Novel microdeletion in the transforming growth factor beta type II receptor gene is associated with giant and large cell variants of nonsmall cell lung carcinoma.
Mutations in the tumor suppressor gene transforming growth factor beta (TGFB) Type II receptor (TGFBR2) are frequently found in many cancers with microsatellite instability, but are less common in lung cancer. In the present study, we looked for mutations in TGFBR2 in nonsmall cell lung carcinoma (NSCLC) cells and tissues. A novel homozygous microdeletion (c.492_507del) was identified in two cell lines derived from the same giant cell carcinoma (GCC) and was confirmed in the corresponding tumor tissues. Furthermore, a heterozygous c.492_507del was found in the germ-line of one patient, as well as in the other GCC cases and some large cell carcinomas (LCC) but not in other subtypes of NSCLC. The 16 bp-microdeletion introduced a premature stop codon at positions 590-592 of the cDNA, resulting in a truncated TGFBR2 protein with a mutated transmembrane domain and loss of kinase domain. The GCC cells were characterized as being unresponsive to TGFB induction both in growth inhibition and stimulation of extracellular matrix protein. Moreover, after the reconstitution of wild-type TGFBR2 expression, the sensitivity to TGFB was restored. Therefore, mutated TGFBR2 seems to play an important role in the abrogation of TGFB signal transduction in GCC cells.
Wang
Jiu-Cun
JC
The State Key Laboratory of Genetic Engineering, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, Shanghai 200433, People's Republic of China.
Su
Cheng-Chang
CC
Xu
Ji-Bin
JB
Chen
Le-Zhen
LZ
Hu
Xiao-Hua
XH
Wang
Gui-Ying
GY
Bao
Yang
Y
Huang
Qiang
Q
Fu
Song-Bin
SB
Li
Pu
P
Lu
Chen-Qi
CQ
Zhang
Rong-Mei
RM
Luo
Z W
ZW
D000328:Adult; D000368:Aged; D001483:Base Sequence; D018286:Carcinoma, Giant Cell / Q000235:genetics*; D018287:Carcinoma, Large Cell / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics*; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II