MSH6 mutation

A better diagnostic approach is to perform genetic testing to rule out the risk as early as possible when a newborn presents with cafe-au-lait spots, which are a typical feature of hereditary syndromes. Therefore, it is important to use germline genetic testing, combined with clinical phenotypic observation, to establish a diagnosis of a cancer susceptibility syndrome caused by an MMR gene mutation.

The results validate our previous findings from mice and highlight early mitotic abnormalities as an important contributor and precancerous marker of colorectal tumourigenesis in LS.

Reduced MSH6 expression could serve as a potential biomarker for predicting better prognosis, active immune status, higher immune checkpoint expression level and better responsiveness to ICIs treatment in EC. MSH6 may become a potential target for treating solid tumors.

MSIsensor scores as low as 3.5% may represent true MMRd in EC tested by NGS. Further testing for MMRd is advised for MSIsensor scores between 3% and 30%, particularly if there is low tumor content or associated high TMB. In this setting, MMR IHC may have superior sensitivity for detection of MMRd compared to DNA-based assays.

In the case of a patient with double primary EC and CRC, a careful evaluation of the IHC and the genetic data was presented. The patient carried rare compound heterozygous variants, a germline missense mutation, and a somatic frameshift mutation of MSH6, combined with a novel somatic null variant of MSH2. Our study broadened the variant spectrum of double primary cancer and provided insight into the molecular basis for abnormal MSH2 protein loss and double primary carcinoma.

This case embodied the theoretically understandable clonal expansion of the TP53 mutation with additional mismatch repair gene dysfunction leading to hypermutator phenotype. It thus indicated that TP53 mutation in oligodendroglioma, although not common, may play a critical role in the development of hypermutator after TMZ treatment.

POLE/POLD1 mutations frequently co-exist with MSI-H disease in CRC. Patients with MSS-CRC harboring POLE/POLD1 mutations represent a smaller subgroup of CRC (~1%). The incidence of POLE/POLD1 somatic mutations was more common among patients with colon cancer than those with rectal cancer.

This study elucidated the comprehensive mutational landscape of advanced gastrointestinal cancer through liquid biopsy, thereby contributing novel biomarkers for clinical diagnosis and facilitating targeted therapy mechanism investigations.

This study revealed that high expression of MMR proteins is a common feature of DLBCL associated with lower tumor-infiltrating T cells, MYC and p53 overexpression, and context-dependent prognostic effects. In contrast, dMMR and loss of MMR proteins are infrequent and have no significant prognostic effects in DLBCL treated with standard chemoimmunotherapy. These results may have implications for understanding DLBCL biology and the low efficacy of PD-1 blockade immunotherapy in DLBCL.

To conclude, we provide evidence that neurotoxicity, including sensory neurotoxcity, is triggered by CisPt-induced DNA intra- and interstrand crosslinks that are subject of repair by NER and ICL repair. We hypothesize that especially ERCC1/XPF, CSB and MSH6-related DNA repair protects from chemotherapy-induced neuropathy in the context of CisPt-based anticancer therapy.

Our findings highlighted the importance of accurately interpreting heterogeneous MMR protein staining patterns for developing a more efficient personalized genetic investigation strategy.

Using current screening guidelines, a significant proportion of patients with LS-associated UTUC may be missed. We suggest universal immunohistochemical MMRp screening for all UTUCs, regardless of age and clinical history.

The case is unique suggesting a possible interaction between the two pathways and contributing to carcinogenesis in this patient. This also suggests need for a thorough germline and somatic mutation evaluation in select colorectal cancer patients to direct a tailored therapy.

The findings support expanding the definition of DEC to include DEC-HG, a previously under-recognised phenomenon with genomic similarities to DEC-LG.

Methods We examined 57 patients with low grade G1/G2 PanNET treated by TMZ +/- capecitabine in one expert center between 2009 and 2020. In both cohorts, none of the TMB-high samples showed the glioblastoma-specific MSH6 mutation, suggesting a better immunogenic potential. Conclusions These results suggest that TMZ induces an hyperprogressor and hypermutator phenotype in a subset of PanNETs, through a potentially immunogenic mechanism, thereby opening the path to immunotherapy, a treatment not otherwise effective in patients with treatment naive PanNET.

