endoscopy (CCE) and CT colonography (CTC) are minimally invasive techniques for colorectal cancer (CRC) screening. Our objective is to compare CCE and CTC for the identification of patients with colorectal neoplasia among participants in a CRC screening programme with positive faecal immunochemical test (FIT). Primary outcome was to compare the performance of CCE and CTC in detecting patients with neoplastic lesions. The VICOCA study is a prospective, single-centre, randomised trial conducted from March 2014 to May 2016; 662 individuals were invited and 349 were randomised to CCE or CTC before colonoscopy. Endoscopists were blinded to the results of CCE and CTC. Three hundred forty-nine individuals were included: 173 in the CCE group and 176 in the CTC group. Two hundred ninety individuals agreed to participate: 147 in the CCE group and 143 in the CTC group. In the intention-to-screen analysis, sensitivity, specificity and positive and negative predictive values for the identification of individuals with colorectal neoplasia were 98.1%, 76.6%, 93.7% and 92.0% in the CCE group and 64.9%, 95.7%, 96.8% and 57.7% in the CTC group. In terms of detecting significant neoplastic lesions, the sensitivity of CCE and CTC was 96.1% and 79.3%, respectively. Detection rate for advanced colorectal neoplasm was higher in the CCE group than in the CTC group (100% and 93.1%, respectively; RR = 1.07; p = 0.08). Both CCE and CTC identified all patients with cancer. CCE detected more patients with any lesion than CTC (98.6% and 81.0%, respectively; RR = 1.22; p = 0.002). Although both techniques seem to be similar in detecting patients with advanced colorectal neoplasms, CCE is more sensitive for the detection of any neoplastic lesion. ClinicalTrials.gov Identifier: NCT02081742 . Registered: September 16, 2013.

24 citations



Journal ArticleDOI
TL;DR: The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.
Abstract: Introduction Lynch syndrome (LS) and constitutional mismatch repair deficiency (CMMRD) are hereditary cancer syndromes associated with mismatch repair (MMR) deficiency. Tumours show microsatellite instability (MSI), also reported at low levels in non-neoplastic tissues. Our aim was to evaluate the performance of high-sensitivity MSI (hs-MSI) assessment for the identification of LS and CMMRD in non-neoplastic tissues. Materials and methods Blood DNA samples from 131 individuals were grouped into three cohorts: baseline (22 controls), training (11 CMMRD, 48 LS and 15 controls) and validation (18 CMMRD and 18 controls). Custom next generation sequencing panel and bioinformatics pipeline were used to detect insertions and deletions in microsatellite markers. An hs-MSI score was calculated representing the percentage of unstable markers. Results The hs-MSI score was significantly higher in CMMRD blood samples when compared with controls in the training cohort (p Conclusions The hs-MSI approach is a valuable tool for CMMRD diagnosis, especially in suspected patients harbouring MMR variants of unknown significance or non-detected biallelic germline mutations.

20 citations


Journal ArticleDOI
TL;DR: MCM8 is suggested as a gene involved in CRC germline predisposition with a recessive pattern of inheritance and microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM 8 in MMR.
Abstract: Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance.

19 citations


Journal ArticleDOI
TL;DR: The results of the clinical trials that led to their accelerated approval by the U.S. Food and Drug Administration in 2017 are summarized and the burgeoning evidence for a potential use of ICIs in other settings than mCRC will also be mentioned.
Abstract: During the last 20 years, chemotherapy has improved survival rates of colorectal cancer (CRC). However, the majority of metastatic cases do not respond to or progress after first line conventional chemotherapy and contribute to the fatalities of patients with CRC. Insights into the immune contexture of the tumor microenvironment (TME) have enabled the development of new systemic treatments that boost the host immune system against the tumor—the immune checkpoint inhibitors (ICI). These promising drugs have already shown astonishing efficacies in other cancer types and have raised new hope for the treatment of metastatic CRC (mCRC). In this review, we will summarize the results of the clinical trials that led to their accelerated approval by the U.S. Food and Drug Administration (FDA) in 2017, as well as all relevant recent studies conducted since then—some of which are not published yet. We will focus on therapeutic efficacy, but also discuss the available data for drug safety and security, changes in quality of life indicators and predictive biomarkers for treatment response. The burgeoning evidence for a potential use of ICIs in other settings than mCRC will also be mentioned. For each trial, we have made a preliminary assessment of the quality of clinical trial design and of the “European Society of Medical Oncology (ESMO) magnitude of clinical benefit” (ESMO-MCBS) in order to provide the first evidence-based recommendation to the reader.

