Novel biomarkers that assist in accurate discrimination of squamous cell carcinoma from adenocarcinoma of the lung.
BACKGROUND
Targeted therapies based on the molecular and histological features of cancer types are becoming standard practice. The most effective regimen in lung cancers is different between squamous cell carcinoma (SCC) and adenocarcinoma (AD). Therefore a precise diagnosis is crucial, but this has been difficult, particularly for poorly differentiated SCC (PDSCC) and AD without a lepidic growth component (non-lepidic AD). Biomarkers enabling a precise diagnosis are therefore urgently needed.


METHODS
Cap Analysis of Gene Expression (CAGE) is a method used to quantify promoter activities across the whole genome by determining the 5' ends of capped RNA molecules with next-generation sequencing. We performed CAGE on 97 frozen tissues from surgically resected lung cancers (22 SCC and 75 AD), and confirmed the findings by immunohistochemical analysis (IHC) in an independent group (29 SCC and 45 AD).


RESULTS
Using the genome-wide promoter activity profiles, we confirmed that the expression of known molecular markers used in IHC for SCC (CK5, CK6, p40 and desmoglein-3) and AD (TTF-1 and napsin A) were different between SCC and AD. We identified two novel marker candidates, SPATS2 for SCC and ST6GALNAC1 for AD, as showing comparable performance and complementary utility to the known markers in discriminating PDSCC and non-lepidic AD. We subsequently confirmed their utility at the protein level by IHC in an independent group.


CONCLUSIONS
We identified two genes, SPATS2 and ST6GALNAC1, as novel complemental biomarkers discriminating SCC and AD. These findings will contribute to a more accurate diagnosis of NSCLC, which is crucial for precision medicine for lung cancer.
Department of General Thoracic Surgery, Juntendo University School of Medicine, 1-3, Hongo 3-chome, Bunkyo-ku, Tokyo, 113-8431, Japan. ktakamo@juntendo.ac.jp.
Kazuya
http://orcid.org/0000-0002-1721-6364
K
Takamochi
Preventive Medicine and Applied Genomics Unit, RIKEN Advanced Center for Computing and Communication, 1-7-22 Suehiro-cho, Tsurumi-ku, 230-0045, Yokohama, Japan.
Hiroko
H
Ohmiya
RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Masayoshi
M
Itoh
Center for Genomic and Regenerative Medicine, Juntendo University School of Medicine, 1-3, Hongo 3-chome, Bunkyo-ku, Tokyo, 113-8431, Japan.
Kaoru
K
Mogushi
Department of Human Pathology, Juntendo University School of Medicine, 1-3, Hongo 3-chome, Bunkyo-ku, Tokyo, 113-8431, Japan.
Tsuyoshi
T
Saito
Department of Human Pathology, Juntendo University School of Medicine, 1-3, Hongo 3-chome, Bunkyo-ku, Tokyo, 113-8431, Japan.
Kieko
K
Hara
Department of Human Pathology, Juntendo University School of Medicine, 1-3, Hongo 3-chome, Bunkyo-ku, Tokyo, 113-8431, Japan.
Keiko
K
Mitani
RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Yasushi
Y
Kogo
RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Yasunari
Y
Yamanaka
RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Jun
J
Kawai
RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Yoshihide
Y
Hayashizaki
Department of General Thoracic Surgery, Juntendo University School of Medicine, 1-3, Hongo 3-chome, Bunkyo-ku, Tokyo, 113-8431, Japan.
Shiaki
S
Oh
Department of General Thoracic Surgery, Juntendo University School of Medicine, 1-3, Hongo 3-chome, Bunkyo-ku, Tokyo, 113-8431, Japan.
Kenji
K
Suzuki
Preventive Medicine and Applied Genomics Unit, RIKEN Advanced Center for Computing and Communication, 1-7-22 Suehiro-cho, Tsurumi-ku, 230-0045, Yokohama, Japan.|RIKEN Preventive Medicine and Diagnosis Innovation Program, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan.
Hideya
H
Kawaji
Stem Cells. 2014 Nov;32(11):2998-3011
25069783
Hum Mol Genet. 2010 Nov 1;19(21):4273-7
20724461
Nature. 2014 Mar 27;507(7493):462-70
24670764
Bioinformatics. 2010 Jan 1;26(1):139-40
19910308
Methods Mol Biol. 2014;1164:67-85
24927836
Chest. 2005 Jul;128(1):452-62
16002972
PLoS Genet. 2012 Jul;8(7):e1002824
22792082
Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13790-5
11707567
Mod Pathol. 2011 Oct;24(10):1348-59
21623384
Biochem Biophys Res Commun. 2002 Apr 12;292(4):992-8
11944913
Science. 2015 Feb 27;347(6225):1010-4
25678556
Nature. 2014 Mar 27;507(7493):455-61
24670763
Bioinformatics. 2009 Aug 15;25(16):2078-9
19505943
Genome Biol. 2004;5(10):R80
15461798
Bioinformatics. 2010 Mar 1;26(5):589-95
20080505
Oncologist. 2009 Mar;14(3):253-63
19221167
Am J Clin Pathol. 2013 Jul;140(1):37-46
23765532
J Thorac Oncol. 2015 Sep;10(9):1240-2
26291007
BMC Bioinformatics. 2014 May 16;15:144
24884663
J Clin Pathol. 2000 Jul;53(7):537-40
10961178
Arch Pathol Lab Med. 2013 Sep;137(9):1274-81
23289761
Blood. 2014 Apr 24;123(17):e58-67
24671954
Am J Surg Pathol. 2012 Jun;36(6):895-9
22367298
J Clin Oncol. 2009 Mar 10;27(8):1227-34
19188680
Arch Pathol Lab Med. 2012 Feb;136(2):155-62
22288962
Glycobiology. 2006 Jan;16(1):46-53
16177266
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15776-81
14663149
Nat Commun. 2015 Jan 14;6:6066
25585899
J Thorac Oncol. 2012 Feb;7(2):281-90
22071786
Acta Biochim Biophys Sin (Shanghai). 2007 Nov;39(11):879-84
17989879
Mod Pathol. 2012 Mar;25(3):405-15
22056955
J Thorac Oncol. 2014 Sep;9(9):1354-62
25122431
BMC Genomics. 2014 Dec 24;15:1177
25539566
Hum Mol Genet. 2011 Dec 15;20(24):4786-96
21908516
N Engl J Med. 2006 Dec 14;355(24):2542-50
17167137
Am J Pathol. 2009 May;174(5):1629-37
19342368