Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation.
Aberrant Wnt signaling can drive cancer development. In many cancer types, the genetic basis of Wnt pathway activation remains incompletely understood. Here, we report recurrent somatic mutations of the Drosophila melanogaster tumor suppressor-related gene FAT1 in glioblastoma (20.5%), colorectal cancer (7.7%), and head and neck cancer (6.7%). FAT1 encodes a cadherin-like protein, which we found is able to potently suppress cancer cell growth in vitro and in vivo by binding β-catenin and antagonizing its nuclear localization. Inactivation of FAT1 via mutation therefore promotes Wnt signaling and tumorigenesis and affects patient survival. Taken together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer. Loss of FAT1 function is a frequent event during oncogenesis. These findings address two outstanding issues in cancer biology: the basis of Wnt activation in non-colorectal tumors and the identity of a 4q35 tumor suppressor.
Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Luc G T
LG
Morris
Andrew M
AM
Kaufman
Yongxing
Y
Gong
Deepa
D
Ramaswami
Logan A
LA
Walsh
Şevin
Ş
Turcan
Stephanie
S
Eng
Kasthuri
K
Kannan
Yilong
Y
Zou
Luke
L
Peng
Victoria E
VE
Banuchi
Phillip
P
Paty
Zhaoshi
Z
Zeng
Efsevia
E
Vakiani
David
D
Solit
Bhuvanesh
B
Singh
Ian
I
Ganly
Linda
L
Liau
Timothy C
TC
Cloughesy
Paul S
PS
Mischel
Ingo K
IK
Mellinghoff
Timothy A
TA
Chan
D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics*
D015820:Cadherins; D029721:Drosophila Proteins; C502403:FAT1 protein, human