17 citations


Journal ArticleDOI
TL;DR: Complete colonoscopies with adequate bowel preparation and chromoendoscopy use are associated with improved adenoma detection, while surveillance intervals less than 3 years areassociated with reduction of PCCRC incidence.

Journal ArticleDOI
TL;DR: In whole-exome sequencing analyses of patients from families with a history of CRC,Variants in FAF1 that associate with development of CRC are identified that increase resistance of CRC cells to apoptosis and increase activity of b-catenin and NF-kB.

Journal ArticleDOI
TL;DR: A number of practical recommendations regarding patient management and the stepwise resumption of healthcare activity are prepared, based on the sparse, changing evidence available, and will be updated in the future according to daily needs and the availability of expendable materials.
Abstract: El articulo recoge el conjunto de medidas propuestas por la SEPD, la AEEH, GETECCU y la AEG que pretenden servir de ayuda a los servicios en su reincorporacion a la actividad habitual. Hemos confeccionado una serie de recomendaciones practicas respecto al manejo y a la reintroduccion progresiva de la actividad asistencial. Estas recomendaciones estan guiadas por la escasa y cambiante evidencia disponible y seran objeto de futuras actualizaciones, en base a las necesidades diarias y la disponibilidad del material fungible para adecuarse a las mismas; y se podran implementar en cada servicio en funcion de la incidencia acumulada de SARS-CoV-2 en cada region y de la carga que la epidemia ha ocasionado en cada uno de los hospitales. Los objetivos generales de estas recomendaciones son: • Proteger a nuestros pacientes de los riesgos de la infeccion por SARS-CoV-2 y prestarles una atencion de calidad. • Proteger a todos los profesionales sanitarios de los riesgos de la infeccion por SARS-CoV-2. • Recuperar el normal funcionamiento de nuestros servicios en un entorno de riesgo continuado de infeccion por SARS-CoV-2.

Journal ArticleDOI
TL;DR: Genetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584-GREM1, rs16892766-EIF3H and rs3217810-CCND2.
Abstract: Background Serrated polyposis syndrome (SPS) is a clinical entity characterised by large and/ormultiple serrated polyps throughout the colon and increased risk for colorectal cancer (CRC). The basis for SPS genetic predisposition is largely unknown. Common, low-penetrance genetic variants have been consistently associated with CRC susceptibility, however, their role in SPS genetic predisposition has not been yet explored. Objective The aim of this study was to evaluate if common, low-penetrance genetic variants for CRC risk are also implicated in SPS genetic susceptibility. Methods A case-control study was performed in 219 SPS patients and 548 asymptomatic controls analysing 65 CRC susceptibility variants. A risk prediction model for SPS predisposition was developed. Results Statistically significant associations with SPS were found for seven genetic variants (rs4779584-GREM1, rs16892766-EIF3H, rs3217810-CCND2, rs992157-PNKD1/TMBIM1, rs704017-ZMIZ1, rs11196172-TCF7L2, rs6061231-LAMA5). The GREM1 risk allele was remarkably over-represented in SPS cases compared with controls (OR=1.573, 1.21–2.04, p value=0.0006). A fourfold increase in SPS risk was observed when comparing subjects within the highest decile of variants (≥65) with those in the first decile (≤50). Conclusions Genetic variants for CRC risk are also involved in SPS susceptibility, being the most relevant ones rs4779584-GREM1, rs16892766-EIF3H and rs3217810-CCND2.

