Pengyuan Liu
3
y
Carl Morrison
1
y
Liang Wang
0
y
Donghai Xiong
7
y
Peter Vedell
7
y
Peng Cui
7
y
Xing Hua
2
3
y
Feng Ding
7
Yan Lu
3
Michael James
7
John D.Ebben
7
Haiming Xu
3
Alex A.Adjei
1
Karen Head
1
Jaime W.Andrae
3
Michael R.Tschannen
3
Howard Jacob
3
Jing Pan
7
Qi Zhang
7
Francoise Van den Bergh
7
Haijie Xiao
7
Ken C.Lo
5
Jigar Patel
5
Todd Richmond
5
Mary-Anne Watt
5
Thomas Albert
5
Rebecca Selzer
5
Marshall Anderson
4
Jiang Wang
9
Yian Wang
8
Sandra Starnes
2
Ping Yang
0
y
Ming You
7
y
To whom correspondence should be addressed. Tel:
3
Fax:
3
Email:
0
Department of Health Science Research, Mayo Clinic
,
Rochester, MN 55905, USA
1
Roswell Park Cancer Institute
, Buffalo,
NY 14263, USA
2
Department of Surgery, University of Cincinnati College of Medicine
, Cincinnati,
OH 45267, USA
3
Department of Physiology and the Cancer Center, Medical College of Wisconsin
,
Milwaukee, WI 53226, USA
4
Department of Medicine and the Cancer Center, Medical College of Wisconsin
,
Milwaukee, WI 53226, USA
5
Roche NimbleGen Research and Development
,
Madison, WI 53719, USA
6
Department of Statistics and Finance, University of Science and Technology of China
, Hefei, Anhui 230026,
China
7
Department of Pharmacology and Toxicology, Medical College of Wisconsin Cancer Center
,
Milwaukee, WI 53226, USA
8
Department of Surgery, Washington University in St. Louis
,
St. Louis, MO 63110, USA
9
Department of Pathology, University of Cincinnati College of Medicine
, Cincinnati,
OH 45267, USA
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[email protected]
-
Lung cancer is the leading cause of cancer-related death, with
non-small cell lung cancer (NSCLC) being the predominant form
of the disease. Most lung cancer is caused by the accumulation of
genomic alterations due to tobacco exposure. To uncover its
mutational landscape, we performed whole-exome sequencing in 31
NSCLCs and their matched normal tissue samples. We identified
both common and unique mutation spectra and pathway
activation in lung adenocarcinomas and squamous cell carcinomas, two
major histologies in NSCLC. In addition to identifying previously
known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and
RB1), the analysis revealed many genes not previously implicated
in this malignancy. Notably, a novel gene CSMD3 was identified as
the second most frequently mutated gene (next to TP53) in lung
cancer. We further demonstrated that loss of CSMD3 results in
increased proliferation of airway epithelial cells. The study
provides unprecedented insights into mutational processes, cellular
pathways and gene networks associated with lung cancer. Of
potential immediate clinical relevance, several highly mutated genes
identified in our study are promising druggable targets in cancer
therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX,
PIK3C2B, PIK3CG and ROCK2.
Introduction
Lung cancer is the leading cause of cancer-related death in the USA.
In 2011, there will be an estimated 220 000 cases of lung cancer
diagnosed, and only 15% of those patients are expected to survive
for .5 years (1). Although active cigarette smoking causes most
lung cancer deaths, 1015% of patients diagnosed with lung cancer
Abbreviations: ADC, adenocarcinomas; BAC, bronchioloalveolar carcinoma;
NSCLC, non-small cell lung cancer; SNVs, sequence nucleotide variations;
SCC, squamous cell carcinomas.
yThese authors contributed equally.
have never smoked. Prolonged exposure to carcinogens found in
tobacco smoke and other environmental carcinogens that interact with
various genetic susceptibility and/or resistance factors contribute to
the accumulation of genomic alterations, including nucleotide
substitutions, small insertions and deletions, copy number variations and
chromosomal rearrangements, in human lung cancers.
Several tumor suppressor genes are inactivated in many cases of
lung cancer including TP53 (2), RB1 (3,4) and PTEN (5), whereas
activating mutations are found in EGFR (6) and KRAS (7) in some
cases. Recent DNA sequencing of 623 genes with known or potential
relationships to cancer revealed .1000 somatic mutations in lung
adenocarcinomas (ADC), a major subtype of non-small cell lung
cancer (NSCLC). The newly identified genes include tumor
suppressor genes (NF1, ATM and APC) along with tyrosine kinase genes
(ephrin receptor genes, ERBB4, KDR, FGFR4 and NTRK genes) that
may function as proto-oncogenes (8). More recently, the genomes of
a small-cell cancer line NCI-H209 and a male Caucasian diagnosed
with ADC were sequenced (9,10). Although a broad spectrum of
mutations was observed in these whole-genome sequencing studies,
the large majority of mutations are predicted to be passenger
mutations. It is not yet clear whether the somatic alterations identified in
these two whole-genome sequencing samples will be found
recurrentl (...truncated)