Re iew A icle
Genome Wide Associa ion S udies in Small-Cell
Lung Cance . A Sys ema ic Re iew
José Ramón Enjo-Ba ei o,
1 , 2 , #
Albe o Ruano-Ra ina,
1 , 3 , 4
Mónica Pé ez-Ríos,
1 , 3 , 4
Ka l Kelsey,
5
Juan Miguel Ba os-Dios,
1 , 3 , 4
Leono Va ela-Lema
1 , 3 , 4
Abs ac
Small cell lung cance (SCLC) is one o he deadlies o ms o lung cance , bu ew in o ma ion exis s ega ding he
ole o gene ics, pa icula ly on Genome Wide Associa ion S udies (GWAS). The aim o he s udy is o explo e he
e idence a ailable ob ained h ough GWAS s udies o SCLC using a sys ema ic e iew. We pe o med a li e a u e
sea ch in he main da abases un il July 31s , 2023. We included all human based s udies on GWAS o lung cance
which p esen ed esul s o SCLC. Only s udies wi h pa icipan s diagnosed o SCLC wi h ana omopa hological confi -
ma ion we e included. Fou een s udies we e iden ified; 8 s udies showed a ela ionship be ween ASCL1 o e exp ession
and SCLC, which may egula e CHRNA5/A3/B4 clus e , p oducing a consequen nAChR o e exp ession. Nine pape s,
including 8 o he p e ious, ound a posi i e associa ion be ween SNPs loca ed in ch omosome 15 and SCLC. The
mos impo an clus e o genes ound is CHRNA5/A3/B4 bu he mechanism o he ole o hese genes is unclea .
Kyo o Encyclopaedia o Genes and Genome (KEGG) shows ha hese ecep o s we e ound o be o e exp essed
whe e nico ine, 4-(me hylni osamino)-1-(3-py idyl)-1-bu anone (NNK) and N’-Ni osono nico ine (NNN) ac s, in ol ing
di e en ou es in SCLC ca cinogenesis.
Clinical Lung Cance , Vol. 25, No. 1, 9–17 © 2023 The Au ho (s). Published by Else ie Inc.
This is an open access a icle unde he CC BY-NC-ND license ( h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/ )
Keywo ds: Lung neoplasm, Small-cell lung ca cinoma, Oncogenes, CHRNA5/A3/B4, ASCL1
In oduc ion
Lung cance , acco ding o GLOBOCAN 2020, ep esen s he
leading cause o cance dea h, comp ising 18% o all cance dea hs
wo ldwide.
1 The main isk ac o o de eloping lung cance
is obacco consump ion, ollowed by indoo adon exposu e.
2 , 3
Howe e , hough mos o lung cance s a e o igina ed by obacco o
indoo adon exposu e, p oduced mainly by he adioac i e decay o
u anium,
4
no all exposed o hese subs ances de elop lung cance ,
sugges ing ha he e a e o he ac o s in ol ed, among hese, gene ic
suscep ibili y ac o s.
1
Depa men o P e en i e Medicine, Uni e si y o San iago de Compos ela, San iago
de Compos ela, Spain
2
Se ice o P e en i e Medicine, A Co uña Uni e si y Teaching Hospi al Complex, A
Co uña, Spain
3
Conso ium o Biomedical Resea ch in Epidemiology and Public Heal h
(CIBERESP), San iago de Compos ela, Spain
4
Heal h Resea ch Ins i u e o San iago de Compos ela (Ins i u o de In es igación
Sani a ia de San iago de Compos ela - IDIS), San iago de Compos ela, Spain
5
Depa men o Epidemiology, B own School o Public Heal h, B own Uni e si y,
P o idence, RI
Submi ed: May 12, 2023; Re ised: Aug 28, 2023; Accep ed: Oc 9, 2023; Epub: 12
Oc obe 2023
Add ess o co espondence: Ruano-Ra ina Albe o, PhD, Depa men o P e en-
i e Medicine and Public Heal h, School o Medicine, Uni e si y o San iago de
Compos ela, C/ San F ancisco s/n, San iago de Compos ela 15782, Spain.
E-mail con ac : albe o. [email protected]
# This esea ch is pa o he PhD wo k o José Ramón Enjo-Ba ei o.
Lung cance is usually classi ied in 2 main his ological g oups
a ending o he cha ac e is ics o he umo and he ea men
esponse: non-small cell lung cance (NSCLC) and small-cell lung
cance (SCLC). SCLC ep esen s only 15% o lung cance cases bu
i is cha ac e ized by he lowes su i al a e, wi h 5-yea su i al
lowe han 7%.
