RGD Reference Report - Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling. - Rat Genome Database

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Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling.

Authors: Fujita, Masashi  Matsubara, Nagahide  Matsuda, Ikuo  Maejima, Kazuhiro  Oosawa, Ayako  Yamano, Tomoki  Fujimoto, Akihiro  Furuta, Mayuko  Nakano, Kaoru  Oku-Sasaki, Aya  Tanaka, Hiroko  Shiraishi, Yuichi  Mateos, Raúl Nicolás  Nakai, Kenta  Miyano, Satoru  Tomita, Naohiro  Hirota, Seiichi  Ikeuchi, Hiroki  Nakagawa, Hidewaki 
Citation: Fujita M, etal., Oncotarget. 2017 Dec 12;9(1):969-981. doi: 10.18632/oncotarget.22867. eCollection 2018 Jan 2.
RGD ID: 151361225
Pubmed: PMID:29416670   (View Abstract at PubMed)
PMCID: PMC5787528   (View Article at PubMed Central)
DOI: DOI:10.18632/oncotarget.22867   (Journal Full-text)

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer, known as colitis-associated cancer (CAC). It is still unclear what driver mutations are caused by chronic inflammation and lead to CAC development. To get insight into this issue, we investigated somatic alterations in CAC. We performed exome sequencing of 22 fresh CACs and targeted sequencing of 43 genes on 90 archive specimens from Japanese CAC patients, of which 58 were ulcerative colitis (UC) and 32 were Crohn's disease (CD). Consistently with the previous reports, TP53 was commonly mutated (66%) whereas APC, KRAS and SMAD4 were mutated less frequently (16%, 11% and 11%, respectively). Mucinous CD-CACs in the anus, an Asian-specific subtype of CD-CAC, had less somatic mutations in our target genes. We also found that RNF43, a negative regulator of the Wnt signaling, was somatically mutated in a significant fraction of CACs (10 of 90; 11%). Two lines of evidence indicated that somatic mutations of RNF43 were related to chronic inflammation. First, somatic mutations of RNF43 were significantly associated with longer duration of IBD. Second, clinico-pathological features suggested many of the APC-mutated CACs were actually sporadic colorectal cancer whereas RNF43-mutated CACs did not have this tendency. RNA-Seq analysis showed that RNF43-mutated CACs had elevated expression of c-Myc and its target genes, suggesting that RNF43 is a bona fide driver of CAC development. This study provides evidence that somatic mutation of RNF43 is the driver genetic alteration that links chronic inflammation and cancer development in about 10% of CACs.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RNF43Humanirritable bowel syndrome exacerbatesIAGP associated with Colitis-Associated Neoplasms and DNA:mutations:multiple: (human)RGD 
Rnf43Ratirritable bowel syndrome exacerbatesISORNF43 (Homo sapiens)associated with Colitis-Associated Neoplasms and DNA:mutations:multiple: (human)RGD 
Rnf43Mouseirritable bowel syndrome exacerbatesISORNF43 (Homo sapiens)associated with Colitis-Associated Neoplasms and DNA:mutations:multiple: (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RNF43HumanInflammation of the large intestine exacerbatesIAGP associated with Colitis-Associated Neoplasms and DNA:mutations:multiple:RGD 
Objects Annotated

Genes (Rattus norvegicus)
Rnf43  (ring finger protein 43)

Genes (Mus musculus)
Rnf43  (ring finger protein 43)

Genes (Homo sapiens)
RNF43  (ring finger protein 43)


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