Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome

Defective mismatch repair leads to increased mutation rates, and germline loss-of-function variants in the repair component MLH1 cause the hereditary cancer predisposition disorder known as Lynch syndrome. Early diagnosis is important, but complicated by many variants being of unknown significance. Here we show that a majority of the disease-linked MLH1 variants we studied are present at reduced cellular levels. We show that destabilized MLH1 variants are targeted for chaperone-assisted proteasomal degradation, resulting also in degradation of co-factors PMS1 and PMS2. In silico saturation mutagenesis and computational predictions of thermodynamic stability of MLH1 missense variants revealed a correlation between structural destabilization, reduced steady-state levels and loss-of-function. Thus, we suggest that loss of stability and cellular degradation is an important mechanism underlying manyMLH1 variants in Lynch syndrome. Combined with analyses of conservation, the thermodynamic stability predictions separate disease-linked from benignMLH1 variants, and therefore hold potential for Lynch syndrome diagnostics.
Source: eLife - Category: Biomedical Science Tags: Cancer Biology Computational and Systems Biology Source Type: research

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AbstractLynch syndrome accounts for 3 –5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genesMLH1,MSH2,MSH6, andPMS2. Somatic hypermethylation of theMLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors locate...
Source: Familial Cancer - Category: Cancer & Oncology Source Type: research
CONCLUSIONS: Patients with POLE EDM EEC have been shown to have a favorable prognosis. In this real-world cohort of patients, de novo metastatic disease and recurrences in initially uterine-confined cases were observed. Further research is warranted before incorporating the presence of POLE EDM into decision-making regarding adjuvant therapy. PMID: 31757464 [PubMed - as supplied by publisher]
Source: Gynecologic Oncology - Category: Cancer & Oncology Authors: Tags: Gynecol Oncol Source Type: research
We report the case of a Lynch syndrome patient with metastatic CRC and urothelial cancer who was treated sequentially with pembrolizumab (targeting PD1), atezolizumab (targeting PD‐L1), brief rechallenge with pembrolizumab, and finally the combination of ipilimumab (targeting CTLA‐4) and nivolumab (targeting PD1). Over a 28‐month period the patient experienced prolonged disease control with each different regimen the first time it was given, including metabolic response by positron emission tomography and computed tomography scanning and tumor marker reductions. The case suggests that some patients with advanced MMR...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Precision Medicine Clinic: Molecular Tumor Board, Gastrointestinal Cancer Precision Medicine Clinic: Molecular Tumor Boards Source Type: research
Since 2017, the National Institute for Health and Care Excellence (NICE) has recommended molecular testing of all patients with newly diagnosed colorectal cancer (CRC) to identify those with suspected Lynch syndrome who should be referred to clinical genetics for germline testing. The pathway involves firstly determining the mismatch repair (MMR) expression status by immunohistochemistry (IHC) or performing microsatellite instability testing. This may be followed by BRAF V600E mutation testing and then MLH1 promoter hypermethylation analysis depending on the result.
Source: Diagnostic Histopathology - Category: Pathology Authors: Tags: Mini-symposium: Gastrointestinal/Hepato-Pancreato-Biliary Pathology Source Type: research
CONCLUSION: This is the first audit of a Canadian-based universal LS screening protocol of patients with endometrial cancer. The success of the protocol is endorsed by the 80% compliance and by the 2% prevalence of LS, which is within the published range. PMID: 31679916 [PubMed - as supplied by publisher]
Source: Journal of Obstetrics and Gynaecology Canada : JOGC - Category: OBGYN Tags: J Obstet Gynaecol Can Source Type: research
Conclusions: Our results suggest that transcriptional patterns are indicative for TMM pathway activation with subtle differences between TEL and ALT mechanisms in a CRC subtype-specific fashion. Sequencing data potentially provide a suited measure to study alterations of telomere length and of underlying transcriptional regulation. Further studies are needed to improve this method.
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
(Abstracted from Cancer 2019;125(18):3172–3183) Lynch syndrome caused by germline mutations in several DNA mismatch repair (MMR) proteins is the most common cause of hereditary and endometrial cancers. Lynch syndrome accounts for approximately 2% to 3% of all endometrial cancers, although the lifetime risk of endometrial cancer for patients with Lynch syndrome varies depending on the specific mutation.
Source: Obstetrical and Gynecological Survey - Category: OBGYN Tags: GYNECOLOGY: GYNECOLOGIC ONCOLOGY Source Type: research
AbstractPurpose of reviewIdentification of Lynch syndrome is important from an individual patient and public health standpoint. As paradigms for Lynch syndrome diagnosis have shifted in recent years, this review will discuss rationale and limitations for current strategies as well as provide an overview of future directions in the field.Recent findingsIn recent years, the use of clinical criteria and risk scores for identification of Lynch syndrome has been augmented by universal testing of all newly diagnosed colorectal cancers with molecular methods to screen for mismatch repair deficiency with high sensitivity and speci...
Source: Current Treatment Options in Gastroenterology - Category: Gastroenterology Source Type: research
CONCLUSION:  LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed. PMID: 31739377 [PubMed - in process]
Source: Zeitschrift fur Gastroenterologie - Category: Gastroenterology Authors: Tags: Z Gastroenterol Source Type: research
Lynch syndrome (LS) is an autosomal dominant hereditary cancer predisposition syndrome caused by pathogenic germline variants in DNA mismatch repair genes (MMR) MLH1, MSH2, MSH6 and PMS2. LS accounts for 3 –5% of all colorectal cancers (CRC). LS associated CRC generally has microsatellite instability and lacks for MMR protein expression. The risk of CRC in LS patients is between 10 and 82% depending on the involved MMR gene. LS patients are at high risk to develop synchronous/metachronous cancer bot h colonic and extracolonic (e.g.
Source: Digestive and Liver Disease - Category: Gastroenterology Authors: Tags: Correspondence Source Type: research
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