5 , 6
SCLC occu s in he pulmona y neu oendoc ine cells in he p oxi-
mal ai ways, hese cells sense s imuli such as nico ine and oxygen
7
.
These ype o cells highly exp ess mammalian achae e-scu e complex
homolog-1 ( ASCL1 ) and neu al cell adhesion molecule ( NCAM1 ),
which a e impo an o neu onal di e en ia ion and ma u a ion,
ha ing an impo an ole in SCLC de elopmen .
8 Cu en ly, his
disease is s a ing o be conside ed a no uni o m pa hology, because
au ho s like Rudin e al.
9 desc ibe 4 molecula sub ypes classi-
ied by he di e en exp ession o 4 key ansc ip ion egula-
o s.
6 , 9
Mo eo e , despi e SCLC and NSCLC a e di e en umo s,
i is obse ed ha a small g oup o NSCLC wi h an epide mal
g ow ac o ecep o (EGFR)-mu a ion display some esis ance o
he apies agains EGFR showing a his ological ans o ma ion o
SCLC.
10 , 11
Rega ding SCLC we know ha some mu a ions a e ela ed o
he de elopmen o his ype o cance , bu he molecula landscape
o his umo is highly complex. To s udy his, GWAS is a use ul
esea ch app oach, which combine molecula gene ic analysis
echniques and epidemiological s udy designs, o sequence he
1525-7304/$ - see on ma e © 2023 The Au ho (s). Published by Else ie Inc.
This is an open access a icle unde he CC BY-NC-ND license ( h p://c ea i ecommons.o g/licenses/by-
nc-nd/4.0/ )
h ps://doi.o g/10.1016/j.cllc.2023.10.002 Clinical Lung Cance Janua y 2024 9
Genome Wide Associa ion S udies in Small-Cell Lung Cance
human genome and calcula e he polygenic isk sco e o speci ic
gene ic a ian s. Al e na i ely, geno ype impu a ion combine
wi h low-pass sequencing is showing a highe s a is ical powe in
compa ison wi h geno yping a ays, being an in e es ing subs i u e
o polygenic sco es calcula ion and ai mapping in genome-wide
associa ion s udies.
12 GWAS e idence ha e made a slow p og ess
p obably due o he low numbe o cases included in many s udies.
The mos common gene ic al e a ions o SCLC a e he loss
o umo supp esso P53 and e inoblas oma suscep ibili y gene
(RB1).
13 Ne e heless, he a ailable s udies a e sca ce, p obably
due o he lowe equency o SCLC compa ed wi h NSCLC. The
esul s o hese s udies a e he e ogeneous and he e is a need o ha e
a global pic u e o he gene ic ai s in ol ed in SCLC appea ance.
To his end, Genome Wide Associa ion S udies (GWAS) a e a good
ool o disen angle he ole o gene ics on he onse o small cell lung
cance om a global app oach o he whole genome sequencing
wi h no a p io i hypo heses.
We aim o compile he knowledge ob ained h ough he a ail-
able genome-wide associa ion s udies and cha ac e ize which genes
migh be mo e associa ed wi h he onse o his speci ic ype o lung
cance om hei esul s, using a sys ema ic e iew o he scien i ic
li e a u e.
Me hods
Li e a u e Resea ch
A li e a u e esea ch was pe o med ollowing he PRISMA
me hodology.
14 We sea ched he ollowing da abases: PubMed
(Medline), EMBASE, Web o Science and GWAS Ca alog. We used
Mesh e ms in ou sea ch s a egy (genome-wide associa ion s udies;
small-cell lung ca cinoma and lung neoplasms) combined wi h ee
ex . The sea ch pe iod comp ised un il July 31s , 2023, wi hou
any s a ing da e. This e iew is egis e ed in PROSPERO wi h he
ID CRD42022319166.
Eligibili y C i e ia
S udies we e selec ed by 2 in es iga o s ollowing speci ic inclu-
sion and exclusion c i e ia. We only selec ed s udies pe o med
in humans which included SCLC cases. Due o he absence o
speci ic GWAS ha app oached SCLC, we included s udies based
on GWAS o lung cance which p esen ed esul s o SCLC. Only
s udies wi h pa icipan s diagnosed o SCLC wi h ana omopa ho-
logical con i ma ion we e included. The sea ch s a egy included
only s udies w i en in Spanish and English.
