MSH3 mutation

This study establishes MRPL12 as a novel oncogene in LUAD, contributing to LUAD pathogenesis by orchestrating mitochondrial metabolism reprogramming towards oxidative phosphorylation (OXPHOS). Furthermore, it confirms Y60 as a specific phosphorylation modification site regulating MRPL12's oncogenic functions, offering insights for the development of LUAD-specific targeted drugs and clinical interventions.

This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H.

P1/2, N=58, Completed, Asan Medical Center | Active, not recruiting --> Completed

This is one of the largest studies to investigate the landscape of immunogenic neoantigens in CRC. We were able to identify candidate recurrent peptides with high HLA binding affinity and an association with a positive TIS signature supporting the role of neoantigens as potential cancer immunotherapy targets.

CDK12 is associated with tandem-duplications, and we here demonstrate that this association can accurately predict gene deficiency in prostate cancers (area under the ROC curve=0.97). Our novel associations include mono- or biallelic LOF variants of ATRX, IDH1, HERC2, CDKN2A, PTEN, and SMARCA4, and our systematic approach yielded a catalogue of predictive models, which may provide targets for further research and development of treatment, and potentially help guide therapy.

P1/2, N=58, Active, not recruiting, Asan Medical Center | Unknown status --> Active, not recruiting | Trial completion date: Jun 2021 --> Jun 2023 | Trial primary completion date: Jun 2021 --> Jun 2023

Analysis of 180,000 tumors revealed a high concordance of IHC-MMR/NGS-MSI with a rate of 99.7%. In 20% of MMRp/MSI-H cases, interpretation of IHC lead to misdiagnosis that the NGS-MSI would have avoided. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd.

Here we report from >28,000 CRC tumors that the concordance of IHC-MMR/NGS-MSI is 99.74%. Clinical outcome from a large cohort of patients show NGS is not inferior compared to IHC in identifying patients with MSI-H/MMRd. The additional lens that NGS-MSI offers is of value in identifying CRC patients who may benefit from ICI therapy.

Individualized combination therapies based on whole-exome sequencing displayed significant clinical benefits in this case. Germline MSH3 and ERCC4 mutation may induce a secondary osteosarcoma in glioblastoma patients.

Despite the unique environment of the augmented tissue, the resulting tumors demonstrate a spectrum of driver mutations similar to that of primary gastrointestinal adenocarcinomas. Importantly, molecular alterations potentially amenable to targeted therapy were identified in the majority of cases.

Mechanistically, we hypothesize that mutant MSH3 protein (1) may be sequestered in cytoplasm; (2) may be resistant to protein degradation; and (3) may compete with MSH6 for MSH2 binding causing a reduction of MutSα. To test our hypothesis, MSH3-knockout cells will be used to evaluate biological effects of both c.2436-1G>A or c.3265>T mutations.

Finally, we constructed an OS predict model of PT-DLBCL patients using above factors with a high accuracy. In conclusion, our results revealed genomic characterization of PT-DLBCL, and the mutation of BTG2 was an independent factor predicting a poor prognosis.

Chinese patients with bowel cancer exhibited a distinct spectrum of germline variants, with distinct molecular characteristics such as TMB and DDR. Furthermore, the information on somatic mutations obtained from TCGA database indicated that a deeper understanding of the interactions among DDR and immune cells would be useful to further investigate the role of DDR in bowel cancer.

Our data suggest that MSH3-related colorectal carcinogenesis seems to follow the classical APC-driven pathway. In line with the specific function of MSH3 in the mismatch repair (MMR) system, we identified a characteristic APC mutational pattern in MSH3-deficient adenomas, and confirmed further driver genes for colorectal tumourigenesis.

Materials/ We assembled a cohort of 34 patients with locally advanced esophageal adenocarcinoma, with the majority (21) receiving concurrent chemoradiotherapy with carboplatin/paclitaxel. We have identified a 3-gene signature (EPHA5, BCL6 and ERBB2) that is predictive of response to neoadjuvant therapy and a separate 9 gene classifier which prognosticates for survival outcomes. These provide significant potential for personalized management of locally advanced esophageal cancer.

We have identified a 3-gene signature (EPHA5, BCL6 and ERBB2) that is predictive of response to neoadjuvant therapy and a separate 9 gene classifier which prognosticates for survival outcomes. These provide significant potential for personalized management of locally advanced esophageal cancer.

This study revealed a heterogeneous molecular landscape with a high prevalence of TSC1 / 2 mutations that were in part associated with transcriptional up-regulation of the PIK3-Akt-mTOR pathway. This might explain why only a part of PEComa patients benefitted clinically when treated with the mTOR inhibitor nab-sirolismus. Furthermore, the relatively immune-cold TME compared to melanoma suggests increased lymphocyte infiltration may be required to increase the efficacy of immune checkpoint inhibitors for PEComa.

