Gene Expression Changes Accompanying the Duodenal Adenoma-Carcinoma Sequence in Familial Adenomatous Polyposis

Thiruvengadam, Sushrut S.; O’Malley, Margaret; LaGuardia, Lisa; López, Rocío; Wang, Zhen; Shadrach, Bonnie; Chen, Yanwen; Li, Chunbiao; Veigl, Martina L.; Barnholtz‐Sloan, Jill S.; Pai, Rish K.; Church, James M.; Kalady, Matthew F.; Walsh, R. Matthew; Burke, Carol A.

doi:10.14309/ctg.0000000000000053

Cited by 11 publications

(16 citation statements)

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“…CLCA1 decreased expression was also described in serum and CRC tissues, showing an inverse correlation with CRC metastasis and tumor stage [ 34 ]. CLCA1 and ADH1C were shown to be downregulated in familial adenomatous polyposis [ 35 ]. S LC4A4 associated with proliferation and migration in colon and breast cancer [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

ETV4 plays a role on the primary events during the adenoma-adenocarcinoma progression in colorectal cancer

Fonseca

Ramão

Bürger³

et al. 2021

BMC Cancer

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Background Colorectal cancer (CRC) is one of the most common cancers worldwide; it is the fourth leading cause of death in the world and the third in Brazil. Mutations in the APC, DCC, KRAS and TP53 genes have been associated with the progression of sporadic CRC, occurring at defined pathological stages of the tumor progression and consequently modulating several genes in the corresponding signaling pathways. Therefore, the identification of gene signatures that occur at each stage during the CRC progression is critical and can present an impact on the diagnosis and prognosis of the patient. In this study, our main goal was to determine these signatures, by evaluating the gene expression of paired colorectal adenoma and adenocarcinoma samples to identify novel genetic markers in association to the adenoma-adenocarcinoma stage transition. Methods Ten paired adenoma and adenocarcinoma colorectal samples were subjected to microarray gene expression analysis. In addition, mutations in APC, KRAS and TP53 genes were investigated by DNA sequencing in paired samples of adenoma, adenocarcinoma, normal tissue, and peripheral blood from ten patients. Results Gene expression analysis revealed a signature of 689 differentially expressed genes (DEG) (fold-change> 2, p< 0.05), between the adenoma and adenocarcinoma paired samples analyzed. Gene pathway analysis using the 689 DEG identified important cancer pathways such as remodeling of the extracellular matrix and epithelial-mesenchymal transition. Among these DEG, the ETV4 stood out as one of the most expressed in the adenocarcinoma samples, further confirmed in the adenocarcinoma set of samples from the TCGA database. Subsequent in vitro siRNA assays against ETV4 resulted in the decrease of cell proliferation, colony formation and cell migration in the HT29 and SW480 colorectal cell lines. DNA sequencing analysis revealed KRAS and TP53 gene pathogenic mutations, exclusively in the adenocarcinomas samples. Conclusion Our study identified a set of genes with high potential to be used as biomarkers in CRC, with a special emphasis on the ETV4 gene, which demonstrated involvement in proliferation and migration.

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Section: Discussionmentioning

confidence: 99%

ETV4 plays a role on the primary events during the adenoma-adenocarcinoma progression in colorectal cancer

Fonseca

Ramão

Bürger³

et al. 2021

BMC Cancer

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“…The translatability between experimental models was analyzed by comparison of microarrays data from the CR mouse duodenum to normal human duodenum expression ( Figure 1A ) (25). We found 17,760 expressed genes in the normal human duodenum and 20,727 in the normal mouse duodenum (Methods).…”

Section: Resultsmentioning

confidence: 99%

“…We analysed gene sequences and annotated gene symbols associated with multiple p.s. We analysed normal human duodenum gene expression profiles (25) using statistical methods (Suppl. Methods) and studied correlations in the gene expression of mouse and human DM.…”

Section: Methodsmentioning

confidence: 99%

“…Next, we compared CR response genes found in mice DM with the DEGs of normaladenoma-carcinoma patterns (25,(30)(31)(32). Human duodenal adenoma/adenocarcinoma and colorectal adenoma transcription expression data (orthologs with corresponding mouse CR DEGs matched regulation directionality changes) indicated 53 significant cancer-associated genes of the 467 CR DEGs:15 upregulated genes, 38 suppressed (Supplementary Data 3A-F).…”

Section: % Of Cr Response Genes Are Involved In Mucosa Normal-adenomentioning

confidence: 99%

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Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction

