MLH1 mutation

P1/2, N=60, Recruiting, National Cancer Institute (NCI) | Trial completion date: Mar 2025 --> Jul 2025 | Trial primary completion date: Mar 2025 --> Jul 2025

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.

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

The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.

These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.

P=N/A, N=500, Recruiting, Beth Israel Deaconess Medical Center | Trial completion date: Jul 2026 --> Mar 2028 | Trial primary completion date: Jul 2025 --> Mar 2027

P1/2, N=60, Recruiting, National Cancer Institute (NCI) | N=45 --> 60 | Trial completion date: Jul 2025 --> Mar 2025 | Trial primary completion date: Jul 2025 --> Mar 2025

P2, N=40, Recruiting, M.D. Anderson Cancer Center | Phase classification: P2a --> P2

Variations by ancestry in prevalence and mechanism of MMR-D/MSI-H tumors have also been reported and may influence health disparities given observed differences in tumors of Black compared to White patients which may affect ICI eligibility. These observations highlight the need for additional prospective studies to evaluate the nuances regarding MMR-D heterogeneity as well as markers of resistance to inform future trials of combination therapies to further improve outcomes for patients with EC.

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

MSI estimation using NGS is suitable as a quick screening tool. Since thresholds for MSI-H might differ enormously between entities, additional IHC testing is recommended at least in samples where VUS or pathogenic mutations are found in one of the mismatch repair genes. Downloaded from http://karger.com/ort/article-pdf/47/Suppl.

P=N/A, N=77, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Feb 2024 --> Feb 2025

Follow-up to October 2023 showed that the patient had endometrial and cervical polyps, one case had colorectal cancer, and two cases had intestinal polyps, all were treated with early intervention and therapy; two cases did not show any clinical symptoms. This study is the first to report a new mutation site for the potentially pathogenic MLH1 c.463dupC, providing a rationale for the pathogenicity of the mutation and standardized health management for familial carriers.

P=N/A, N=64, Recruiting, National Institute of Cancerología

Our findings support RefT in dMLH1 CRC patients within the LS diagnostic pathway, as it reduces the number of GC sessions needed and increases the diagnostic yield of GT.

Our results suggest that ONC201 in combination with TRAIL may be an effective and non-toxic option for the treatment of gastric adenocarcinoma by inducing apoptosis via activation of the ISR, increased cell surface expression of DR5 and down-regulation of inhibitors of apoptosis. Our results demonstrate in vivo anti-tumor effects of ONC201 plus TLY012 against gastric cancer that could be further investigated in clinical trials.

P=N/A, N=21, Completed, M.D. Anderson Cancer Center | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jan 2024 | Trial primary completion date: Dec 2024 --> Jan 2024

This review aims to discuss these susceptibility genes and provide an explanation of their functions based on the signaling pathway background. Additionally, the association network between genetic signatures and different tumor pairs will be summarized.

P=N/A, N=21, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

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.

A majority of dMMR/MSI-H cases with an indication for GT were referred for genetic counseling, but only a small subset completed testing. This analysis identified multiple areas for improvement, including a lack of recognition by providers for the need for GT, and lack of completion of testing by patients at multiple levels. Further evaluation of VHA-specific barriers is needed to improve the quality of delivered care.

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.

The mutation frequency of FLT4 gene was significantly higher than that of OSCC group (P < 0.05). FLT4 gene may be related to OSF cancerization and is expected to be an early diagnostic biomarker for OSF cancerization.

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.

(4) MLH1 hypermethylation should not be exclusively considered as a sporadic cancer mechanism, as a non-negligible number of LS-related cancers are MLH1 hypermethylated. Current flow charts for universal LS screening, which include MLH1 methylation, should be applied, paying attention to a patient's family and personal history.

Fourteen patients (13.1%) showed intertumoral MMR discordance (at least one dMMR and one pMMR) and in 5 patients, nodal metastases were present: 2 patients harbored metastases only from their pMMR cancer, 2 only from their dMMR cancer and in 1 patient both pMMR/dMMR metastases were present. In conclusion, all multiple primary CRCs should be analyzed for MMR status as discordant MMR is possible as well as discordant metastatic nodal deposits and this may be important for patient management.