Increased copy number of chromosome arm 8q was most prevalent among tumors with microsatellite instability, including a case of translocation involving 8q. Subclonal analysis identified co-occurring driver mutations previously known to be exclusive.

We report a rare case of leiomyosarcoma with MSI-high status, high TMB (>10/megabase), MMR protein loss and significant PD- L1 expression. The presence of a significant number of tumour infiltrating lymphocytes within the tumour and at the periphery may be a histologic clue to MSI high status. However, more study is needed.

Within this study we discovered a heterogeneous molecular landscape with a high prevalence of TSC1/2 mutations that were in part associated with transcriptional up-regulation of the PIK3-Akt-mTOR pathway . Furthermore, the relatively immune-cold TME compared to melanoma suggests increased lymphocyte infiltration may be required to increase the efficacy of immune checkpoint inhibitors for PEComa.

Only TNM stage was a statistically significant predictor of outcomes independent of CIMP profiles in MSI-high CRC patients. Sporadic MSI-high CRCs with different mechanisms of carcinogenesis have specific mutation profiles and clinicopathological features.

Notably, CCNE1 amplification is a novel potential prognostic marker and therapeutic target for non-BRCA carriers with TNBC. Cyclin E1 may be used instead of CCNE1 to improve clinical applicability.

NGS using 44 tumor tissue showed the following results : group1, pathogenic MLH1 mutation(n=6) and pathogenic PMS2 mutation(n=2); group2, pathogenic MSH6 frameshift variant mutation(n=1) and MSH2 Conflicting interpretations of pathogenicity(n=1); group3, MSH2 mutation(n=5), MSH6 mutation(n=2) and pathogenic MSH3 mutation(n=3); group4, pathogenic MSH6 and MSH3 mutation(n=1); group6, pathogenic MSH6 mutation(n=7), MSH2 mutation(n=7) and Pathogenic MSH3 mutation(n=1); group7, MSH2 mutation(n=1). Conclusion NGS is useful to understanding the molecular mechanism of MMR protein deficiency in CRCs.

NGS using 44 tumor tissue showed the following results : group1, pathogenic MLH1 mutation(n=6) and pathogenic PMS2 mutation(n=2); group2, pathogenic MSH6 frameshift variant mutation(n=1) and MSH2 Conflicting interpretations of pathogenicity(n=1); group3, MSH2 mutation(n=5), MSH6 mutation(n=2) and pathogenic MSH3 mutation(n=3); group4, pathogenic MSH6 and MSH3 mutation(n=1); group6, pathogenic MSH6 mutation(n=7), MSH2 mutation(n=7) and Pathogenic MSH3 mutation(n=1); group7, MSH2 mutation(n=1). Conclusion NGS is useful to understanding the molecular mechanism of MMR protein deficiency in CRCs.

NGS using 44 tumor tissue showed the following results : group1, pathogenic MLH1 mutation(n=6) and pathogenic PMS2 mutation(n=2); group2, pathogenic MSH6 frameshift variant mutation(n=1) and MSH2 Conflicting interpretations of pathogenicity(n=1); group3, MSH2 mutation(n=5), MSH6 mutation(n=2) and pathogenic MSH3 mutation(n=3); group4, pathogenic MSH6 and MSH3 mutation(n=1); group6, pathogenic MSH6 mutation(n=7), MSH2 mutation(n=7) and Pathogenic MSH3 mutation(n=1); group7, MSH2 mutation(n=1). Conclusion NGS is useful to understanding the molecular mechanism of MMR protein deficiency in CRCs.

In summary, we report the mutational landscape of CRC in a Taiwanese population. NGS is a cost-effective and time-saving method, and we believe that NGS will help clinicians to treat CRC patients in the near future.

Here is an interesting lung cancer case which was called EGFR T790M, TP53 and MSH2 somatic mutations without any germline mutations, and this patient showed no response to Osimertinib... MMR deficiency was found in 4.3% chinese lung cancer and 27% of them concurrent with EGFR. Research Funding: None

Our preliminary data suggest high rates of germline mutations in early onset lethal PCa. This aggressive subset of disease requires further studying to better characterize the underlying clinical/genomic factors driving this disease. Research Funding: Prostate Cancer Foundation

EEC G3 harbored the most MMR mutations among EC. EEC G3 and USC could be more considered to screen MMR mutation due to more MMR mutations occurred in EEC G3 and USC than did among EEC G2 and EEC G1. Besides MLH1, MSH2, MSH6, PMS2 and EPCAM mutation, MLH3, MSH3, PMS1 mutation could be screened in patients with newly diagnosed endometrial carcinoma.

A cohort of 31 EAC patients treated with chemotherapy or chemoradiotherapy was assembled, with a majority of patients receiving carboplatin, paclitaxel and concurrent radiotherapy. Using a systematic biomarker discovery approach, we have developed a novel biomarker signature that robustly predicts response to CRT in EAC patients and has a significant potential for personalized management of locally advanced EAC patients. Research Funding: None