Specific Mutations in APC, but Not Alterations in DNA Damage Response, Associate With Outcomes of Patients With Metastatic Colorectal Cancer

Mondaca, Sebastián; Walch, Henry; Nandakumar, Subhiksha; Chatila, Walid K.; Schultz, Nikolaus; Yaeger, Rona

doi:10.1053/j.gastro.2020.07.041

Cited by 30 publications

(32 citation statements)

References 9 publications

(2 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The study by Wang F et al showed that wild type APC activated lncRNA (lncRNA-APC1) was down-regulated in CRC compared with normal colorectal tissues and inhibited cell growth, angiogenesis and metastasis [16] . However, APC mutation but not APC down-expression was found in most sporadic CRC [25,26] , and APC mutation was one of the most important inducer for CRC tumorigenesis and progression [27] . In the present study, we demonstrated that mutated APC protein mediated stabilization of β-catenin protein promotes the transcription of SURC via binding to its promoter.…”

Section: Discussionmentioning

confidence: 98%

A specific Upregulated lncRNA in Colorectal Cancer Promotes Cancer Progression by Modulating miR-185-5p/CCND2 Axis

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

BackgroundAdenomatous polyposis coli (APC) gene mutations were found in most colorectal cancer patients and functioned as an important inducer of tumorigenesis. Long non-coding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). Here we investigated the role of SURC which is specific upregulated in CRC progression. MethodsBased on the previous microarray results, weighted correlation network analysis (WGCNA) and lncRNA-mRNA co-expression network analysis were used to identify a lncRNA (SURC) and found it was specific up-regulated in CRC patients by qPCR and FISH staining. Chromatin immunoprecipitation (ChIP) assay was used to demonstrate the regulatory effect and mechanism of APC mutation on SURC expression. The effects of SURC on proliferation and cell cycle were determined by in vitro and in vivo experiments. Chromatin Isolation by RNA Purification (CHIRP) and luciferase reporter assay were carried out to illustrate the interaction between SURC, miR-185-5p and CCND2.ResultsWe found that SURC was specific up-regulated in CRC, but not in other solid tumor, when compared with normal adjacent tissues. High expression of SURC correlates with poorer disease-free survival and overall survival of CRC patients. Mutated APC protein resulted in stabilization of β-catenin in CRC, which promotes the transcription of SURC via binding to its promoter. Knockdown of SURC impaired CRC cell proliferation, colony formation and CRC tumor growth. Mechanistically, after transcription, SURC was transferred to cytoplasm and inhibits miR-185-5p expression via binding to miR-185-5p and inhibiting the synthesis of miR-185-5p from pri-miR-185-5p, which results in CCND2 expression.ConclusionCollectively, these results indicated that SURC promoted CRC tumor growth via interacting with miR-185-5p and regulating the activity of miR-185-5p/CCND2 axis which would be a novel diagnosis and prognosis prediction target for CRC.

show abstract

Section: Discussionmentioning

confidence: 98%

A specific Upregulated lncRNA in Colorectal Cancer Promotes Cancer Progression by Modulating miR-185-5p/CCND2 Axis

Chen

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…To expand our data, we downloaded a CRC cohort for chemotherapy (Mondaca-CRC; https://www.cbioportal.org/study/clinicalData?id=crc_apc_impact_2020 ) from the cbioportal web tool ( Mondaca et al, 2020 ), as well as the entirety of the exon sequencing data and clinical data (including Tumor mutational burden (TMB), Microsatellite instability (MSI) scores, MSI status, gender, TNM stage, ECOG and age). We downloaded the RNA sequencing data, mutation data, and clinical prognosis data of TCGA-COAD and TCGA-READ from TCGA database ( https://portal.gdc.cancer.gov/ ) using TCGAbiolinks R package ( Colaprico et al, 2016 ).…”

Section: Methodsmentioning

confidence: 99%

Homologous Recombination Pathway Alternation Predicts Prognosis of Colorectal Cancer With Chemotherapy

