Turcot syndrome

Constitutional mismatch repair deficiency is a rare hereditary, autosomal recessive childhood cancer predisposition syndrome with four main tumor types: HEMATOLOGIC NEOPLASMS; BRAIN NEOPLASMS and CENTRAL NERVOUS SYSTEM NEOPLASMS; COLORECTAL NEOPLASMS and multiple INTESTINAL POLYPS, and other malignancies including embryonic tumors and RHABDOMYOSARCOMA. Many patients show signs reminiscent of NEUROFIBROMATOSIS TYPE I (OMIM: 162200). 'Turcot syndrome' classically refers to the combination of colorectal polyposis and primary tumors of the central nervous system. Mutations in the MLH1, MSH2, MSH6, and PMS2 genes have been identified. OMIM: 276300

Also Known As:

Networked: 665 relevant articles (41 outcomes, 55 trials/studies)

Relationship Network

Disease Context: Research Results

Related Diseases

1.	Neoplasms (Cancer)
2.	Microsatellite Instability
3.	Colorectal Neoplasms (Colorectal Cancer)
4.	Endometrial Neoplasms (Endometrial Cancer)
5.	Carcinoma (Carcinomatosis)

Experts

1.	Kloor, Matthias: 12 articles (01/2022 - 04/2007)
2.	Buchanan, Daniel D: 7 articles (03/2022 - 01/2009)
3.	Tabori, Uri: 7 articles (01/2021 - 01/2016)
4.	Shia, Jinru: 6 articles (07/2022 - 11/2012)
5.	André, Thierry: 6 articles (06/2022 - 02/2019)
6.	Cohen, Romain: 6 articles (06/2022 - 02/2019)
7.	Svrcek, Magali: 6 articles (06/2022 - 04/2013)
8.	von Knebel Doeberitz, Magnus: 6 articles (10/2021 - 04/2007)
9.	Aronson, Melyssa: 6 articles (01/2021 - 04/2005)
10.	Le, Dung T: 6 articles (01/2019 - 06/2015)

Drugs and Biologics

Drugs and Important Biological Agents (IBA) related to Turcot syndrome:

1.	Immune Checkpoint InhibitorsIBA 01/01/2023 - "Notably, patients with MMR deficiency had benefited from the typing of immune signatures and later immune checkpoint inhibition. " 08/21/2018 - "The results of this study suggest that PLS may be a better candidate for an immune checkpoint inhibitor than MMR deficiency. " 10/01/2023 - "Our data depicted the high incidence of mismatch repair deficiency in T4bM0 mismatch repair deficiency and the effectiveness of the neoadjuvant immune checkpoint inhibition group in organ preservation. " 03/07/2023 - "This observation suggests that an MSH2 c.1808A > T (Asp603Val) variant induces mismatch repair deficiency, resulting in sensitization to immune checkpoint inhibition." 01/01/2022 - "HER2-positive UCS may be less susceptible to immune checkpoint inhibition as they uncommonly show MMR deficiency and/or strong PD-L1 expression. "
2.	Biomarkers (Surrogate Marker)IBA 12/01/2014 - "This study compared two biomarkers in tumours with mismatch repair deficiency; quantification of methylation of the MLH1 promoter region using a novel assay and BRAF c.1799T>A, p.(Val600Glu) mutation status in the identification of constitutional mutations. " 07/24/2023 - "By the extrapolation of the metastatic setting, we explore known predictive biomarkers, i.e., PD-L1, mismatch repair deficiency and tumour mutational burden, as well as potential early-disease-specific biomarkers. " 01/01/2022 - "It provides an update on the established predictive biomarkers (tumour PD-L1 expression, tumour mismatch repair deficiency and tumour mutational burden) and assesses the evidence for new potential biomarkers." 07/20/2020 - "We investigated the association of selected driver mutations, including BRAF, RAS, PIK3CA, TERT promoter, TP53, POLE, and mismatch repair deficiency (MMR-D) with the clinicopathological features of ATC to identify prognostic and predictive biomarkers. " 01/01/2019 - "Even though multiple predictive biomarkers such as PD-L1 expression, mismatch-repair deficiency, and status of tumor infiltrating lymphocytes have been adopted for patient selection, frequent resistance to ICI monotherapy has not been completely resolved. "
3.	pembrolizumabIBA 12/01/2018 - "The patient harboring a MSH2 mutation experienced a long-term complete response after pembrolizumab, while the patient with high mutational burden and absence of mismatch repair deficiency did not have any response. " 06/01/2019 - "Interestingly, after identification of its mismatch repair-deficiency (MLH1/PMS2-absent, MSH2/MSH6-intact), pembrolizumab-based immunotherapy was initiated, leading to a marked clinical response. " 01/01/2019 - "Immune therapy with the PD1 inhibitor pembrolizumab has been approved to treat unresectable/metastatic solid tumours exhibiting mismatch repair (MMR) deficiency. " 07/26/2021 - "The United States Food and Drug Administration has approved treatment with pembrolizumab for patients with advanced GC with PD-L1 expression or microsatellite instability-high/mismatch repair deficiency. " 01/01/2021 - "Prolonged benefit to pembrolizumab in anaplastic oligodendroglioma patient with mismatch repair deficiency: a case report."
4.	DNA (Deoxyribonucleic Acid)IBA 04/16/2013 - "This large multicentre study demonstrated that KRAS mutations and DNA MMR deficiency have a role in a small subgroup of GC irrespective of country of origin, suggesting that this subgroup of GC may have developed along a common pathway. " 01/01/2023 - "Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. " 01/01/2021 - "An Integrative DNA Sequencing and Methylation Panel to Assess Mismatch Repair Deficiency." 01/01/2020 - "We analyzed gene copy number (n = 191) and DNA sequencing data (n = 184) from primary MOC to evaluate signatures of mismatch repair deficiency and homologous recombination deficiency, and other genetic events. " 01/01/2019 - "DNA mismatch repair (MMR) is essential to process O6-MeG adducts and MMR-deficiency leads to tolerance of lesions, resistance to TMZ and further DNA mutations. "
5.	LigandsIBA 08/15/2023 - "Programmed cell death-ligand 1 overexpression or mismatch repair deficiency was not observed in any of the cases. " 06/01/2021 - "The patient had abundant infiltration of programmed death ligand 1-positive macrophages, cytotoxic T cells (CD8-positive lymphocytes), and programmed death 1-positive lymphocytes as well as a high combined positive score of 33.1, high-frequency microsatellite instability, and mismatch repair deficiency. " 01/01/2015 - "Mismatch repair deficiency associated with complete remission to combination programmed cell death ligand immune therapy in a patient with sporadic urothelial carcinoma: immunotheranostic considerations." 01/01/2018 - "Mismatch repair (MMR) deficiency in solid tumors has recently been linked to susceptibility to immunotherapies targeting the programmed cell death-1 (PD-1)/programmed cell death-1 ligand (PD-L1) axis. " 01/01/2019 - "Immunotherapy against the interaction between programmed cell death 1/programmed cell death ligand 1 (PD-L1) has emerged as a promising strategy for colorectal cancer with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H). "
