MSH6 expression

P3, N=700, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Apr 2024 --> Apr 2025 | Trial primary completion date: Apr 2024 --> Apr 2025

Geographical and ethnic factors might influence peculiarities in MMR protein loss. Our findings also highlight new gene expression networks and crucial regulatory molecules in CRC metastasis, enhancing our comprehension of the mechanisms driving distant metastasis.

P3, N=400, Recruiting, Massachusetts General Hospital | Trial completion date: Apr 2026 --> Dec 2027 | Trial primary completion date: Apr 2025 --> Dec 2026

P2, N=44, Completed, University of California, San Francisco | Active, not recruiting --> Completed | Trial completion date: Nov 2025 --> Jan 2024 | Trial primary completion date: Nov 2025 --> Jan 2024

The findings suggest a potential correlation between the abundance of B. fragilis and alterations in the expression of MMR genes. Since these genes can play a role in modifying colon cancer, investigating microbial characteristics and gene expression changes in CRC could offer a viable solution for CRC diagnosis.

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.

P2, N=240, Recruiting, National Cancer Institute (NCI) | Initiation date: Jun 2024 --> Dec 2023

P2, N=21, Recruiting, University of Texas Southwestern Medical Center | Not yet recruiting --> Recruiting

Modified FOLFOX6(mFOLFOX6)regimen was given as a first line chemotherapy and was followed by pembrolizumab after 1 cycle of the mFOLFOX6, because microsatellite instability(MSI)test of the tumor showed high-frequency MSI...Genetic test identified a MSH2 pathogenic variant leading to the diagnosis of Lynch syndrome. The present case shows the importance of MSI test or IHC-MMR before the treatment of metastatic colorectal cancer.

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.

This case highlights the complexities of understanding genetic susceptibility in childhood cancers. We propose a multifactorial oligogenic inheritance of cancer susceptibility in this patient through several mechanisms of genomic instability.

P2, N=21, Not yet recruiting, University of Texas Southwestern Medical Center | Trial completion date: Oct 2026 --> Oct 2028 | Initiation date: Oct 2023 --> Jan 2024 | Trial primary completion date: Oct 2025 --> Oct 2026

Secondary rectal cancer with endometrial origination in the absence of endometriosis and serosal implants was extremely rare. Therefore, we should pay more attention to this rare but possible presentation for appropriate diagnosis and treatment of these patients.

P2, N=35, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Oct 2025 --> Oct 2026 | Trial primary completion date: Oct 2023 --> Oct 2024

Functional investigation of this inversion in a laboratory setting revealed a resultant abnormal protein function. Thus, we have identified an unusual, small germline inversion in a mismatch repair gene that does not lead to a premature stop codon yet appears likely to be causal for the observed cancers.

PD-1/PD-L1 expression may contribute to the progression and poor prognosis of bladder cancer. However, further studies are required to research the clinical utility.

Analysis of clinical samples showed that USP7 expression was significantly higher in hypertrophic scars (0.35±0.05), scar ulcers (0.43±0.04), and scar cancers (0.61±0.03) than in normal skin (0.18±0.04), P<0.05. USP7 may be a clinical biomarker for the progression of cicatricial ulcer cancer.

Of these patients, 14 (23.7%) had MMR deficiency. The MMR deficient group had a higher proportion of early stage (stage I and II) compared to the MMR proficient group (78.6% vs. 64.4%).

This study showed a high prevalence of dMMR in cholangiocarcinoma with dMMR being the independent prognostic factor for good survival, especially in early-stage CCA and for patients who received adjuvant chemotherapy. dMMR should be the marker for selecting patients to receive a specific adjuvant treatment after resection for CCA.

In this study, immunohistochemical screening of MMR proteins for Lynch syndrome was performed in a series of prostate cancer cases. The prevalence of Lynch syndrome in localized prostate cancer was 0.8%, which is low compared with other Lynch syndrome-associated cancers.

Our study establishes MSH6 or MSH2 as an oncogene that is prominently overexpressed during HCC progression which provides new targets for HCC with MVI.

P2, N=240, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | Initiation date: Sep 2023 --> Jun 2024

Interestingly, all 16 medullary carcinomas that were analyzed showed characteristics corresponding to the presence of both dMLH1 and BRAFV600E mutation (P = .01). These results suggest that colorectal medullary carcinomas can be diagnosed based on their unique characteristics of harboring the BRAFV600E mutation and exhibiting dMLH1 expression.

MTS is a unique condition that necessitates continuous surveillance. When sebaceous adenoma arises in atypical regions, it is important to consider additional screening to eliminate the likelihood of MTS. Poster type: Poster Defense

MSI analysis of FFPE DNA by NGS is feasible and the results show a high concordance in comparison with the monomorphic marker MSI-PCR. However, cases with a subtle MSI+ phenotype, most frequently manifest in EC, have a risk of a false-negative result by NGS and should be preferentially analyzed by capillary electrophoresis.