This study highlights the utility of tumor sequencing to guide sensitive ddPCR testing to detect low-level mosaicism in the MMR genes. Further investigation of the prevalence of MMR mosaicism is needed to inform routine diagnostic approaches and genetic counselling.

MMR gene mutation testing is recommended for prostate cancer patients with early onset, low initial PSA, metastasis or early resistance to castration therapy.

Lynch syndrome was present in 2% of patients with CCC. However, some cases with MSH6 mutation can evade all testing methods, including IHC, PCR, and NGS-MSI.

In summary, subclonal MMR loss reflects subclonal and often complex genomic and epigenetic alterations, which may have therapeutic implications and therefore must be reported when present. In addition, subclonal loss can occur in both POLE-mutated and Lynch syndrome-associated ECs.

The microsatellite status of patients with heterogeneous MMR protein staining is unpredictable. Given the heterogeneity of mismatch repair, microsatellite status should be assessed for all specimens if sufficient specimens can be obtained.

In addition, we identified several mutated genes associated with MSI-high phenotypes, including known mismatch repair genes (e.g., MSH3, POLD1, MLH1, and MSH6) and novel mutated genes (e.g., RNF43, ARID1A, ARID1B, NOTCH3, SMARCA4, KMT2C, and CREBBP), in endometrial cancer (n=32 genes), in colorectal cancer (n=29 genes) and in stomach cancer (n=18 genes), at a Bonferroni-corrected P < 0.05.Our study revealed large discrepancies in prevalence between MSI-high and TMB-high in many cancer types,, highlighting the need to consider distinct or combined biomarkers for immunotherapies. Our study also identified novel mutated genes associated with MSI-high cancers, providing additional insights into MSI-high carcinogenesis and candidate genetic biomarkers to screen patients for potential immunotherapy.

Based on our in silico analysis, the deleterious effect of the detected missense mutation in the active site of ATP binding motif of MSH6 affects the structure and function of MSH6. This may result in the accumulation of mono-, or di-nucleotide repeats instability in the genome, leading to genomic alterations that associate with carcinogenesis in African American CRC patients.

MMRD gliomas with TMB and MSI-H may be sensitive to immunotherapy but resistant to temozolomide...Half of the MMRD-gliomas and all Lynch syndrome-associated GBMs were high in microsatellite instability. These tumors had high mutational burdens and tended to have shorter progression-free survival than glioma without MMRD.

PMRDIA occurs in the context of primary mismatch repair deficiency, is characterized by frequent MSH6 mutations, hypermutation, low frequency of MGMT promoter methylation, and poor clinical outcomes. Finally, oligosarcoma is a tumor featuring oligodendroglial and sarcomatous areas, and is characterized by worse outcome and frequent 1p/19q copy number loss of heterozygosity.

Overall, these findings suggest that cervical HPV-associated NETs are genomically silent and high-grade NECs (regardless of small or large cell morphology) share molecular pathways with common cervical carcinomas as it has been reported in the endometrium and are different from NECs at other sites. Molecular analysis of these highly malignant neoplasms might inform the clinical management for potential therapeutic targets.

Lastly, we did not find significantly different mutant germline genes, but MSH-6 mutation may be a potential MP-OC driver. In short, our preliminary results show that MP-OC and P-OC have different molecular characteristics.

The findings highlight challenges in MSI detection in endometrial cancer using PCR-based methods. The imperfect correlation between IHC for MMR and molecular MSI testing has been acknowledged. The automated rapid Idylla MSI assay yields negative results in more than 60% of dMMR endometrial cancer cases when manufacturer's instructions are followed.