Journal ArticleDOI
TL;DR: Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data with already available NGS data from families with several sequenced members to further identify candidate genes involved germ line predisposition to disease.
Abstract: Colorectal cancer (CRC) is a complex disorder for which the majority of the underlying germline predisposition factors remain still unidentified. Here, we combined whole-exome sequencing (WES) and linkage analysis in families with multiple relatives affected by CRC to identify candidate genes harboring rare variants with potential high-penetrance effects. Forty-seven affected subjects from 18 extended CRC families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. Suggestive linkage peaks were identified on chromosomes 1q22-q24.2 (maxSNP = rs2134095; LODlinear = 2.38, LODexp = 2.196), 7q31.2-q34 (maxSNP = rs6953296; LODlinear = 2.197, LODexp = 2.149) and 10q21.2-q23.1 (maxSNP = rs1904589; LODlinear = 1.445, LODexp = 2.195). These linkage signals were replicated in 10 independent sets of random markers from each of these regions. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 89 rare variants predicted to be deleterious from 78 genes under the linkage intervals. This analysis showed significant segregation of rare variants with CRC in 18 genes (weighted p-value > 0.0028). Protein network analysis and functional evaluation were used to suggest a plausible candidate gene for germline CRC predisposition. Etiologic rare variants implicated in cancer germline predisposition may be identified by combining traditional linkage with WES data. This approach can be used with already available NGS data from families with several sequenced members to further identify candidate genes involved germline predisposition to disease. This approach resulted in one candidate gene associated with increased risk of CRC but needs evidence from further studies.

Journal ArticleDOI
23 Aug 2020-Cancers
TL;DR: The selection of patients based on clinical criteria leads to high diagnostic yield, detecting a causative germline mutation in almost half of the cases; therefore, both meticulous genetic counseling and use of multi-gen panels is crucial.
Abstract: The identification of high-risk groups of gastric (GC) and pancreatic adenocarcinoma (PC) due to a hereditary basis could imply a benefit in the affected families by establishing personalized preventive strategies. We aimed at assessing the diagnostic yield of GC/PC hereditary syndromes in individuals evaluated based on specific clinical criteria. In total, 77 unrelated individuals (45 from GC group/32 from PC group) were recruited: 51 (66.2%) cancer diagnosis ≤60 years, 3 (4%) with personal history of GC/PC and other cancer and 23 (29.8%) due to family history. Immunohistochemical analysis of DNA mismatch repair proteins was performed in 38 (49.3%) available tumors, being pathological in one (2%) GC. A genetic analysis was performed if clinical criteria of hereditary syndrome were fulfilled, identifying a mutation in 10/22 (45.5%) families [7/16 (43.7%) with GC and 3/6 (50%) with PC] and 19 (24.7%) fulfilled criteria of familial cancer. Diagnosis of cancer <40 years and personal history of other cancers were independent risk factors of a hereditary syndrome [OR:11.3 (95%IC 1.9–67); p = 0.007 and OR:17.4 (95% IC 2.5–119.9); p = 0.004; respectively]. The selection of patients based on clinical criteria leads to high diagnostic yield, detecting a causative germline mutation in almost half of the cases; therefore, both meticulous genetic counseling and use of multi-gen panels is crucial.

Journal ArticleDOI
09 Aug 2020-Cancers
TL;DR: FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS, and their management should take into account this increased risk.
Abstract: Lynch syndrome (LS) is a common cause of hereditary colorectal cancer (CRC). Some CRC patients develop mismatch repair deficiency without germline pathogenic mutation, known as Lynch-like syndrome (LLS). We compared the risk of CRC in first-degree relatives (FDRs) in LLS and LS patients. LLS was diagnosed when tumors showed immunohistochemical loss of MSH2, MSH6, and PMS2; or loss of MLH1 with BRAF wild type; and/or no MLH1 methylation and absence of pathogenic mutation in these genes. CRC and other LS-related neoplasms were followed in patients diagnosed with LS and LLS and among their FDRs. Standardized incidence ratios (SIRs) were calculated for CRC and other neoplasms associated with LS among FDRs of LS and LLS patients. In total, 205 LS (1205 FDRs) and 131 LLS families (698 FDRs) had complete pedigrees. FDRs of patients with LLS had a high incidence of CRC (SIR, 2.08; 95% confidence interval (CI), 1.56–2.71), which was significantly lower than that in FDRs of patients with LS (SIR, 4.25; 95% CI, 3.67–4.90; p < 0.001). The risk of developing other neoplasms associated with LS also increased among FDR of LLS patients (SIR, 2.04; 95% CI, 1.44–2.80) but was lower than that among FDR of patients with LS (SIR, 5.01, 95% CI, 4.26–5.84; p < 0.001). FDRs with LLS have an increased risk of developing CRC as well as LS-related neoplasms, although this risk is lower than that of families with LS. Thus, their management should take into account this increased risk.