Assessmen o he S udy Quali y
We c ea ed a quali y sco e o he pu pose o anking he di e -
en pape s based on hei quali y. This scale is composed by se e al
i ems simila o o he sco es p e iously used in o he s udies on
lung cance .
15 , 16
The i ems included in he sco e we e: sample size,
numbe o SCLC cases included in he s udy, co a ia es adjus men
and s udy design. We assigned a weigh o each i em acco ding o i s
ele ance. The sco e wi h i s i ems and weigh s assigned is shown in
Table 1 .
Syn hesis o he E idence
We e ie ed he same in o ma ion, om he di e en s udies
included, in a sp eadshee o m de eloped ad hoc . I was no possi-
ble o conduc a me a-analysis due o he di e en esul s collec ed
among he published s udies. A quali a i e syn hesis o he in o ma-
ion compiled was he e o e ob ained.
Resul s
Sea ch Resul s
We iden i ied 901 pape s in Medline (PubMed), 904 in Embase,
70 in Web o Science and 3 a he GWAS ca alog. A e emo -
ing duplica es, and pape s ha we e dis ega ded by i le and eading
all he abs ac s o he esul ing a icles, we selec ed 310 pape s o
ull- ex eading, as shown in he PRISMA low-diag am ( Figu e 1 ).
Only 14 ul illed he inclusion/exclusion c i e ia and hei cha ac-
e is ics a e shown in Table 2 . We included: 2 GWAS s udies,
17 , 18
Table 1 Quali y Scale.
I em Values Weigh
Sample size 50-100 0
101-500 1
> 500 2
SCLC cases N/A 0
1-50 1
51-100 2
> 100 3
Adjus ed co a iables 2 (gende and age) 0
> 2 2
S udy design Hospi al-based case-con ol s udy o se ies o cases 0
Popula ion-based case-con ol s udy 1
Pooling s udy o me a-analysis 2
TWAS, GWAS o C oss-ances y GWAS me a-analysis 3
To al 10
10 Clinical Lung Cance Janua y 2024
José Ramón Enjo-Ba ei o e al
Table 2 A icles Included in he Sys ema ic Re iew.
Au ho (yea ) S udy Design Popula ion Sample Size
(Numbe o SCLC)
Resul s Conclusion To al Sco e
Niu X. (2010)
21 Case-con ol Han Chinese 1,096 (42) Risk s3743073 (CHRNA3) was associa ed wi h SCLC isk 6
Shi aishi K. (2009)
22 Case-con ol Japanese 2,186 (297) Risk s8034191 (LOC123688), s1051730 (CHRNA3) and haplo ype
CAA we e associa ed wi h SCLC isk.
8
Deng Q. (2013)
23 Case-con ol Han Chinese and
Japanese
8,063 (561)/7,906 (554) Risk s2282987 (CDK6)/ s2706748 (SH3RF1) we e associa ed wi h
SCLC
8
Cheng Y. (2017)
24 Case-con ol Chinese 3,255 (178) Risk s6495304 (HYKK - 15q25) was associa ed wi h SCLC isk. 8
Bossé Y. (2020)
20 TWAS Eu opean 85,716 (2,664) Risk IREB2 (15q25), CHRNA3 (15q25), HIST1H2BD (6p22.2) and
TMA16 (4q32.2) we e associa ed wi h SCLC isk
10
Hu Z. (2011)
17 GWAS Han Chinese 5,408 (178) Risk/P o ec i e s465498 (CLPTM1L-5p15.33) p o ec i e, s2736100
(TERT-5p15.33) and s17728461 (NORMAD2), s36600
(MTMR3-22q.12.2) isk
10
B enne D.R.
(2015)
25
Me a-analysis Eu opean 4,505 (2,216) Risk 15q25 ( s12914385 - CHRNA3 and s3813565) we e associa ed
wi h SCLC isk.
9
Timo ee a M.
(2012)
26
Me a-analysis Eu opean 28,400 (1,964)/28,442
(1,969)
Risk s3117582 (6p21.3) and s1051730 (CHRNA3) we e associa ed
wi h SLCL isk.
