Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum

Fernández–Rozadilla, Ceres; Álvarez-Barona, Miriam; Schamschula, Esther; Bodo, Sahra; López-Novo, Anael; Dacal, Andrés; Calviño-Costas, Consuelo; Lancho, A.; Amigo, Jorge; Bello, Xabier; Cameselle-Teijeiro, José; Carracedo, Ángel; Colas, Chrystelle; Muleris, Martine; Wimmer, Katharina; Ruíz-Ponte, Clara

doi:10.3390/cancers11081081

Cited by 8 publications

(6 citation statements)

References 32 publications

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“…When both are in the same gene it causes constitutional mismatch repair deficiency (CMMR-D) syndrome. CMMR-D is a classic recessive DNA repair disorder typically characterised by childhood-onset leukaemia, lymphoma, and colorectal and brain cancers, but also, in contrast to LS, some patients may have multiple colorectal adenomas [42][43][44]. Signs suggestive of neurofibromatosis type 1 also often occur, such as café-au-lait macules and cutaneous neurofibromata, plus other features such as immune deficiency [45].…”

Section: Other Genetic Conditions Relating To Lynch Syndromementioning

confidence: 99%

“…Finally, Turcot syndrome, a combination of colorectal cancer or adenomas and central nervous system tumours, with dominant or recessive inheritance, is another historical descriptive diagnosis that has been related to Molecular pathology of Lynch syndrome 519 LS. However, it is now known that it can be due to CMMR-D, familial adenomatous polyposis (FAP), and probably other conditions, and so as an ambiguous term it should be abandoned [42,44,50].…”

Section: Other Genetic Conditions Relating To Lynch Syndromementioning

confidence: 99%

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Molecular pathology of Lynch syndrome

Cerretelli

Ager

Arends

et al. 2020

The Journal of Pathology

117

106

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Lynch syndrome (LS) is characterised by predisposition to colorectal, endometrial, and other cancers and is caused by inherited pathogenic variants affecting the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. It is probably the most common predisposition to cancer, having an estimated prevalence of between 1/100 and 1/180. Resources such as the International Society for Gastrointestinal Hereditary Cancer's MMR gene variant database, the Prospective Lynch Syndrome Database (PLSD), and the Colon Cancer Family Register (CCFR), as well as pathological and immunological studies, are enabling advances in the understanding of LS. These include defined criteria by which to interpret gene variants, the function of MMR in the normal control of apoptosis, definition of the risks of the various cancers, and the mechanisms and pathways by which the colorectal and endometrial tumours develop, including the critical role of the immune system. Colorectal cancers in LS can develop along three pathways, including flat intramucosal lesions, which depend on the underlying affected MMR gene. This gives insights into the limitations of colonoscopic surveillance and highlights the need for other forms of anti-cancer prophylaxis in LS. Finally, it shows that the processes of autoimmunisation and immunoediting fundamentally constrain the development of tumours in LS and explain the efficacy of immune checkpoint blockade therapy in MMR-deficient tumours.

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Section: Other Genetic Conditions Relating To Lynch Syndromementioning

confidence: 99%

Section: Other Genetic Conditions Relating To Lynch Syndromementioning

confidence: 99%

Molecular pathology of Lynch syndrome

Cerretelli

Ager

Arends

et al. 2020

The Journal of Pathology

117

106

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“…Interestingly, a number of paternally-inherited low/moderate penetrance variants in other cancer predisposing genes and genes described as genetic modifiers of Lynch syndrome were identified. The assembled data on this patient suggest that the combination of several low-risk modifier alleles together with a pathogenic MSH2 variant may be responsible for the CMMRD-like phenotype in this patient [ 9 ].…”