6.	A-Form DNA (A-DNA)IBA 08/01/2009 - "The findings of this study could suggest the relationship of a DNA mismatch repair deficiency with high-risk subtypes of PA and the implication of its role in the origin and progression of these subtypes." 01/01/2018 - "Lesions of both sites showed a DNA mismatch repair deficiency with immunohistochemical loss of MLH1 and PMS2 expression without MLH1 promoter hypermethylation. " 06/15/1996 - "A mutator phenotype due to a DNA mismatch repair deficiency is usually detected by typing a number of microsatellite markets. " 02/01/2001 - "The presence in these neoplasms of multiple mutations in tumor suppressor genes suggests the involvement of a novel disease mechanism but there was no indication of a DNA mismatch repair deficiency or of an inherited tumor syndrome." 10/01/2000 - "These findings suggest that a DNA mismatch repair deficiency may contribute to the pathogenesis of ovarian granulosa cell tumors, and that this deficiency may be an early event in their development and/or progression."
7.	Hormones (Hormone)IBA 05/28/2010 - "However, recent studies have reported an association between mismatch repair deficiency and loss of specific hormone receptors, inferring a potential role for mismatch repair deficiency in this transition. " 01/01/2021 - "A total of 57 endometrial biopsy specimens obtained before hormone therapy were evaluated, and patients were classified according to the Proactive Molecular Risk Classifier for Endometrial Cancer molecular subtypes (mismatch repair deficiency, DNA polymerase epsilon mutation, wild-type p53, and abnormal p53). " 01/01/2020 - "APA glands appeared analogous to atypical endometrial hyperplasia (endometrioid cytokeratins pattern, Ki67≤50%, common PTEN loss, and occasional mismatch repair deficiency); the prominent expression of hormone receptors and nuclear β-catenin suggest that APA may be a precursor of "copy number-low," CTNNB1-mutant endometrial cancers. " 09/01/2022 - "In this review, we summarized several main prognostic and predictive biomarkers in breast cancer at genomic, transcriptomic and proteomic levels, including hormone receptors, HER2, Ki67, multiple gene expression assays, PD-L1 testing, mismatch repair deficiency/microsatellite instability, tumor mutational burden, PIK3CA, ESR1 andNTRK and briefly introduced the roles of digital imaging analysis in breast biomarker evaluation." 10/01/2020 - "Medical treatment depends on histological type, presence of hormone receptors and patient's profile to refer to chemotherapy (carboplatin-paclitaxel) or hormone therapy (for example of the progestogen type); in the event of MMR-deficiency, immunotherapy trial is the best option. "
8.	AntibodiesIBA 11/01/2021 - "PD-L1 positivity significantly correlated with TILs > 5% and MMR deficiency, and PD-L1-positive cases (overall and IC) showed significantly longer overall survival (OS) with both antibodies.The" 01/01/2010 - "We propose that staining for PMS2 and MSH6 alone will be sufficient to detect all cases of mismatch repair deficiency and should replace routine screening with all four antibodies. " 01/01/2004 - "Immunohistochemistry to demonstrate loss of expression of DNA mismatch repair genes serves as a highly reliable test of mismatch repair deficiency if antibodies to hMLH1, hMSH2, hMSH6 and hPMS2 are employed." 01/01/2019 - "Mismatch repair deficiency (dMMR) results in microsatellite instability (MSI) and is strongly associated with responsiveness to programmed death-1 receptor (PD-1)-blocking antibodies. " 01/01/2010 - "Currently, testing for mismatch repair deficiency in colorectal cancers is initiated by performing immunohistochemistry with four antibodies (MLH1, PMS2, MSH2 and MSH6). "
9.	NivolumabIBA 12/01/2023 - "Efficacy of Nivolumab in Pediatric Cancers with High Mutation Burden and Mismatch Repair Deficiency." 12/01/2023 - "We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD). " 12/01/2018 - "Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency." 01/01/2024 - "Pediatric glioblastoma in the setting of constitutional mismatch-repair deficiency treated with upfront lomustine and nivolumab." 12/01/2020 - "This report highlights an extremely rare genetic condition constitutional mismatch repair deficiency (CMMRD) in an Indian pediatric patient with dual malignancies, who suffered from transient encephalopathy, a rare side effect of the drug Nivolumab and the associated challenge during CSF protein electrophoresis interpretation."
10.	dostarlimabIBA 01/01/2023 - "Recent clinical trials have shown that dostarlimab is effective in treating mismatch repair deficiency (dMMR) in endometrial cancer patients, leading to its approval in the United States and the European Union in 2021. " 01/01/2022 - "Dostarlimab treatment showed an encouraging response rate in endometrial cancer patients with mismatch repair deficiency. " 01/01/2022 - "In this case report, we describe an exceptional and rapid response to dostarlimab in a platinum refractory endometrial cancer patient with high disease burden harboring a mismatch repair deficiency." 11/01/2023 - "Mismatch repair deficiency (dMMR) occurs in various cancers, and these tumors are attractive candidates for anti-programmed cell death 1 therapies, such as dostarlimab, a recently approved immune checkpoint inhibitor. " 06/01/2023 - "In addition to these approvals, dostarlimab for mismatch repair deficiency(dMMR), dabrafenib and trametinib for BRAF V600E, and selpercatinib for RET fusion gene have been approved in the United States as tumor agnostic biomarkers and their treatment. "