Our findings of the associations between MMR deficiency and poor prognostic factors, such as LVSI and LN metastasis, may suggest the prognostic value of MMR status in EC and need further prospective validation studies.

This study indicates that the combined use of MMR-IHC and PCR-CE MSI analyses may effectively avoid misdiagnoses of EC patients with dMMR/MSI-H. However, use of PCR-CE alone to evaluate MMR/MSI status may lead to missed diagnosis, especially for EC patients with MSH6 deficiency and presenting MSS.

dMMR CRC had a higher histological grade with a higher frequency of mucinous differentiation and higher T-stage. Conversely, the presence of LVI, PNI, and higher N stages were associated with pMMR CRC.

P2, N=21, Not yet recruiting, University of Texas Southwestern Medical Center

We present the case of a 73-year-old woman with a mismatch repair deficient (MMRd) undifferentiated cardiac sarcoma, who achieved a complete and durable response with the anti-PD1 inhibitor pembrolizumab after the failure of standard treatment consisting of doxorubicin together with olaratumab. The genomic analysis of the cardiac UDS displayed several markers known to predict response to ICIs: the tumor harbored a high TMB (> 10 mutations/Mb) and a MMRd/MSI signature. Of note, inactivating mutations of both FAT1 and NOTCH2 have also been associated with ICI therapy response in epithelial tumors. Moreover, the tumor displayed an extensive infiltrate by CD8+ T cells, and PD-L1 was expressed in the tumor immune microenvironment.

Deletion of MMR proteins and expression of PD-L1 are closely related to clinicopathological characteristics and overall prognosis of CRC patients. This suggests the relevance of MMR and PD-L1 as potential biomarkers for treatment of CRC patients.

The identification of LS-associated GBM can provide significant benefits to both patients and their family members, including accurate diagnosis, genetic counseling, and appropriate screening or surveillance protocols. Our study serves as a reminder to clinicians and pathologists to consider the possibility of concurrent genetic syndromes in individuals or families.

Case Description/ An 89-year-old female with a history of unprovoked PE (on Eliquis) hypothyroidism, HTN, essential tremors, Stage IV pancreatic cancer pancreatic body/tail, with an uncharacterized liver lesion, Ca 19-9 positive >4000-not currently on chemotherapy...This case highlights the importance of endoscopic examinations & several biopsies for detecting and diagnosing gastric metastases. Figure: figure A, B and C shows numerous hepatic lesions, Also pancreatic mass is evident in figure A

Research on optimal chemotherapy regimens is undergoing, and further studies are needed for this rare entity. Figure: Figure 1: Colonoscopy showing a near circumferential 7 cm mass in the right colon (arrow) Figure 2: Microscopy showing large neoplasm with solid and syncytial growth pattern showing a pushing border Figure 3: Microscopy showing prominent lymphocyte infiltration Figure 4: Microscopy showing large nuclei with prominent nucleoli

Even when treated with standard therapy, such as surgery followed by carboplatin and paclitaxel chemotherapy, the prognosis remains unfavorable. Patients with MSI had a lower CD8/PD-1 ratio and more relapses (p = 0.03). In conclusion, analysis of immunotherapeutic markers in paraffin-embedded advanced serous ovarian carcinoma samples is feasible and may assist in prognosis.

Within the limitation of our small sample size, we can conclude that MMRd tumours are low/intermediate grade and present in early stages. However further studies may confirm this correlation.

Following reclassification of this case, 100% tumors with MMR deficiency by immunohistochemistry had at least 1 confirmed somatic MMR pathogenic variant, and 86% were MSI-high. These results demonstrate that when correctly interpreted immunohistochemistry is a strong surrogate for somatic MMR pathogenic variants and support its use as the frontline MMR biomarker in endometrial cancer for heritable screening, molecular prognostic classification, and immunotherapeutic biomarker testing purposes.

Although not showing statistical significance there seems to be a possibility for CD44 and EGFR to predict prognosis and guide therapy. These findings should be confirmed in further multicentric studies.

Thus, in CRC, only cases with small focal clonal heterogeneous expression of MSH6 have a high likelihood of MSI-H, and further PCR-CE or NGS testing is recommended. The possibility of MSI-H cannot be ruled out in EC cases with glandular mosaic heterogeneous expression of MMR proteins; PCR-CE or NGS detection is therefore necessary.

Pathology of the brain tumors showed mucinous adenocarcinoma without expression of MSH2 and MSH6, while multi-gene panel testing demonstrated not only high microsatellite instability and a high tumor mutation burden, but also germline BRCA2 variants. Further, germline testing in relatives confirmed both variants were from the paternal line, from which many LS-related cancers develop, but not BRCA-related cancer.