Journal ArticleDOI
TL;DR: The set of measures proposed by SEPD, AEEH, GETECCU and AEG are aimed to help departments in their resumption of usual activity and to protect patients against the risks of infection with SARS-CoV-2.

Journal ArticleDOI
29 Sep 2020-Cancers
TL;DR: It is demonstrated that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present, with 100% specificity to identify LS patients due to EPCam 3′-end deletions in MSH 2-negative CRC and MSh2-negative colorectal polyps.
Abstract: The use of epithelial cell adhesion molecule (EPCAM) immunohistochemistry (IHC) is not included in the colorectal cancer (CRC) screening algorithm to detect Lynch syndrome (LS) patients. The aim of the present study was to demonstrate that EPCAM IHC is a useful tool to guide the LS germ-line analysis when a loss of MSH2 expression was present. We retrospectively studied MSH2 and EPCAM IHC in a large series of 190 lesions composed of malignant neoplasms (102), precursor lesions of gastrointestinal (71) and extra-gastrointestinal origin (9), and benign neoplasms (8) from different organs of 71 patients suspicious of being LS due to MSH2 alterations. LS was confirmed in 68 patients, 53 with MSH2 mutations and 15 with EPCAM 3'-end deletions. Tissue microarrays were constructed with human normal tissues and their malignant counterparts to assist in the evaluation of EPCAM staining. Among 154 MSH2-negative lesions, 17 were EPCAM-negative, including 10 CRC and 7 colorectal polyps, and 5 of them showed only isolated negative glands. All lesions showing a lack of EPCAM expression belonged to patients with EPCAM 3'-end deletions. EPCAM IHC is a useful screening tool, with 100% specificity to identify LS patients due to EPCAM 3'-end deletions in MSH2-negative CRC and MSH2-negative colorectal polyps.


Journal ArticleDOI
Mev Dominguez-Valentin1, Julian R. Sampson2, Toni T. Seppälä3, Sanne W. ten Broeke4, John-Paul Plazzer5, Sigve Nakken1, Christoph Engel6, Stefan Aretz7, Mark A. Jenkins8, Lone Sunde9, Inge Bernstein10, Gabriel Capellá, Francesc Balaguer11, Huw Thomas, D. Gareth Evans12, John Burn13, Marc S. Greenblatt14, Eivind Hovig1, Wouter H. de Vos tot Nederveen Cappel, Rolf H. Sijmons15, Lucio Bertario, Maria Grazia Tibiletti, Giulia Martina Cavestro16, Annika Lindblom17, Adriana Della Valle, Francisco López-Köstner, Nathan Gluck18, Lior H. Katz19, Karl Heinimann20, Carlos A. Vaccaro21, Reinhard Büttner22, Heike Görgens23, Elke Holinski-Feder24, Monika Morak24, Stefanie Holzapfel7, Robert Hüneburg7, Magnus von Knebel Doeberitz25, Magnus von Knebel Doeberitz26, Markus Loeffler6, Nils Rahner27, Hans K. Schackert23, Verena Steinke-Lange24, Wolff Schmiegel28, Deepak Vangala28, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo3, John L. Hopper8, Aung Ko Win8, Robert W. Haile29, Noralane M. Lindor, Steven Gallinger30, Loic Le Marchand, Polly A. Newcomb31, Jane C. Figueiredo32, Stephen N. Thibodeau, Karin Wadt33, Christina Therkildsen33, Henrik Okkels10, Zohreh Ketabi33, Leticia Moreira11, Ariadna Sánchez11, Miquel Serra-Burriel11, Marta Pineda, Matilde Navarro, Ignacio Blanco, Kate Green12, Fiona Lalloo12, Emma J Crosbie34, James Hill12, Oliver G. Denton2, Ian M. Frayling2, Einar Andreas Rødland1, Hans F. A. Vasen4, Miriam Mints17, Florencia Neffa, Patricia Esperon, Karin Alvarez, Revital Kariv18, Guy Rosner18, Tamara Alejandra Piñero21, María Laura Gonzalez21, Pablo Kalfayan21, Douglas Tjandra8, Ingrid Winship8, Ingrid Winship5, Finlay A. Macrae5, Finlay A. Macrae8, Gabriela Möslein, Jukka-Pekka Mecklin35, Maartje Nielsen4, Pål Møller1 
TL;DR: An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Journal ArticleDOI
TL;DR: A novel miRNA biomarker panel for the identification and predicting survival in CRC patients with mucinous differentiation is reported and an integrative risk-assessment model is established by combining the miRNA-based risk scores together with TNM staging, which was a superior predictor of prognosis in mucinous CRC patients.
Abstract: Accumulating evidence supports the fact that the mere presence of mucinous differentiation in colorectal cancer (CRC), rather than its proportion, is a more accurate representative of a particular CRC subtype with distinct clinical and molecular features. In addition, the prognostic significance of the mucinous carcinoma (MC) subtype remains poorly understood and biomarkers have been barely explored in this disease. Herein, we have performed a systematic and comprehensive analysis in MCs and non-MCs and identified a panel of microRNAs (miRNAs) that are differentially expressed between these two subtypes of CRC. Next, we interrogated their clinical significance and demonstrated their robust diagnostic and prognostic clinical ability in CRCs with mucinous differentiation. Finally, we established an integrative risk-assessment model by combining the miRNA-based risk scores together with TNM staging, which was a superior predictor of prognosis in mucinous CRC patients. Collectively, we report a novel miRNA biomarker panel for the identification and predicting survival in CRC patients with mucinous differentiation.

