Open AccessSMAD4 is critical in suppression of BRAF-V600E serrated tumorigenesis
Author(s) -
Kevin Tong,
Om A. Kothari,
Katherine S. Haro,
Anshuman Panda,
Manisha M. Bandari,
Jillian N. Carrick,
Joseph Hur,
Lanjing Zhang,
Chang S. Chan,
Jinchuan Xing,
Michael L. Gatza,
Shridar Ganesan,
Michael P. Verzi
Publication year - 2021
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/s41388-021-01997-x
Subject(s) - biology , wnt signaling pathway , carcinogenesis , cancer research , v600e , microsatellite instability , mutation , colorectal cancer , mlh1 , cancer , msh2 , dna mismatch repair , genetics , gene , microsatellite , allele
BRAF-driven colorectal cancer is among the poorest prognosis subtypes of colon cancer. Previous studies suggest that BRAF-mutant serrated cancers frequently exhibit Microsatellite Instability (MSI) and elevated levels of WNT signaling. The loss of tumor-suppressor Smad4 in oncogenic BRAF-V600E mouse models promotes rapid serrated tumor development and progression, and SMAD4 mutations co-occur in human patient tumors with BRAF-V600E mutations. This study assesses the role of SMAD4 in early-stage serrated tumorigenesis. SMAD4 loss promotes microsatellite stable (MSS) serrated tumors in an oncogenic BRAF-V600E context, providing a model for MSS serrated cancers. Inactivation of Msh2 in these mice accelerated tumor formation, and whole-exome sequencing of both MSS and MSI serrated tumors derived from these mouse models revealed that all serrated tumors developed oncogenic WNT mutations, predominantly in the WNT-effector gene Ctnnb1 (β-catenin). Mouse models mimicking the oncogenic β-catenin mutation show that the combination of three oncogenic mutations (Ctnnb1, Braf, and Smad4) are critical to drive rapid serrated dysplasia formation. Re-analysis of human tumor data reveals BRAF-V600E mutations co-occur with oncogenic mutations in both WNT and SMAD4/TGFβ pathways. These findings identify SMAD4 as a critical factor in early-stage serrated cancers and helps broaden the knowledge of this rare but aggressive subset of colorectal cancer.