APC mutation

Our findings support the growing recognition of mosaicism as a critical factor in CRC susceptibility and underscore the importance of incorporating mosaicism screening into routine genetic testing for at-risk patients.

We attempted to elucidate the underlying causes and mechanisms behind this lack of response, and to provide new insights into treatment options for these patients. Mutations of key genes within tumor-related signaling pathways and the infiltration of CD8+T cells in the tumor microenvironment may influence the efficacy of immunotherapy for MSI-H solid tumors.

We elucidate that an underappreciated function of truncated APC in CRC is its ability to drive an immunosuppressive program that boosts tumor progression. Our work could provide a new perspective for the clinical application of immunotherapy in patients with CRC resistant to ICB therapy.

© 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

CD represents a promising therapeutic strategy for treating both DTs and CRC.

IDH could be a promising therapeutic agent for inhibiting DTs and CRC by targeting TOPO II.

P2, N=60, Active, not recruiting, Recursion Pharmaceuticals Inc. | Recruiting --> Active, not recruiting

These findings demonstrate the oncogenic role of KLK6 in the mutant Apc-mediated intestinal tumorigenesis and suggest the utility of KLK6 for early diagnosis of colorectal tumors.

We report a genome-wide evaluation of co-occurring mutations in MSS CRCs, and suggest that co-mutations can improve the prognostic stratification compared to single mutations alone.

Hybrid cysts are rare entities consisting in 4% of the tumors analyzed in our study. Our results suggest that most hybrid cysts occur sporadically and are associated with CTNNB1 somatic mutations.

The authors described the molecular characteristics of CRC. Loss of LRP1B leads to changes in immune cell infiltration and can be used as a therapeutic target for colorectal cancer.

CEA rebound between pre-hepatectomy chemotherapy discontinuation and CLM resection is associated with worse oncologic outcomes, particularly in patients with aggressive tumor biology, and may help frame patient and surgeon expectations ahead of CLM resection.

Furthermore, it has been observed that these truncated proteins have a crucial role in the activation of the Wnt signaling pathway and the subsequent loss of tumor inhibitory function. This review aimed to provide an overview of the recent advancements in understanding the mechanism behind APC truncation and its association with the onset and progression of CRC.

Additionally, genetic testing of the patient's child indicated that the child does not carry the APC pathogenic variant. In conclusion, our study highlights the importance of genetic testing in raising awareness of GS among clinicians to ensure early diagnosis and effective management, thereby reducing the risk of development and progression of colorectal cancer.

Further, polyclonal tumours have accelerated growth dynamics, suggesting a link between polyclonality and tumour progression. Together, these findings demonstrate the role of interclonal interactions in promoting tumorigenesis through non-cell autonomous pathways that are dependent on the differential activation of oncogenic pathways between clones.

This study highlights the associations between HRD scores, clinical characteristics, and genomic mutations in ESCC, suggesting HRD as a potential prognostic biomarker. HRD assessment may aid in patient stratification and personalized treatment strategies, warranting further investigation to validate the therapeutic implications of HRD scores in ESCC.

CDX2-suppressed colorectal cancers constitute a genomically distinct subset of colon and rectal cancers that have a lower prevalence of KRAS, APC, and TP53 mutations, but a high prevalence of mutations in less commonly mutated colorectal cancer genes. These alterations could serve as targets for personalized therapeutics in this subset.

Two consecutive events apparent in these patients, namely, the first event leading to cell proliferation and the second driving hormonal hypersecretion, supported the two-hit model of APA development. The two-hit model usually occurs in the larger adenomas, and the driving factors of the first hit that promote cell proliferation still require further research and exploration.

Our findings shed light on the heterogeneous microenvironments in IBD and APC-mutant CRC. Furthermore, we identify APOE as a potential biomarker for CRC recurrence.

Increased TMB was observed in cases of KRAS and BRAF mutation combined with APC single mutation; furthermore, the expression of TMB in G12V was the highest, and G12D presented the lowest TMB in single KRAS-mutant subtypes or the combination with APC mutations. The TMB driven by KRAS co-mutations may have the potential to be used as a key biomarker for prediction of treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with CRC, especially with APC co-mutation.

P=N/A, N=419, Active, not recruiting, Mayo Clinic | N=2000 --> 419

We also show that eIF3a expression is regulated by the Wnt/β-catenin signaling pathway with an active TCF/LEF binding site in its promoter and that eIF3a knockdown inhibits APC mutation-induced spontaneous colon tumorigenesis in APCmin/+ mice. Together, we conclude that eIF3a upregulation in colon cancer is due to APC mutation and it participates in colon tumorigenesis by adding a translational control axis in Wnt/β-catenin signaling pathway and that it can serve as a potential target for colon cancer intervention.

One-third of patients with FAP present an aggressive phenotype, without a demonstrated correlation between the type of genetic alteration and the phenotypic manifestations.

In conclusion, our study documents distinct MMRp-crypts in MSH6-CMMRD, a phenomenon in keeping with MSH6 being a frequent target of MSI-H due to its coding microsatellite and suggesting that MSH6-CMMRD can potentially serve as a unique model system to further our understanding of MSH6's role in MSI-H tumor formation and evolution. Our findings also bear diagnostic implications; when using MMR immunohistochemistry as an ancillary tool in detecting CMMRD, awareness of these MMRp crypts can help avoid diagnostic pitfalls.