9
Han S. (2015)
29 Pooling analysis Han Chinese 1,560 (520) P o ec i e s7963551 (RAD52 - 12p13.33) was associa ed wi h SCLC isk. 9
O´
B ien T.D. (2018)
30 Pooling analysis Eu opean 11,587 (678) Risk CHRNA5, PSMA4, RP11-650, L12.2, MYL4 and RPRML we e
associa ed wi h SCLC isk.
9
T uong T. (2010)
28 Pooling analysis N/A 11,703 (1,106) Risk s16969968 (CHRNA5) was associa ed wi h SCLC isk. 9
Imp ogo Ma.R.D.
(2010)
27
Se ies o cases N/A 123 (7) Risk ASCL1 egula e and o e exp ess CHRNA5/A3/B4 gene clus e
associa ing i wi h SCLC isk.
2
Byun J. (2022)
19 C oss-ances y
GWMA
Eu opean, Eas Asian
and A ican
70,156 (2,482) Risk s141178913 (IL17RC) o A ican and Eu opean ances y and
s191133092 (LINC01556, HCGA15) o A ican
10
Enjo-Ba ei o J.R.
(2023)
18
GWAS Eu opean 828 (271) Risk/P o ec i e s47363076 (MAP4), s47363076 (KLHL18), s47546915
(ELP6), s48185972 (CDC25A), s81020709 (TLE1), s2397873
(CD81) and s59440199 (DIAPH3) isk and s47098239,
s47160943, s47247614 (HTR2A), s126519658 (GRAMD2B),
s44750305 (DBF4B) and s44647003 (LINC01180) p o ec i e.
10
Clinical Lung Cance Janua y 2024 11
Genome Wide Associa ion S udies in Small-Cell Lung Cance
Figu e 1 PRISMA low-diag am.
1 Genome wide me a-analysis,
19 1 ansc ip ome wide associa ion
s udy (TWAS),
20 4 case-con ol s udies,
21–24 2 me a-analysis,
25 , 26
1 case-se ies,
27 and 3 pooling analyses.
28-30 The mos common
exclusion c i e ia we e no including esul s o SCLC in GWAS
pe o med in lung cance pa ien s. Ten s udies we e selec ed because
hey we e based on p e ious GWAS o lung cance .
Included Pape s
Hu e al.
17
analyses, in hei GWAS s udy, he genes implica ed in
lung cance o Han Chinese popula ion, including 178 SCLC cases
and iden i ying 3 single nucleo ide polymo phism (SNPs) ela ed
wi h an inc eased isk o SCLC: s2736100 (TERT), s17728461
(HORMAD2) and s36600 (MTMR3) and 1 p o ec i e o his
his ological ype: s465498 (CLPTM1L).
Enjo-Ba ei o e al.
18 iden i ied, in hei GWAS s udy, se e al
in e es ing SNPs wi hou eaching he genome-wide signi icance bu
bo de ing i . This s udy included 271 SCLC cases and has been
de eloped a a adon-p one a ea, adjus ing he analysis by indoo
adon exposu e. In addi ion, i is he only one de eloped o SCLC
exclusi ely. Se en SNPs we e iden i ied as isk ac o s o SCLC:
s47363076 (MAP4), s47363076 (KLHL18), s47546915 (ELP6),
s48185972 (CDC25A), s81020709 (TLE1), s2397873 (CD81)
and s59440199 (DIAPH3) and 6 as p o ec i e: s47098239,
s47160943, s47247614 (HTR2A), s126519658 (GRAMD2B),
s44750305 (DBF4B) and s44647003 (LINC01180).
Byun e al.
19 pe o med a c oss-ances y genome-wide Me a-
analysis (GWMA) including 2482 cases o SCLC among o he
his ological sub ypes o lung cance and con ols. Da a we e
alida ed in combina ion wi h an ex e nal alida ion da ase , which
added 1297 SCLC cases. This s udy included cases o Eu opean,
A ican, and eas Asian ances y. The s1411789913 (IL17RC)
showed a s ong associa ion wi h SCLC o A ican and Eu opean
ances y case. The s191133092 (LINC01556, HCG15) was associ-
a ed wi h SCLC o A ican ances y cases.
12 Clinical Lung Cance Janua y 2024
José Ramón Enjo-Ba ei o e al
The TWAS s udy
20
was pe o med on a p e ious GWAS. In his
pape 2664 SCLC we e included s udying he gene ic a ian s in
ne e - and e e -smoke s. The esul s showed a signi ican associa-
ion o SCLC o IREB2 and CHRNA3 on 15q25, HIST1H2BD
on 6p22.2 and TMA16 on 4q32.2.
