PMS2 (PMS1 protein homolog 2)

In colorectal adenocarcinoma, MSI and BRAF mutation are associated with parameters, indicating the host immune response and prognostic histopathological parameters, including tumor size and histological grade. The evaluation of MSI status and BRAF mutation can be particularly informative for predicting the prognosis and guiding the treatment management in poorly differentiated colorectal adenocarcinoma. Understanding the mechanisms of molecular carcinogenesis in colorectal carcinoma and organizing treatment algorithms based on molecular foundations will increase the success of the treatment.

More routinely available TME, SIR and tumor markers alone and in combination deliver reliable prognostic data for choosing the patients with higher risk for propagation. CMS4 is linked with high TSR and poor prognosis, but in overall, CMS-classification showed only limited effect on SIR- and tumor-markers.

The majority of the recruited EC patients in this study showed advanced age and a high percentage of d-MMR status.

Besides the c.1A>C variant, which is already known to be pathogenic, we implicate six additional variants as ACMG/AMP pathogenic supporting (PP) variants and classify ten as benign supporting (BP). In summary, we present a method developed for the classification of human PMS2 Kozak sequence variants that can contribute to the re-classification of VUSs identified in patients.

In this rare case, colonic adenomatous polyposis of unknown etiology, with numerous adenomatous polyps and multiple adenocarcinomas localized in the right side of the colon, was successfully treated with right hemicolectomy and regional lymph node dissection. Despite genetic analysis, no causative germline variants were identified. Segmental colectomy according to the distribution of polyps might be a curative approach.

The observed low rates of PV detection in non-AJ non-TNBC cases ≥age 50 years at diagnosis, mostly for clinically insignificant variants, questions the justification of unselected genotyping in this subset of patients.

Our results indicate that the MMR genes, and especially MSH2 and MSH6, are associated with a significant risk of PCa, and a high number of tumors show aggressive characteristics. While the impact of screening on patient outcomes remains to be more firmly established, the high SIR values we observe provide support for continued PSA screening of MSH2 and MSH6 carriers. Studies are needed to provide optimal recommendations for PSA-threshold and to evaluate whether MLH1 and PMS2 carriers should not be recommended screening.

Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.

Identifying MSI in CRCs may help personalize therapy planning. As the distribution of the features may vary from population to population, further investigations are needed on this topic.

Our findings suggested that NOTCH2 may be a potential diagnostic target for GC due to the fact that its high expression is closely associated with the early stages of cancer.

Finally, CENPA and BRCA1 were identified as potential common targets for IHF and cancer. These findings provide new perspectives for expanding our understanding of the etiology and underlying mechanisms of HF and cancer.

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.

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.

Our study confirms the accuracy of the hs-MSI assay as ancillary testing for CMMRD diagnosis, which can also characterize MSI patterns in CMMRD-associated cancers. Hs-MSI is a powerful tool to pinpoint PMS2 as the affected germline gene and thus potentially personalize cancer risk.

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.

Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

Our findings reveal that MRE11A is a negative regulator of human MMR.

Other markers (mainly p53 followed by POLE and PTEN) are investigated in particular in Spain and Switzerland in a consistent number of cases. Guidelines consultation and standardization of laboratory procedures are efficient means for EC prognostic risk stratification and improving the quality of care.

Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).

We report on the real-world characteristics of prostate cancer patients who underwent mainstream germline genetic testing. Personal history and family history of cancer cannot reliably stratify patients for the presence of pathogenic germline variants.

SWI/SNF complex deficiency in gastrointestinal tumors is associated with dedifferentiation and often accompanied by mismatch repair protein deficiency. Compared to the cases with intact mismatch repair proteins, the cases with defective mismatch repair protein have an earlier clinical stage and a lower risk of lymph node metastasis.

MMR gene alterations can be identified by clinical NGS platforms in a small proportion of patients with MSS GI cancers. They are associated with elevated TMB, which may suggest a hypermutated profile serving as a basis for potential role of immune checkpoint inhibitor in MSS GI cancers.

ASCO/CAP guidelines are accurate and resource-effective in determining HER2 overexpression in mucinous ovarian carcinoma. HER2-low is common in these tumors; further studies to determine the role of HER2-targeted therapy including antibody-drug conjugates are indicated.

