Ethnic differences and functional analysis of MET mutations in lung cancer.
OBJECTIVE
African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53.


METHODS
Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies.


RESULTS
Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies.


CONCLUSIONS
MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding.
Krishnaswamy
Soundararajan
S
Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
Kanteti
Rajani
R
Duke-Cohan
Jonathan S
JS
Loganathan
Sivakumar
S
Liu
Wanqing
W
Ma
Patrick C
PC
Sattler
Martin
M
Singleton
Patrick A
PA
Ramnath
Nithya
N
Innocenti
Federico
F
Nicolae
Dan L
DL
Ouyang
Zheng
Z
Liang
Jie
J
Minna
John
J
Kozloff
Mark F
MF
Ferguson
Mark K
MK
Natarajan
Viswanathan
V
Wang
Yi-Ching
YC
Garcia
Joe G N
JG
Vokes
Everett E
EE
Salgia
Ravi
R
D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics; D044383:Black People / Q000235:genetics; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005006:Ethnicity / Q000235:genetics; D005091:Exons; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D044469:Racial Groups / Q000235:genetics*; D039961:Semaphorins / Q000737:chemistry / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D044465:White People / Q000235:genetics; D001741:Black or African American
C478479:((3Z)-N-(3-chlorophenyl)-3-((3,5-dimethyl-4-((4-methylpiperazin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-N-methyl-2-oxo-2,3-dihydro-1H-indole-5-sulfonamide); D004791:Enzyme Inhibitors; D007211:Indoles; C000715470:MAS1 protein, human; D010879:Piperazines; D000090063:Proto-Oncogene Mas; D039961:Semaphorins; D013449:Sulfonamides; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met