The 4 case-con ol s udies included analyzed di e en SNPs o
lung cance , based on p e ious GWAS, de ailing speci ic esul s
o SCLC. Niu e al.
21 iden i ied ha s3743073, loca ed in
CHRNA3 gene, inc eases SCLC isk in Asian popula ion, and i
is also ela ed o NSCLC, ha may p edic i s isk and p ogno-
sis in NSCLC ad anced s ages.
21 Shi aishi e al.
22 obse ed ha
s8034191 (LOC123688), s1051730 (CHRNA3) and he Haplo-
ype CAA ( s1800624, s1800625 and s2070600, loca ed in
ad anced glycosyla ion end p oduc -speci ic ecep o [RAGE]), also
inc ease SCLC isk. Deng e al.
23 desc ibed an associa ion o
s2282987 (CDK6) and s2706748 (SH3RF1). Cheng e al.
24
iden i ied s6495304 (HYKK) as ha ing an associa ion wi h SCLC.
The 3 pooling analysis
28-30 we e based in p e ious GWAS o
lung cance which iden i ied di e en SNPs which had been s udied
o di e en his ological sub ypes including SCLC. T uong e al.
28
in 2009 pe o med a pooling analysis o 21 case-con ol s udies.
They obse ed ha , o 1,106 SCLC cases, s16969968 (CHRNA5)
showed an OR o 1.21 (95% CI 1.10-1.33). The second s udy
selec ed
30 was based on he esul s o a GWAS which ob ained
he cases and con ols om 4 s udies, obse ing ha CHRNA5,
PSMA4, RP11-650, L12.2, MYL4 and RPRML posed an associa-
ion wi h SCLC. On he o he hand, Han e al.
29
in 2015 pe o med
ano he pooling analysis o 2 case-con ol s udies, which included
520 SCLC cases, ob aining as a esul ha s7963551 (RAD52 –a
DNA epai p o ein) had a p o ec i e ole o SCLC in Han Chinese
popula ion.
One case-se ies was selec ed.
27 In his pape he co ela ion
be ween SCLC and he nico inic ace ylcholine ecep o s (nAChR)
gene clus e was s udied based on GWAS e idence, and i was
obse ed, in acco dance wi h p e ious li e a u e, ha his gene
clus e is o e exp essed and ASCL1 may be he esponsible o his
de egula ion.
Rega ding he 2 me a-analyses selec ed,
25 , 26 he one published
by B enne e al.
25 in 2015 was based in 13 lung cance GWAS
ha included 2216 SCLC pa ien s, obse ing ha mu a ions on
s12914385 and s3813565 a he 15q25 egion inc eased he isk
o SCLC. On he con a y, mu a ions on s8034191 and s1051730
had a p o ec i e e ec on his umo . Timo ee a e al.
26 ound
ha s3117582 (6p21.3) inc eased he isk (OR = 1.16) o SCLC
(n = 1964) and s1051730 (CHRNA3), in con as wi h B enne
e al.,
25
showed a simila isk (OR = 1.31) o SCLC (n = 1969).
On he o he hand, s10849605 (RAD52) had a p o ec i e e ec
(OR = 0.86; 95%CI: 0.80-0.91).
Table 3 syn hesized he isk o he SNPs o genes o he
s udies included in he e iew. This in o ma ion should be analyzed
cau iously due o he di e en s udy designs and me hodologies.
Quali y o he Included S udies
We included a TWAS, 2 GWAS and a C oss-ances y GWMA
ha achie ed he highes punc ua ion based on he i ems eco ded
in Table 1 , based on p e ious e iews.
15 , 16
Two me a-analyses, he e
pooling o cases and 3 case-con ol s udies achie ed he highes
sco e, only limi ed by he s udy design. One case-con ol ob ained
a sco e o 6 o e 10, due o he sca ce numbe o SCLC included,
and he a icle wi h lowe punc ua ion is a case se ies ha includes
a low numbe o SCLC, bu i s esul s a e in acco dance wi h he
e idence a ailable. Thei quali y anged om 1 o 10 as desc ibed
in Tables 1 and 2 .
