Fine mapping of chromosome 6q23-25 region in familial lung cancer families reveals RGS17 as a likely candidate gene.
OBJECTIVE
We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP).


METHODS
Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members.


RESULTS
A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels.


CONCLUSIONS
RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25.
Washington University, St. Louis, Missouri 63110, USA. youm@wudosis.wustl.edu
Ming
M
You
Daolong
D
Wang
Pengyuan
P
Liu
Haris
H
Vikis
Michael
M
James
Yan
Y
Lu
Yian
Y
Wang
Min
M
Wang
Qiong
Q
Chen
Dongmei
D
Jia
Yan
Y
Liu
Weidong
W
Wen
Ping
P
Yang
Zhifu
Z
Sun
Susan M
SM
Pinney
Wei
W
Zheng
Xiao-Ou
XO
Shu
Jirong
J
Long
Yu-Tang
YT
Gao
Yong-Bing
YB
Xiang
Wong-Ho
WH
Chow
Nat
N
Rothman
Gloria M
GM
Petersen
Mariza
M
de Andrade
Yanhong
Y
Wu
Julie M
JM
Cunningham
Jonathan S
JS
Wiest
Pamela R
PR
Fain
Ann G
AG
Schwartz
Luc
L
Girard
Adi
A
Gazdar
Colette
C
Gaba
Henry
H
Rothschild
Diptasri
D
Mandal
Teresa
T
Coons
Juwon
J
Lee
Elena
E
Kupert
Daniela
D
Seminara
John
J
Minna
Joan E
JE
Bailey-Wilson
Christopher I
CI
Amos
Marshall W
MW
Anderson
D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D005260:Female; D055785:Gene Knockdown Techniques; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020710:RGS Proteins / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014183:Transplantation, Heterologous / Q000473:pathology
D020710:RGS Proteins; D034741:RNA, Small Interfering