While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in similar to 60% of cases and often together (p=0.04). CDX2(Null)/BRAF(V600E) expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAF(V600E) potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2(Null)/BRAF(V600E)-mutant epithelium expressed gastric markers. Organoids from CDX2(Null)/BRAF(V600E)-mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAF(V600E). The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.

Sakamoto, N., Feng, Y., Stolfi, C., Kurosu, Y., Green, M., Lin, J., et al. (2017). BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. ELIFE, 6 [10.7554/eLife.20331].

BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis

Stolfi, C.;
2017-01-01

Abstract

While 20-30% of colorectal cancers (CRCs) may arise from precursors with serrated glands, only 8-10% of CRCs manifest serrated morphology at diagnosis. Markers for distinguishing CRCs arising from 'serrated' versus 'conventional adenoma' precursors are lacking. We studied 36 human serrated CRCs and found CDX2 loss or BRAF mutations in similar to 60% of cases and often together (p=0.04). CDX2(Null)/BRAF(V600E) expression in adult mouse intestinal epithelium led to serrated morphology tumors (including carcinomas) and BRAF(V600E) potently interacted with CDX2 silencing to alter gene expression. Like human serrated lesions, CDX2(Null)/BRAF(V600E)-mutant epithelium expressed gastric markers. Organoids from CDX2(Null)/BRAF(V600E)-mutant colon epithelium showed serrated features, and partially recapitulated the gene expression pattern in mouse colon tissues. We present a novel mouse tumor model based on signature defects seen in many human serrated CRCs - CDX2 loss and BRAF(V600E). The mouse intestinal tumors show significant phenotypic similarities to human serrated CRCs and inform about serrated CRC pathogenesis.
2017
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA
English
cancer biology
cancer diagnosis
colorectal cancer
homeobox gene
human
human biology
intestinal differentiation
medicine
mouse
oncogene
tumor suppressor gene
Animals
CDX2 Transcription Factor
Colon
Colorectal Neoplasms
Disease Models, Animal
Gene Expression Profiling
Intestinal Mucosa
Mice
Organoids
Proto-Oncogene Proteins B-raf
Carcinogenesis
Sakamoto, N., Feng, Y., Stolfi, C., Kurosu, Y., Green, M., Lin, J., et al. (2017). BRAFV600E cooperates with CDX2 inactivation to promote serrated colorectal tumorigenesis. ELIFE, 6 [10.7554/eLife.20331].
Sakamoto, N; Feng, Y; Stolfi, C; Kurosu, Y; Green, M; Lin, J; Green, Me; Sentani, K; Yasui, W; Mcmahon, M; Hardiman, Km; Spence, Jr; Horita, N; Greenson, Jk; Kuick, R; Cho, Kr; Fearon, Er
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/253632
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