No abstract available

MMR gene alterations (hMLH1/hMSH2) play an important role in the development of MSI in sporadic EAC. Most presumed sporadic, MSI-positive EACs are associated with epigenetic silencing of MLH1, via promoter hypermethylation. A smaller fraction have somatic mutations in MSH6, or loss of MSH2 protein expression.

We developed endometrial cancer organoids representing the 4 TCGA molecular classifications, which will provide useful experimental models for translational research.

The literature search revealed 2,494 observational studies, of which 26 met inclusion criteria for full-text abstraction. For HDGC, ranges for cumulative incidence of diffuse gastric cancer (DGC) varied widely across four studies. In men, four studies showed cumulative incidence by the eighth decade of life ranged from 37.2% (95% CI, 8.7-89.5) to 70.0% (95% CI, 40-94), while ranges for women were uniformly lower by the eighth decade, ranging from 24.7% (95% CI 6.1-68.9) to 63% (95% CI 19-99).

No significant immunophenotype features special for different morphological subtypes of DGC were identified, but we suggest that further studies of mucin profile in patients with MSI are of value. We suppose that older age and MSI are indicative for DGT originating from intestinal-type gastric cancer. Whether mixed type gastric cancer may represent a transitional form between IGC and DGT remains a question.

MSI unstable tumors were found to have higher PFS and higher OS in our study. It needs prospective validation in larger studies in Indian scenario.

Non-endometrioid histology was more prevalent in patients with MSH6 or PMS2 mutations (41.7%) than those with MLH1 or MSH2 mutations (5.6%, p = 0.026). In this pre-selected cohort of endometrial cancer patients who underwent next generation sequencing, the prevalence of LS was 13%, thus supporting the use of gene panel testing for endometrial cancer patients.

A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A patient's subset whose tumors displayed the MSH6 mutation, the TMZ mutational signature and increased TMB, achieved disease stabilization upon pembrolizumab treatment.

The clinical features were different between ovarian cancer in Lynch syndrome and sporadic cases. More research are needed for a greater understanding of the prevention and medical treatment of LS-associated OC.

Intriguingly, the immunogenicity of recurrent gliomas did not increase significantly compared to the primary tumors. Genomic analysis of recurrent gliomas provided an opportunity to identify potentially clinically informative alterations not detected in clinically sampled primary tumors.

Offered therapies included ibrutinib for DLBCL with a CD78B mutation, romidepsin for T cell lymphoma with a TET2 mutation, and ruxolitinib for T cell lymphoma with JAK2 fusion...Identified resistance mutations included alterations in BTK , PLCG2 , and BCL2 genes, which led to changes in therapy from a BTK inhibitor to venetoclax or vice versa...Conclusion Comprehensive genomic profiling of non-myeloid hematologic malignancies identified variants of clinical significance in 72% of patients and led to changes in practice in 22% of patients. CGP was often sent late in the clinical course.

MSI-H/dMMR BRAFV600E CRCs undergo broad metabolic reprogramming (e.g., glycerophospholipidgalactose, nucleotide). A rise in lipid metabolism, particularly with NK inflammation, suggests that BRAFV600Emutated tumors may be associated with a non-classical immune component. BRAFV600E and BRAFwt CRCs exhibited similar NTB and T cell infiltration, suggesting that both are likely to benefit from immune checkpoint inhibitors.

We found possible genes and related signaling pathways that affect metastasis. These results can improve our understanding of the mutation characteristics of SCLC and identify potential biomarkers to guide targeted therapies.

LS is an autosomal dominant cancer predisposition syndrome caused by germline mutation of mismatch repair (MMR) genes, most frequently associated with colorectal and endometrial sarcomas starting in the 4th decade.This is very rarely associated with sarcomas, with only 3 patients described with RMS. Lymphomas are overall rare but have been described more frequently in LS pedigrees. This is the first description of a patient with LS harboring a FP-ARMS.

These novel somatic mutations indicate the existence of additional/alternative lymphomagenesis pathways in OAML. Moreover, the difference between our and previous studies suggests genetic heterogeneity of OAML between Asian and Western individuals.