Discussion
This e iew o GWAS pe o med on SCLC pa ien s shows ha
i is possible ha speci ic genes may be in ol ed in SCLC onse .
This is he case o CHRNA3, CHRNA5, o RAD52. These indings
migh pa e he way o he de elopmen o d ugs di ec ed o ce ain
molecula a ge s loca ed in hose genomic egions. O he ele an
esul is he lack o in o ma ion based on GWAS s udies on he
deadlies his ological lung cance ype, which calls o u he and
ambi ious esea ch.
SCLC comp ises only app oxima ely 15% o all lung cance cases
and his may pa ially explain he lack o e idence on he causes
o i s gene ic onse when compa ed o o he mo e equen his o-
logical ypes. The a ailable s udies mus ha e a mul icen ic na u e
wi h a long ec ui men pe iod o achie e a high sample size and
his explains he low numbe o pa icipan s diagnosed wi h SCLC
included, along wi h he small numbe o GWAS wi h in o ma ion
o SCLC compa ed o NSCLC s udies.
Some au ho s s a ed conside ing SCLC a he e ogeneous disease
due o he highly di e en gene exp ession. Rudin e al.
9
classi ied
i in 4 g oups by key ansc ip ion egula o s; on he one hand, we
ha e 2 di e en ypes o neu oendoc ine cance s: he i s is when
ASCL1 is o e exp essed, and in he second NEUROD1 is o e ex-
p essed. These 2 ansc ip ion ac o s a ge di e en oncogenic
genes: ASCL1 a ge s MYCL1, BCL2, SOX2, and DLL3. On he
con a y, NEURO1 ac s o e MYC, bu hey also ha e common
a ge s as INSM1, HES1, an inhibi o o HES1 and a NOTCH
media ed ep ession o ASCL1 ansc ip ional ac i i y.
9 , 31
The o he
2 g oups o SCLC do no exp ess neu oendoc ine ma ke s such as
ASCL1 o NEUROD1 , hey a e yes-associa ed p o ein 1 ( YAP1 ),
which is o e exp essed in some umo s, and POU class 2 homeobox
3 (POU2F3 ), which sugges ha his SCLC may ha e a di e en cell
o igin.
9
Howe e , a e Baine e al.
32
immunohis ochemical analysis
concluded ha he ole o sub ype-de ining ansc ip ional d i e s
is no well es ablished, au ho s such as Gay e al.
33 disag ee wi h
conside ing YAP1 o e exp ession as a single g oup.
In e ms o he o igin o SCLC, he e is a mino i y o cases o
SCLC ha a e likely o ha e a isen om an EGFR-mu a ed NSCLC
ha has shown esis ance o EGRF inhibi o s, bu his is no exclu-
si e o his mu a ion. P53 and RB1 down egula ions and TERT
ampli ica ion may also a o his ans o ma ion.
In ela ion wi h he esul s obse ed in ou e iew, due o he
lack o GWAS speci ically de eloped o SCLC, we ough o include
a icles ocused on expanding he in o ma ion ob ained in p e ious
GWAS de eloped o lung cance , including mos ly o he his ologi-
cal ypes.
Fi s ly, we obse ed ha ASCL1 is he mos common key
ansc ip ion egula o implica ed. I is a gene ha codi ies a p o ein
iden i ied wi h he same name, which is o e exp essed in his ype
Clinical Lung Cance Janua y 2024 13

Genome Wide Associa ion S udies in Small-Cell Lung Cance
Table 3 Risk o he SNPs and Genes Iden i ied by he S udies Included.