Journal ArticleDOI
TL;DR: In this article, a serie of recomendaciones practicas respecto al manejo and a reintroduccion progresiva de la actividad asistencial are confeccionado.


Journal ArticleDOI
TL;DR: In Lynch syndrome patients, the "diagnose-and-leave-in strategy" for diminutive rectosigmoid polyps would be feasible and safe and avoid unnecessary polypectomies at expenses.
Abstract: Background and study aim: The ‘diagnose-and-leave-in’ policy has been established to reduce risks and costs related to unnecessary polypectomies in the average-risk population. In Lynch syndrome individuals, due 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 Lynch syndrome individuals. Patients and 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 centres, in which 256 individuals with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with the level of confidence of all detected lesions were obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Our 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, showing a NPV of 96.0% (95% confidence interval, [88.9%–98.6%]) and accuracy of 89.3% (95% confidence interval, [81.9%–93.9%]). By following the ‘diagnose-and-leave-in” policy, we would have avoided 59% (75/128) unnecessary polypectomies at expenses of 2 diminutive low-grade dysplasia adenomas and 1 diminutive sessile serrated lesion that would have been left in situ. Conclusion: In Lynch syndrome patients, the “diagnose-and-leave-in strategy” for diminutive rectosigmoid polyps would be feasible and safe.

Journal ArticleDOI
TL;DR: In this article, the authors presented two cases of patients with adenomatous polyposis who developed chronic myelogenous leukaemia and were treated with imatinib as part of their chemotherapy.
Abstract: Patients with adenomatous polyposis, usually defined as patients with >10 adenomatous polyps in the colorectum, are at increased risk for colorectal cancer (CRC). Since surgical and endoscopic treatment do not completely eliminate the potential for future polyps or extraintestinal neoplasms, there is an unmet medical need to identify pharmacological agents to delay major surgical interventions. We present two cases of patients with adenomatous polyposis who developed chronic myelogenous leukaemia and were treated with imatinib as part of their chemotherapy. A sustained regression of the colonic polyps documented in both cases was observed after the initiation of the tyrosine kinase inhibitor. Despite the presence of potential confounders, we hypothesise the potential role of imatinib as a chemopreventive agent in patients with familial adenomatous polyposis.