In the MMRd without LS group, the 5-year OS rate was significantly worse in seven patients with an aberrant p53 expression pattern than in those with p53 WT (53.6% vs. 93.9%, log-rank test; p = 0.0016). These results suggest that p53 abnormalities and pathogenic germline variants in MMR genes could be potential biomarkers for the molecular classification of EC with MMRd.

No abstract available

The age of onset of surveillance, the yield of GC and DC during EGD surveillance, and its cost-effectiveness should be subject of future studies. None.

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.

According to the findings, CRAs with comedo cribriform patterns are tumors with more aggressive features. It can be said that these tumors have a specific molecular feature related to MSS. Because this feature is important for planning adjuvant chemotherapy, it may be useful to identify cases, particularly with a cribriform comedo pattern >90%. However, because no significant difference in survival rates was found, CCAs may not need to be defined as distinct subtypes.

CLDN18.2+ expression is associated with early stage GACs, but with metastatic disease in E/GEJACs. CLDN18.2+ expression is not affected by preoperative treatment or HER2 status. These findings expand our recognition of subsets of patients who may benefit from targeted CLDN18.2 therapy.

In summary, PTEN IHC expression was retained in the majority of PTEN- and POLE-mutated ECs with frequent missense mutations in codon 130. Some codon 130 mutations (e.g., R130Q) are known to be associated with protein stability. Nearly half of PTEN-mutated MMR-d ECs were associated with PTEN expression (retained, reduced or subclonal loss).

An immunohistochemistry (IHC) panel targeting four MMR proteins (MLH1, PMS2, MSH2, MSH6) has been used to screen for MMRd status in many cancer types and is approved by FDA to identify patients eligible for treatment with ICIs such as pembrolizumab... An unexpected pattern of retained MSH6 IHC is seen in up to 35% of MMRd prostate carcinomas with MSH2 loss, across four participating institutions with three different MSH6 antibody clones. This is a much higher rate compared to only 1% of GI or GYN MMRd cases with isolated MSH2-loss pattern (PMID 36104536). While the mechanisms of this phenomenon remain unknown, the findings suggest against using a two-antibody testing algorithm (PMS2 and MSH6) to screen for MMRd prostate carcinoma.

Concordance between MMR IHC and the Oncomate MSI PCR assay was 100% for CRC but for other cancers may be lower. The MSI PCR test has low sensitivity in cases with isolated MSH6 loss, supporting the recommendation that MMR IHC may be favored over PCR in cancers such as those of endometrium.

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.

Our study is concordant with larger CRC sequencing studies. Although, the main targetable mutations are covered by the Focus Panel, a considerable proportion of specimens had no identifiable mutations. As more treatments become available, more extensive panels are necessary.

AI adds relevant quantitative information to known features of MSI and MSS that can be used to objectively score and compare CRC cases. AI scores identify two distinct histological phenotypes for MLH1/PMS2 vs MSH2/MSH6. The clinical relevance should be further explored.

Claudin 18.2 positive colorectal adenocarcinomas (26/576, 5%) are frequently MMR deficient (19/26, 73%) and demonstrate distinct histologic features. Future studies addressing efficacy of zolbetuximab therapy in this subset of colorectal cancers are needed.

In contrast, CLC has characteristics of dMMR tumors that are not found in iCCA, suggesting that it should be treated distinctly from iCCA.

Patients with mutS co-loss experienced longer mOS in CRC and EC and better response to ICIs in CRC. Among all explored biomarkers, NAL was higher in mutS co-loss and may be a potential driving factor for the observed better outcomes. TMB did not reliably predict NAL.

Our findings revealed that VUSs in DNA repair genes might be associated with increased cancer risk and highlight the need for variant reclassification for better disease management. This will help to improve the genetic diagnosis and therapeutic strategies of cancer patients not only in Tunisia but also in neighboring countries.

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.

Multi-gene NGS tumour testing was capable of identifying all clinically relevant germline variants. Although paired multi-gene tumour-germline testing is required to determine variant origin, over 40% of individuals in this study could have avoided germline testing following negative tumour results. These results suggest that streamlining genetic testing for EOC patients via primary multi-gene tumour testing is possible with further investigation.