Au ho (yea ) SNPs (Gene) Risk o P obabili y
Niu X. (2010)
21 s3743073 (CHRNA3) OR = 1.69; 95% CI (1.06-2.70)
Shi aishi K. (2009)
22 s8034191 (LOC123688) OR = 2.0; 95% CI (1.1-3.4)
s1051730 (CHRNA3) OR = 2.6; 95% CI (1.5-4.7)
s1800624, s1800625 and s2070600 (RAGE) - Haplo ype CAA OR = 2.2; 95% CI (1.0-4.9)
Deng Q. (2013)
23 s2282987 (CDK6) OR = 1.25; 95% CI (1.10-1.43)
s2706748 (SH3RF1) OR = 1.22; 95% CI (1.04-1.44)
Cheng Y. (2017)
24 s6495304 (HYKK) OR = 1.33; 95% CI (1.01-1.77)
Bossé Y. (2020)
20 (IREB2) pTWAS = N/A
(CHRNA3) pTWAS = 3.51 ×10−5
(HIST1H2BD) pTWAS = 1.54 ×10−6
(TMA16) pTWAS = 4.2 ×10−6
Hu Z. (2011)
17 s465498 (CLPTM1L) OR = 0.80; 95% CI (0.69-0.93)
s2736100 (TERT) OR = 1.14; 95% CI (1.02-1.27)
s17728461 (NORMAD2) OR = 1.24; 95% CI (1.09-1.41)
s36600 (MTMR3) OR = 1.45; 95% CI (1.24-1.70)
B enne D.R. (2015)
25 s12914385 (CHRNA3) OR = 1.34; 95% CI (1.24-1.45)
s3813565 (LOC105370913) OR = 1.28; 95% CI (1.18-1.40)
Timo ee a M. (2012)
26 s3117582 (BAG6, APOM) OR = 1.16 ( p = 0.01)
s1051730 (CHRNA3) OR = 1.31 ( p = 3.4 ×10−14
)
Han S. (2015)
29 s7963551 (RAD52) OR = 0.48; 95% CI (0.33-0.69)
O´
B ien T.D. (2018)
30 (CHRNA5) N/A
(PSMA4) N/A
(RP11-650) N/A
(L12.2) N/A
(MYL4) N/A
(RPRML) N/A
T uong T. (2010)
28 s16969968 (CHRNA5) OR = 1.21; 95% CI (1.10-1.33)
Imp ogo Ma.R.D. (2010)
27 ASCL1 N/A
CHRNA5/A3/B4 N/A
Byun J. (2022)
19 s141178913 (IL17RC) EUR: OR = 5.36 ( p = 2.37 ×10−9
)
AFR: OR = 76.69 ( p = 2.37 ×10−9
)
s191133092 (LINC01556, HCGA15) EUR: OR = 12.56 ( p = 1.52 ×10−8
)
AFR: OR = 5.30 ( p = 1.52 ×10−8
)
Enjo-Ba ei o J.R. (2023)
18 s47363076 (MAP4) OR = 5.19; 95% CI (2.58-10.44)
s2397873 (CD81) OR = 5.75; 95% CI (2.76-11.98)
s47363076 (KLHL18) OR = 4.11; 95% CI (2.33-7.22)
s47546915 (ELP6) OR = 4.51; 95% CI (2.37-8.61)
s48185972 (CDC25A) OR = 3.95; 95% CI (2.23-6.99)
s81020709 (TLE1) OR = 1.96; 95% CI (1.47-2.63)
s59440199 (DIAPH3) OR = 2.52; 95% CI (1.7-3.73)
s47098239 (HTR2A) OR = 0.15; 95% CI (0.07-0.33)
s47160943 (HTR2A) OR = 0.07; 95% CI (0.02-0.21)
s47247614 (HTR2A) OR = 0.12; 95% CI (1.7-3.73)
s44647003 (LINC01180) OR = 0.40; 95% CI (0.28-0.58)
s44750305 (DBF4B) OR = 0.49; 95% CI (0.37-0.65)
s126519658 (GRAMD2B) OR = 0.55; 95% CI (0.42-0.71)
Abb e ia ions: OR = odds a io; CI = confidence in e al; N/A = No a ailable; EUR = Eu opean ances y; AFR = A ican ances y.
14 Clinical Lung Cance Janua y 2024
José Ramón Enjo-Ba ei o e al
Figu e 2 ASCL1 o e exp ession in SCLC.
ASCL1 = achae e-scu e complex homolog-1; nAChR = nico inic ace ylcholine ecep o s; α3 = nAChR α3 subuni gene; α5 = nAChR α5 subuni gene;
β4 = nAChR β4 subuni gene; NNK = 4-(me ilni osamino)-1-(3-pi idil)-1-bu anone.
o umo . Imp ogo e al.
27 desc ibed his o e exp ession in lung
cance pa ien s as an impo an ac o in SCLC pa hogenesis, in
acco dance wi h Rudin e al.
9
ASCL1 may egula e he gene clus e
CHRNA5/A3/B4, especially ac ing o e CHRNA3 and CHRNB4,
which in u n egula es he exp ession o he nAChR, o which
ace ylcholine is an endogenous ligand wi h an au oc ine g ow h
ac o unc ion
27 as i is shown in Figu e 2 . In addi ion, Imp ogo
e al
27 desc ibed o SCLC ha a e he knockdown o ASCL1 ,
he nico inic ecep o s o e exp essed in his umo , diminish hei
exp ession, whe eas in NSCLC his pa e n does no change.