Therapies and Procedures

1.	Immunotherapy 01/01/2022 - "Underlying MMR deficiency-associated immunogenicity is important for improving the therapeutic efficacy of immunotherapies. " 12/01/2023 - "Higher SUVmax was associated with MMR deficiency in EC patients with endometrioid type, advanced stage, or deep myometrial invasion, which may be useful for predicting the MMR status and thus aiding in determination of immunotherapy for patients with EC." 01/01/2023 - "Immunotherapy-sensitizing mismatch repair deficiency was identified in 1 patient. " 10/01/2021 - "We investigated the association between MMR-deficiency and PD-L1 in TNBC; aiming to identify PD-L1 negative, TNBC patients that may be candidates for anti-PD-L1 immunotherapy. " 08/01/2020 - "In addition, immunotherapy could be an option, especially for EOC carrying mismatch repair deficiency or POLE mutations."
2.	Therapeutics 01/01/2018 - "Aims of our study are to evaluate whether MMR-deficiency testing leads to (1) identification of LS, (2) change in surgical treatment and (3) adjustment of systemic therapy in patients with dMMR CRC. " 04/01/2023 - "Programmed death ligand-1 (PD-L1) is a co-regulatory molecule that suppresses local immunity, and mismatch repair (MMR) deficiency (dMMR) is reported to influence the response to anti-PD-L1-targeted therapy. " 03/15/2022 - "Some of these are recognized as being susceptible to immune therapies and are said to have mismatch repair deficiency (dMMR). " 10/01/2021 - "Mismatch repair deficiency (dMMR) is correlated with a high level of mutation-associated neoantigens, most recognized by immune cells which could predict a favorable response to anti-PD-1/PD-L1 therapy. " 04/01/2017 - "These may include mismatch repair deficiency and high mutational load that might be germline, somatic, or acquired after therapy. "
3.	Drug Therapy (Chemotherapy) 01/01/2021 - "Chemotherapy and mismatch repair deficiency cooperate to fuel TP53 mutagenesis and ALL relapse." 11/16/2023 - "We also found that HAS patients with recurrent disease treated by emerging therapy had a better survival than those treated with traditional chemotherapy (p = 0.002, median recurrence-to-death survival: 23 months versus 6 months); HAS patients who received anti-HER2 therapy or harbored MMR deficiency had favorable prognosis. " 01/01/2019 - " mutational signature of HSP110 within mismatch repair deficiency-related tumors may help to identify patients likely to benefit from 5-fluorouracil-based chemotherapy.Intensified" 10/03/2023 - "Perioperative Chemotherapy Could Not Improve the Prognosis of Gastric Cancer Patients With Mismatch Repair Deficiency: A Multicenter, Real-World Study." 03/01/2023 - "In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. "
4.	Adjuvant Chemotherapy 03/01/2018 - "Mismatch repair deficiency (dMMR) confers an improved prognosis identifying patients unlikely to benefit from adjuvant chemotherapy. " 10/27/2023 - "The benefit of adjuvant chemotherapy for locally advanced gastric cancer (LAGC) patients with DNA mismatch repair (MMR) deficiency (D-MMR) is controversial due to concerns about its potential detrimental effect. " 01/01/2022 - "Background: The prognostic relevance of the PIK3CA mutation together with PD-L1, c-Met, and mismatch repair deficiency (dMMR) have not been fully investigated in Asian women with breast cancer (BC) who have undergone postoperative adjuvant chemotherapy. " 12/01/2021 - "Prognostic and predictive value of mismatch repair deficiency in gastric and gastroesophageal junction adenocarcinoma patients receiving neoadjuvant or adjuvant chemotherapy." 09/01/2015 - "Mismatch repair deficiency (dMMR) has been shown to confer a superior prognosis and is possibly predictive of a lack of benefit from fluoropyrimidine adjuvant chemotherapy (AC) for early-stage colon cancer (ESCC). "
5.	Chemoprevention 01/01/2017 - "The biology of neoplasia caused by germline mutations has led to paradigm-changing precision prevention efforts, including: tumor testing for mismatch repair (MMR) deficiency in Lynch syndrome establishing a new paradigm, combinatorial chemoprevention efficacy in familial adenomatous polyposis (FAP), signal of benefit from imaging-based early detection research in high-germline risk for pancreatic neoplasia, elucidating early ontogeny in BRCA1-mutation carriers leading to an international breast cancer prevention trial, and insights into the intricate germline-somatic-immunity interaction landscape. " 01/01/2018 - "This underlines that targeting MMR-deficient cells by chemoprevention or vaccines against MMR deficiency-induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome."