A novel large germ line deletion in adenomatous polyposis coli <i>(APC)</i> gene associated with familial adenomatous polyposis

Pouya, Farzaneh; Shariatpanahi, Afsaneh Mojtabanezhad; Ghaffarzadegan, Kamran; Yazdi, Seyed Abbas Tabatabaee; Golmohammadzadeh, Hamed; Soltani, Ghodratollah; Toosi, Kian Aminian; Kerachian, Mohammad Amin

doi:10.1002/mgg3.479

Cited by 5 publications

(3 citation statements)

References 32 publications

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“…It has been shown that the location of germline mutations in the APC gene is the most striking source of variability affecting the number of polyps that will develop in the colon of FAP patients 13 , 41 , 42 . In accordance, the current study found a correlation between the severity of the disease in FAP patients who donated their affected embryos for our FAP-hESC lines and the 3D structure of their derived colon organoids and the location of their germline APC mutations.…”

Section: Discussionmentioning

confidence: 99%

Heterozygous APC germline mutations impart predisposition to colorectal cancer

Preisler

Habib

Shapira

et al. 2021

Sci Rep

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Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.

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Section: Discussionmentioning

confidence: 99%

Heterozygous APC germline mutations impart predisposition to colorectal cancer

Preisler

Habib

Shapira

et al. 2021

Sci Rep

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“…The overall frequency of the APC gene mutation in sporadic colorectal cancer is about 25-30%, but some reports from Iran have revealed a different mutation profile [23][24][25][26] . This may be because of geneenvironmental interaction factors and predominantly because of the heterogeneous nature of colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

The APC gene rs41115 polymorphism is associated with survival in Iranian colorectal cancer patients

et al. 2020

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Introduction: The onset of colorectal cancer is a complex process caused by numerous genetic pathways. APC functions as a ``"gatekeeper" and its mutations occur at the initiation stage of the colorectal tumorigenesis. The main aim of this study was to investigate common somatic mutations of exon 15 APC genes in patients with colorectal cancer in East Azerbaijan, Iran. Methods: This study was designed and performed as a cross-sectional and case-only study. Tissue biopsies were obtained during colonoscopy and confirmed colorectal carcinoma cases were evaluated. Two hotspot regions of exon 15 for APC mutations were evaluated using PCR amplification and Sanger sequence analysis. Results: The synonymous (p.Thr1475Thr) polymorphism was observed in all patients; 35 patients (61.4%) had AG genotype and 22 patients (38.6%) had AA genotype. Also, a missense mutation and two deletions were found. Pearson's correlation test showed a significant correlation between the stage of the disease (rho = 0.23, P =< 0.05), and anatomical subsite of the tumor with rs41115 polymorphism (rho = 0.31, P =< 0.05). Overall comparison of survival function in the different genotypes of the APC gene showed significant differences between groups, and CRCs with AG genotype had 3.24-fold higher hazard of mortality than CRCs with AA genotype (HR = 3.24; 95% CI: 1.21 - 8.68, P = 0.020). Conclusion: APC mutation plays an important predictive role in overall survival. However, the pattern and type of APC gene have a diverse impact on clinical outcomes in the Asian population. Moreover, in CRC patients the APC mutations were reported to be diverse variants.

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“…According to the GLOBOCAN 2018 statistics, CRC is the third most commonly diagnosed malignancy and the second cause of cancer‐related death globally 2 . Approximately 70‐80% of the cases are sporadic, and the rest of them are hereditary CRC 3,4 . In the recent decade, several different CRC screening methods including fecal occult blood test (FOBT), stool DNA test, sigmoidoscopy, CT colonography, colonoscopy, and double‐contrast barium enema have been developed 5 .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of long non‐coding RNA function in colorectal cancer tumorigenesis

Poursheikhani

Abbaszadegan

Kerachian

2020

Asia-Pac J Clncl Oncology

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Colorectal cancer (CRC) is one of the most common cancers globally. Although a variety of CRC screening methods have been developed, many patients are diagnosed at advanced stages of CRC with tumor invasion and distance metastasis. Several studies have suggested the long noncoding RNAs (lncRNAs) as one of the main contributors in CRC tumorigenesis, although the exact underlying mechanism of lncRNAs in CRC is still unknown. Numerous studies have indicated aberrant expression of lncRNAs in CRC through different modes of action such as cell proliferation, apoptosis, cell cycle, DNA repair response, drug‐resistance, migration, and metastasis. Furthermore, lncRNA polymorphisms can influence the risk of CRC development. Accordingly, lncRNAs can be served as promising diagnostic or prognostic biomarkers and also desired therapeutic targets affecting the outcome of patients with CRC. In this review, we summarized the updated and novel evidence that identifies different roles of lncRNAs in the tumorigenesis of CRC.

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A novel large germ line deletion in adenomatous polyposis coli (APC) gene associated with familial adenomatous polyposis

Cited by 5 publications

References 32 publications

Heterozygous APC germline mutations impart predisposition to colorectal cancer

Heterozygous APC germline mutations impart predisposition to colorectal cancer

The APC gene rs41115 polymorphism is associated with survival in Iranian colorectal cancer patients

Mechanisms of long non‐coding RNA function in colorectal cancer tumorigenesis

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