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

In summary, there is no significant association between TMB at baseline and poor survival outcomes in IDH-wildtype GBM. Further research is needed to explore the potential implications of TMB as a prognostic marker and its relevance for personalized treatment strategies in GBM patients.

Factors that may be associated with lower complete and partial response in the NAC and higher risk of metastatic recurrence in the AC cohorts included history of Lynch, smoking history, and preoperative hydronephrosis whereas cisplatin-based chemotherapy may be associated with better outcomes (Table 2)... LS-related UTUC may have distinct biologic behavior and responses to chemotherapy than sporadic UTUC. Given the superior outcomes seen with immunotherapy in metastatic disease and the approved indication for this treatment in those with LS, proper identification of LS-related UTUC is imperative in order to evaluate this paradigm further in the non-metastatic setting. This can be most reliably achieved with universal tumor testing and confirmatory germline sequencing.

This mechanism could explain the rapid tumour progression in MLH1-LS-CRC. The results highlight the importance of mitotic recombination in carcinogenesis and provide an insight into the genetic basis of colorectal carcinoma in the context of Lynch syndrome.

Survival Curve Utilizing a curated Gene Set Developed by a Gradient-Boosting Multivariable Model (A) OS of platinum-based therapy treated KM with curated Gene set. (B) OS of platinum-based therapy treated MSK with curated Gene set.

The Promega OncoMate MSI Dx analysis system shows excellent concordance with the previous Promega MSI analysis system v1.2 and MMR IHC in CRC tumor samples, and has clinical utility in screening for LS in CRC patients.

Due to the almost exceeded total dose of anthracyclines, the patient's treatment included blinatumomab, and subsequently, he was qualified for allogeneic hematopoietic cell transplantation. The patient remains in complete remission for 11 months after allogeneic hematopoietic stem cell transplantation under the care of the transplant center.

Our cases highlight the importance of testing for MMR proteins by simple IHC, in the setting of appropriate clinical scenario, histopathological and immunohistochemical findings. The recognition of these tumors is extremely important to guide further treatment and prompt family screening.

Of the 71 patients recruited, 35 were dMMR and 36 were pMMR. Median follow-up was 44 vs 52 months in dMMR vs pMMR participants, respectively. The dMMR molecular subtypes were 4 (11.4%) Lynch syndrome, 4 (11.4%) somatic MMR mutation, 25 (71.4%) MLH1 methylated and 2 (5.7%) dMMR-uncategorised.

This variant, c.1774_1775insT, represents a novel finding, as it has not been previously reported in existing databases or literature. No other case of 13 metachronous tumors in a patient with Lynch syndrome was found in the literature.

Endometrial cancer patients with MLH1 hypermethylation display significantly decreased survival and discrepant immunotherapy responses compared to patients with MLH1 mutated tumors, which was associated with differential mutational profiles, a more immune cold phenotype, and increased ER/PR expression in MLH1 hypermethylated tumors. Providers may consider early transition from single agent ICI to a multi-agent regimen or hormonal therapy for patients with MLH1 hypermethylated tumors.

MSI plays a role in the oncogenesis of a subset of ITCLs, particularly MEITLs, with potential therapeutic implications. In our series of ITCLs, MSI and MMRd were related to MLH1 or PMS2 locus deletions.

Our study indicates that in patients with SPS, the ratio of sCRCs:aCRCs on average is 50:50. This elevated sCRC:aCRC ratio in patients with SPS, when compared with non-SPS patients, correlates well with the differences in the ratios of the numbers of sessile serrated lesions and conventional adenomas in patients with SPS and non-SPS patients, respectively.

One patient treated with ipilimumab and nivolumab, had a partial response, and was on therapy for 31 months until death from an unrelated cause...The third patient treated with pembrolizumab monotherapy developed progressive disease after 4 months... While rare, Lynch syndrome can be associated with sarcoma. This is most commonly seen with germline MSH2 mutation and undifferentiated pleomorphic sarcoma and leiomyosarcoma subtypes. Immunotherapy has the potential for robust and durable responses and the potential to minimize or obviate surgery in Lynch-associated sarcomas.

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