Maestri

Duszka

Kuznetsov

2021

Preprint

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Systematic analysis of calorie restriction (CR) mechanisms and pathways in cancer biology has not been carried out, leaving therapeutic benefits unclear. Using a systems biology approach and metadata analysis, we studied gene expression changes in the response of normal mouse duodenum mucosa (DM) to short-term (2-weeks) 25% CR as a biological model. We found a high similarity of gene expression profiles in human and mouse DM tissues. Surprisingly, 26% of the 467 CR responding differential expressed genes (DEGs) in mice consist of cancer-associated genes, most never studied in CR contexts. The DEGs were enriched with over-expressed cell cycle, oncogenes, and metabolic reprogramming pathways (MRP) that determine tissue-specific tumorigenesis, cancer, and stem cell activation; tumor suppressors and apoptosis genes were under-expressed. DEG enrichments suggest a misbalance in telomere maintenance and activation of metabolic pathways playing dual (anti-cancer and pro-oncogenic) roles. Immune system genes (ISGs) consist of 37% of the total DEGs; the majority of ISGs are suppressed, including cell-autonomous immunity and tumor immune evasion controls. Thus, CR induces MRP suppressing multiple immune mechanics and activating oncogenic pathways, potentially driving pre-malignant and cancer states. These findings may change the paradigm regarding the anti-cancer role of CR and initiate specific treatment target development.

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“…Duodenal carcinoma in familial adenomatous polyposis (FAP) arises from adenomas. Differentially expressed genes in the duodenal adenoma-carcinoma pathway have been identified in murine FAP models; however, similar data in patients with FAP are limited [ 6 ]. Here, we report about a patient without a familial history of FAP in whom a histopathological finding suggestive of the adenoma-carcinoma sequence was obtained from the biopsy results of a bulging lesion in the duodenum, and the lesion was identified as an APC germline mutation by a genetic analysis.…”

Section: Introductionmentioning

confidence: 99%

Next-Generation Sequencing for Non-Ampullary Duodenal Carcinoma Suggesting the Existence of an Adenoma-Carcinoma Sequence

Yoshida

Kojima

Shimada

et al. 2021

Case Rep Gastroenterol

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Duodenal tumors with a sporadic adenoma-carcinoma sequence are extremely rare. For such clinically suspected cases without a specific family history, performing a comprehensive gene search is important to understand the germline mutation background. We present a 68-year-old woman without a genetic or familial history of familial adenomatous polyposis (FAP), Peutz-Jeghers syndrome, or Lynch syndrome who presented to Kosei Hospital, Japan, with exertional dyspnea induced by abdominal pain lasting 3 weeks. A duodenal tumor was suspected by contrast-enhanced computed tomography. Esophagogastroduodenoscopy showed a lesion accompanied by a white microprotuberance on the descending part of the duodenum opposite the papilla, with a giant ulcerative lesion at the center of the white lesion. Biopsy revealed a low-grade adenoma, high-grade adenoma, and adenocarcinoma. Immunohistochemical analysis of the adenoma and adenocarcinoma showed Ki-67, p53, cytokeratin 20, caudal-type homeobox 2, and carcinoembryonic antigen positivity and cytokeratin 7 negativity. The findings suggested the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma. However, in the mutational analysis using next-generation sequencing, c.4348C>T (p.Arg1450Ter) mutation in APC was detected in all normal mucosal, adenoma, and carcinoma tissues. This mutation is common in FAP patients. Even if the presence of an adenoma-adenocarcinoma sequence in duodenal carcinoma is suggested in cases without a familial FAP history, as in this case, genetic analysis may reveal FAP. Thus, performing a comprehensive genetic analysis of duodenal carcinoma patients with a possible adenoma-carcinoma sequence is necessary to explore their genetic background.

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Gene Expression Changes Accompanying the Duodenal Adenoma-Carcinoma Sequence in Familial Adenomatous Polyposis

Cited by 11 publications

References 50 publications

ETV4 plays a role on the primary events during the adenoma-adenocarcinoma progression in colorectal cancer

ETV4 plays a role on the primary events during the adenoma-adenocarcinoma progression in colorectal cancer

Immunity Depletion, Telomere Imbalance, and Cancer-associated Metabolism Pathway Aberrations in Intestinal Mucosa upon Caloric Restriction

Next-Generation Sequencing for Non-Ampullary Duodenal Carcinoma Suggesting the Existence of an Adenoma-Carcinoma Sequence

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