Section: Cmmrd-like Phenotypesmentioning

confidence: 99%

Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019

et al. 2020

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Constitutional mismatch repair deficiency (CMMRD) is an autosomal recessive condition associated with a high risk of cancer in children, adolescents and young adults. CMMRD is caused by homozygous or compound heterozygous pathogenic germline variants in one of four mismatch repair (MMR) genes (i.e., MLH1, MSH2, MSH6 and PMS2) [1], whereas mono-allelic (heterozygous) MMR gene variants result in autosomal dominant Lynch syndrome [2]. Lynch syndrome is one of the most common cancer predisposition syndromes and in adults leads to an increased risk of colorectal cancer, endometrial cancer and other malignancies [2]. By contrast, CMMRD is rare and leads to an increased risk of brain tumors, hematological malignancies, colorectal cancer and a wide range of other cancers in children, adolescents and young adults [1]. In addition, most patients with CMMRD have non-neoplastic features, with multiple café-au-lait maculae (CALM) being the most prevalent [1, 3]. This report summarizes the 5th meeting held by the 'Care for CMMRD' (C4CMMRD) consortium in Leiden, the Netherlands, on July 6th 2019. The consortium was established in 2013 with a number of explicit goals, including

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“…20 AKT and mTOR are crucial participants in the PI3K-Akt signaling pathway in EMT. 6,21 Notably, AKT and mTOR had a higher degree (reflecting greater network connectivity) in the compoundtarget analysis, as shown in Figure 1A. We therefore hypothesized the inhibition of EMT by dioscin occurred via targeting AKT and mTOR.…”

Section: Network Pharmacology-based Target Prediction For Dioscinmentioning

confidence: 93%

<p>Network Pharmacology and Experimental Evidence Reveal Dioscin Suppresses Proliferation, Invasion, and EMT via AKT/GSK3b/mTOR Signaling in Lung Adenocarcinoma</p>

Mao¹,

Yin²,

Chen³

et al. 2020

DDDT

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Dioscin, a natural glycoside derived from many plants, has been proved to exert anti-cancer activity. Several studies have found that it reverses TGF-β1-induced epithelialmesenchymal transition (EMT). Whether dioscin can reverse EMT by pathways other than TGF-β is still unknown. Methods: We used network-based pharmacological methods to systematically explore the potential mechanisms by which dioscin acts on lung cancer. Cell Counting Kit-8 assay, scratch healing, Transwell assay, Matrigel invasion assay, immunofluorescence assay, and Western blotting were employed to confirm the prediction of key targets and the effects of dioscin on EMT. Results: Here, using network-based pharmacological methods, we found 42 possible lung cancerrelated targets of dioscin, which were assigned to 98 KEGG pathways. Among the 20 with the lowest p-values, the PI3K-AKT signaling pathway is involved and significantly related to EMT. AKT1 and mTOR, with high degrees (reflecting higher connectivity) in the compound-target analysis, participate in the PI3K-AKT signaling pathway. Molecular docking indicated the occurrence of dioscin-AKT1 and dioscin-mTOR binding. Functional experiments demonstrated that dioscin suppressed the proliferation, migration, invasion, and EMT of human lung adenocarcinoma cells in a dose-dependent manner, without TGF-β stimulation. Furthermore, we determined that dioscin downregulated p-AKT, p-mTOR and p-GSK3β in human lung adenocarcinoma cells without affecting their total protein levels. The PI3K inhibitor LY294002 augmented these changes. Conclusion: Dioscin suppressed proliferation, invasion and EMT of lung adenocarcinoma cells via the inactivation of AKT/mTOR/GSK3β signaling, probably by binding to AKT and mTOR, and inhibiting their phosphorylation.

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Early Colorectal Cancers Provide New Evidence for a Lynch Syndrome-to-CMMRD Phenotypic Continuum

Cited by 8 publications

References 32 publications

Molecular pathology of Lynch syndrome

Molecular pathology of Lynch syndrome

Report of the fifth meeting of the European Consortium 'Care for CMMRD' (C4CMMRD), Leiden, The Netherlands, July 6th 2019

<p>Network Pharmacology and Experimental Evidence Reveal Dioscin Suppresses Proliferation, Invasion, and EMT via AKT/GSK3b/mTOR Signaling in Lung Adenocarcinoma</p>

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