As APC has been previously identified as an RNA-binding protein that preferentially binds 3' UTRs during mouse neurogenesis, our results suggest that APC promotes proximal poly(A) site use and that APC loss and altered expression contribute to pervasive APA dysregulation in cancers.

The previously described cases have been elaborated as well. CPA tumor with a background of FAP should raise a differential diagnosis of craniopharyngioma, and similarly, a CPA primary ectopic craniopharyngioma may raise suspicion of underlying APC gene mutation.

Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor-cell-intrinsic mechanism to repress antitumor immunity.

P2, N=12, Completed, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) | Active, not recruiting --> Completed | Trial completion date: Apr 2025 --> Sep 2024 | Trial primary completion date: Apr 2025 --> Sep 2024

Moreover, we detected EGFR and TP53 mutations (no pathogenic APC or KRAS mutations), which are not conventional adenoma-carcinoma mutations. Further studies are warranted to confirm whether GC is a sporadic carcinoma that invades the GALT submucosa.

One novel SMAD4 deleterious mutation (c.1268G > T) was reported. In conclusion, we provide clinicopathological information and new genetic variation data pertinent to CRC in Uganda.

The TCGA multiomics data revealed potential correlations between the CRCRS and the activation of energy production and metabolic pathways, the tumor immune microenvironment, and genetic mutations in APC, SMAD2, EEF1AKMT4, EPG5, and TANC1. In summary, our deep learning algorithm identified the CRCRS as a prognostic indicator in CRC, providing a significant approach for prognostic risk stratification and tailoring precise treatment strategies for individual patients.

These results highlight the protective effects of PVD while reaffirming the carcinogenic properties of MBD diets. In germ-free rats, FMT induced changes reminiscent of dietary effects, including heightened preneoplastic lesions in MBD rats and the transmission of specific diet-related bacterial and metabolic profiles. Importantly, to the best of our knowledge, this is the first study showing that diet-associated cancer risk can be transferred with faeces, establishing gut microbiota as a determinant of diet-associated CRC risk. Therefore, this study marks the pioneering demonstration of faecal transfer as a means of conveying diet-related cancer risk, firmly establishing the gut microbiota as a pivotal factor in diet-associated CRC susceptibility. Video Abstract.

CK7 + tumors showed intriguingly common (31.6%) BRAF V600E mutations corelating with poor prognosis, compared to the frequency described in the literature and databases. Further research on larger cohorts with a non-colorectal immunophenotype and high MUC4 expression is needed.

TMB-H tumors had a significant enrichment for alterations in genes encoding proteins involved in the DNA repair pathway and growth factor receptor signal transduction. Combining immune checkpoint inhibitors with targeted therapies aimed at specific pathways could be further explored to potentially enhance outcomes for patients with solid tumors.

We suggest that considerable SCNAs and TP53 mutations are required for progression from adenoma to carcinoma within the same intramucosal neoplastic lesion.

In our cohort, the prevalence of adrenal tumours among patients with pathogenic and likely pathogenic APC mutations is at least twice to three times higher than the general population prevalence reported from international population-based studies. The hormonal functions of patients with pathogenic APC variants and adrenal tumours can be investigated with routine testing in further research.

We assessed gene signatures indicative of B cell infiltration/TLS presence (Messina et al., 2012; Goc et al., 2014; Cabrita et al., 2020; Meylan, et al., 2022), correlating these with clinical outcomes, including overall survival (OS) and time on treatment (TOT) for ICIs such as pembrolizumab, nivolumab, and ipilimumab. This large TLS atlas based on real-world data demonstrate that TLS gene is a robust biomarker for predicting responses to immunotherapy in solid tumors.

In conclusion, tumour heterogeneity significantly influences colorectal cancer (CRC) prognosis, impacting treatment resistance and overall survival. Understanding and managing this heterogeneity are crucial for personalized medicine advancement. The autopsy and LBx analysis in this report offer insights for collective understanding of tumour evolution under therapy, guiding future research and therapeutic innovations tailored to CRC dynamics.

Inhibiting CUL4B epigenetically activated the expression of G-CSF, promoting the recruitment of MDSCs. These findings offer novel insights into the tumor suppressor-like roles of CUL4B in regulating ApcMin/+ adenomas, suggesting a potential therapeutic strategy for CRC initiation and progression in the context of activated Wnt signaling.

Furthermore, we distinguish them from locally aggressive desmoid fibromatosis regarding their biological behavior, prognosis and indicated therapeutic strategies. Consequently, we call them CTNNB1-mutated superficial fibromas as a sporadic counterpart lesion to syndromic Gardner fibromas.

There is a different genomic profile according to the stage and predisposing disease. dMMR and APC mutation in localized tumour predict a better prognosis.

A lower prevalence of mutations in KRAS and BRAF is consistent with extended survival and superior response to targeted therapies for metastatic disease. Conversely, early-onset CRC is associated with aggressive histological subtypes and TP53 and PTEN mutations, which may serve as therapeutic targets.