Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787528/
https://www.ncbi.nlm.nih.gov/pubmed/29416670
http://dx.doi.org/10.18632/oncotarget.22867
_version_ 1783295949752238080
author 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
author_facet 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
author_sort Fujita, Masashi
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5787528
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher Impact Journals LLC
record_format MEDLINE/PubMed
spelling pubmed-57875282018-02-07 Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling 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 Oncotarget Research Paper 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. Impact Journals LLC 2017-12-12 /pmc/articles/PMC5787528/ /pubmed/29416670 http://dx.doi.org/10.18632/oncotarget.22867 Text en Copyright: © 2018 Fujita et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
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
Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling
title Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling
title_full Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling
title_fullStr Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling
title_full_unstemmed Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling
title_short Genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the Wnt signaling
title_sort genomic landscape of colitis-associated cancer indicates the impact of chronic inflammation and its stratification by mutations in the wnt signaling
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787528/
https://www.ncbi.nlm.nih.gov/pubmed/29416670
http://dx.doi.org/10.18632/oncotarget.22867
work_keys_str_mv AT fujitamasashi genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT matsubaranagahide genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT matsudaikuo genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT maejimakazuhiro genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT oosawaayako genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT yamanotomoki genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT fujimotoakihiro genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT furutamayuko genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT nakanokaoru genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT okusasakiaya genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT tanakahiroko genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT shiraishiyuichi genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT mateosraulnicolas genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT nakaikenta genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT miyanosatoru genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT tomitanaohiro genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT hirotaseiichi genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT ikeuchihiroki genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling
AT nakagawahidewaki genomiclandscapeofcolitisassociatedcancerindicatestheimpactofchronicinflammationanditsstratificationbymutationsinthewntsignaling