Lin

Zhang

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Background: Chemotherapy is the basic treatment for colorectal cancer (CRC). However, colorectal cancer cells often develop resistance to chemotherapy drugs, leading to recurrence and poor prognosis. More and more studies have shown that the Homologous recombination (HR) pathway plays an important role in chemotherapy treatment for tumors. However, the relationship between HR pathway, chemotherapy sensitivity, and the prognosis of CRC patients is still unclear.Methods: We collected 35 samples of CRC patients after chemotherapy treatment from Guangxi Medical University Cancer Hospital, then collected mutation data and clinical prognosis data from the group. We also downloaded Mondaca-CRC, TCGA-CRC cohorts for chemotherapy treatment.Result: We found that HR mutant-type (HR-MUT) patients are less likely to experience tumor metastasis after receiving chemotherapy. Additionally, our univariate and multivariate cox regression models showed that HR-MUT can be used as an independent predictor of the prognosis of chemotherapy for CRC patients. The KM curve showed that patients with HR-MUT CRC had significantly prolonged overall survival (OS) time (log-rank p = 0.017; hazard ratio (HR) = 0.69). Compared to HR mutant-type (HR-WT), HR-MUT has a significantly lower IC50 value with several chemotherapeutic drugs. Pathway enrichment analysis further revealed that the HR-MUT displayed a significantly lower rate of DNA damage repair ability, tumor growth, metastasis activity, and tumor fatty acid metabolism activity than HR-WT, though its immune response activity was notably higher.Conclusion: These findings indicate that HR-MUT may be a relevant marker for CRC patients receiving chemotherapy, as it is closely related to improving OS time and reducing chemotherapy resistance.

show abstract

“…We first examined the gene mutations and their frequency of occurrence as a function of colorectal cancer clinicopathologic parameters using seven clinical colorectal cancer studies (2,575 samples) in cBioportal [25][26][27][28][29][30][31] . Across the seven studies surveyed in cBioportal, the percentage of samples in which somatic mutations in APC occurred was 69.6%, with a corresponding frequency of 13.7% for samples with BRAF mutations.…”

Section: Analysis Of Apc and Braf Gene Mutations In Crc Using Cbioportalmentioning

confidence: 99%

“…This source was used to investigate common gene mutations found in patients with CRC. A total of 7 studies (n=2,575) covering colorectal adenocarcinoma, metastatic colorectal cancer, colon adenocarcinoma, and colon cancer were explored, and a list of frequent mutated genes was generated [25][26][27][28][29][30][31] . Additionally, using the same seven studies, the APC/BRAF gene pairing was selected.…”

Section: Introductionmentioning

confidence: 99%

Development of an accessible gene expression bioinformatics pipeline to study driver mutations of colorectal cancer

Driest

Johnson

Rattray

et al. 2021

Preprint

View full text Add to dashboard Cite

Colorectal cancer (CRC) is a global cause of cancer-related mortality driven by genetic and environmental factors which influence therapeutic outcomes. The emergence of next-generation sequencing technologies enables the rapid and extensive collection and curation of genetic data for each cancer type into clinical gene expression biobanks.In this study we used a combination of bioinformatics tools to investigate the expression patterns and prognostic significance of two genes, adenomatous polyposis coli (APC) and B-Raf proto-oncogene (BRAF), that are commonly dysregulated in colon cancer. Subsequently, we investigated the pathways and biomolecular effectors implicated in APC and BRAF function.Our results show mutation types, frequency, anatomical location and differential expression patterns for APC and BRAF between colorectal tumour and matched healthy tissue. The prognostic values of APC and BRAF was investigated as a function of expression level in CRC and other cancer types.In the era of precision medicine and with significant advancements in biobanking and data curation, there is significant scope to use existing clinical datasets for evaluating the role of mutational drivers in carcinogenesis. This offers the potential for studying combinations of less well-known genes and the discovery of novel biomarkers or studying the association between various effector proteins and pathways.

show abstract

Specific Mutations in APC, but Not Alterations in DNA Damage Response, Associate With Outcomes of Patients With Metastatic Colorectal Cancer

Cited by 30 publications

References 9 publications

A specific Upregulated lncRNA in Colorectal Cancer Promotes Cancer Progression by Modulating miR-185-5p/CCND2 Axis

A specific Upregulated lncRNA in Colorectal Cancer Promotes Cancer Progression by Modulating miR-185-5p/CCND2 Axis

Homologous Recombination Pathway Alternation Predicts Prognosis of Colorectal Cancer With Chemotherapy

Development of an accessible gene expression bioinformatics pipeline to study driver mutations of colorectal cancer

Contact Info

Product

Resources

About