Journal ArticleDOI
TL;DR: FDRs of patients with SPS that underwent colonoscopy and fulfilled the abandoned criterion II 2010 for SPS diagnosis were at increased risk of AN at baseline and during surveillance in this small, retrospective cohort study.
Abstract: The World Health Organization (WHO) recently updated the diagnostic criteria for serrated polyposis syndrome (SPS). One of the three previous diagnostic criteria (criterion II2010) is now abandoned: ≥ 1 serrated polyp (SP) proximal to the sigmoid in a first-degree relative (FDR) of a patient with SPS. Individuals fulfilling this abandoned criterion now receive the same surveillance recommendations as all FDRs of patients with SPS. We aimed to compare the incidence of advanced neoplasia (AN) in FDRs with vs. without fulfillment of the abandoned criterion II2010. We retrospectively recruited FDRs of patients with SPS who underwent a colonoscopy, and stratified them according to fulfilment of criterion II2010 at baseline. Our primary and secondary outcomes were AN incidence during surveillance and at baseline, respectively. We included 224 FDRs of patients with SPS, of whom 36 (16%) fulfilled criterion II2010 at baseline. One hundred and five underwent surveillance after baseline. Criterion II2010-positive FDRs were at increased risk of AN, both during surveillance (hazard ratio 8.94, 95% CI 2.15–37.1, p = .003) as well as at baseline (adjusted odds-ratio 9.30, 95% CI 3.7–23.3, p < .001). FDRs of patients with SPS that underwent colonoscopy and fulfilled the abandoned criterion II2010 for SPS diagnosis were at increased risk of AN at baseline and during surveillance in this small, retrospective cohort study. Our results should be interpreted with caution but suggest that adherence to surveillance recommendations for all FDRs of patients with SPS is important, especially for those that would have fulfilled the now abandoned criterion II2010.

Proceedings ArticleDOI
TL;DR: Utilizing a novel biomarker discovery approach, this work provides first evidence for cell-free DNA methylation biomarkers that offer a robust diagnostic accuracy for the identification of specific cancer types, and demonstrate their potential clinical application as a Pan-cancer panel for the early detection of all gastrointestinal cancers.
Abstract: Purpose: In view of high cancer-specificity, DNA methylation alterations have emerged as front-runners in biomarker development, especially as cell-free DNA (cf-DNA) biomarkers for early detection of cancer. However, much effort to date has focused on developing cancer type-specific biomarkers, but have not explored the possibility of developing a pan-cancer diagnostic assay. In this context, gastrointestinal (GI) cancers, including colorectal (CRC), esophageal squamous cell and adenocarcinoma (ESCC and EAC), gastric (GC), liver (HCC) and pancreatic ductal adenocarcinoma (PDAC) constitute the second leading cause of cancer-related deaths worldwide; yet there is no blood-based assay for the early detection and population screening of GI cancers. Here we undertook a genomewide DNA methylation analysis for multiple GI cancers, followed by development of a novel cf-DNA methylation biomarker panels for the early detection of GI cancers (EpiPanGI Dx). Experimental design: By analyzing the DNA methylation data from 1940 tumor and adjacent normal tissues from TCGA and GSE72872 datasets, we first identified the differentially methylated regions (DMRs) between individual GI cancers and adjacent normal tissues, as well as across all GI cancers. We next prioritized a list of DMRs encompassing a 25.6 Mb genomic region by incorporating all identified DMRs across various GI cancers to design a custom SeqCap Epi, targeted bisulfite sequencing platform, optimized for analysis of low-abundance cf-DNA derived from plasma specimens. Using this approach, we sequenced 300 plasma specimens from all GI cancers, as well as age-matched healthy controls, with a 40X coverage. Finally, using machine learning algorithms, we identified unique DMR panels for the detection of various GI cancers. Results: Methylation profiling data from various GI tissues led to the identification of 67,832 DMRs with an adjusted p Conclusions: Utilizing a novel biomarker discovery approach, we provide first evidence for cell-free DNA methylation biomarkers that offer a robust diagnostic accuracy for the identification of specific cancer types, and demonstrate their potential clinical application as a Pan-cancer panel for the early detection of all gastrointestinal cancers. Citation Format: Raju Kandimalla, Jianfeng Xu, Alexander Link, Takatoshi Matsuyama, Kensuke Yamamura, Iqbal Parker, Hiroyuki Uetake, Eva Hernandez-Illan, Juanjo Lozano, Erkut Borazanci, Susan Tsai, Douglas Evans, Stephen J. Meltzer, Hideo Baba, Randall Brand, Daniel Von Hoff, Francesc Balaguer, Wei Li, Ajay Goel. EpiPanGI-Dx: A cell-free DNA methylation fingerprint for the early detection of gastrointestinal cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1084.