Lynch Syndrome: Widening the Net
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.
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 pre...
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]
European Journal of Human Genetics, Published online: 06 November 2019; doi:10.1038/s41431-019-0538-7Microsatellite instability screening in colorectal adenomas to detect Lynch syndrome patients? A systematic review and meta-analysis
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.
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...
A 44-year-old man was evaluated for recurrent angioedema manifested as more than 10 discrete episodes with swelling of the posterior pharynx and uvula, without urticaria, that would subside spontaneously over 24 hours. These episodes were first noted 2 years ago, were worsened by alcohol, and were not responsive to antihistamines. Medical history was significant for hyperestrogenism, that worsened with testosterone treatment for infertility. His primary family history revealed a father and brother with gynecomastia, a mother with endometrial cancer, and a sister with Lynch syndrome.
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.
CONCLUSIONWhen detecting a lytic spinal tumor in a patient who suffers from LS a SPB should be taken under consideration.
ConclusionWe found a novel largeEPCAM-MSH2 duplication associated with LS and the presence of LOHs in regions containing numerous tumor suppressors, raising the hypothesis that these alterations could contribute to cancer susceptibility. Our results underline the importance to deepen the knowledge of molecular mechanisms in order to determine the role in cancer predisposition of novel genetic alterations.