As we can obse e in he Kyo o Encyclopedia o Genes
and Genomes (KEGG), his ype o ecep o s no only in e ac
wi h nico ine bu also wi h 4-(me ilni osamino)-1-(3-pi idil)-1-
bu anone (NNK), which is classi ied by he IARC as a ca cinogenic
chemical compound o humans, which is de i ed om nico ine
and i uses he nAchR o inhibi he apop o ic p ocess, s imula e he
angiogenesis and he cell p oli e a ion, con ibu ing o ca cinogen-
esis. I is impo an ha NNK is p oduced du ing he combus ion
o cu ed obacco and SCLC is he lung cance mos associa ed wi h
obacco consump ion. I is di icul o ind SCLC ne e smoking
pa ien s
34
and he e o e a ole ela ed wi h speci ic pa hways ela ed
o nico ine addic ion is appa en ly logical.
In ela ion wi h CHRNA5/A3/B4 genes clus e , we ound se e al
pape s
20-22 , 25-28 , 30
ela ing his o e exp ession wi h a highe isk o
de eloping SCLC. The SNP s16969968 (CHRNA5) was ela ed
wi h an inc eased isk o SCLC in Eu opean and Asian popula-
ions in 3 di e en s udies.
21 , 22 , 28
Some o hese pape s expand o
o he e hnici ies he esul s ob ained o Eu opeans, such as Niu
e al.
21
o Han Chinese and Shi aishi e al.
22
o Japanese, because
he mu a ions iden i ied a e less common in Asian popula ion in
con as wi h Eu opeans, con i ming he associa ion desc ibed. Niu
e al ela ed s3743073 (CHRNA3) wi h an inc eased isk o
SCLC, while Shi aishi e al.
22 ela ed s8034191 (LOC123688),
s3743073 (CHRNA3) and s3743073 (CHRNA5). Addi ionally,
Shi aishi e al.
22
obse ed ha pa ien s ca ying his haplo ype ha e
an inc eased OR o smoke s and nonsmoke s, sugges ing ha he
associa ion o hese SNPs a e independen o he pa ien smoking
s a us wi h lung cance . In ag eemen wi h he p e ious au ho s,
Bossé e al.
20
iden i ied in hei TWAS, CHRNA3 (15q25) as a isk
o SCLC among o he genes like IREB2(15q25), HIST1H2BD
(6p22.2) and TMA16 (4q32.2), being he las one, o he i s ime,
associa ed wi h lung cance .
Timo ee a e al.
26 obse ed ha s3117582 (BAG6) on 6p21.3
and s1051730 (CHRNA3) inc ease he isk o SCLC. Rs3117582
is in BAG6, a gene encoding BCL2, which is a a ge o ASCL1,
9
ha may a ec cellula beha io
35 and plays an impo an ole in
p53 apop osis by geno oxic s ess
36
. On he o he hand, his me a-
analysis iden i ied 3 o he SNPs as posing p o ec ion o SCLC such
as s401681 (CLPTM1L), s10849605 (RAD52) and s6495309
(CHRNA3/CHRNB4). Simila ly o Timo ee a e al.,
26
Han e al.
29
iden i ied he SNP s7963551 (RAD52), in a Han Chinese e hnic
g oup, as a p o ec i e ac o , bu i only a ies signi ican ly in
smoke s. This is p obably due o RAD52 gene which codi ies a
p o ein ela ed wi h he DNA epai , impo an in smoke s who
accumula es mo e DNA damage.
Ano he gene has been iden i ied in coo dina ion wi h ASCL1,
known as TTF-1, which egula es he exp ession o Bcl-2, no
ha ing ela ion wi h he o he neu oendoc ine molecula ype, he
Neu ogenic di e en ia ion ac o 1 (NEUROD1) which is mo e
ela ed wi h MYC.
37
Mos pa o hese genes iden i ied a e in ch omosome 15, aking
an especial ele ance he 15q24 and 15q25.1. Se e al o he SNPs
iden i ied o Shi aishi e al.,
22
Bossé e al.,
20
o Niu e al.
21
a e in he
ch omosome 15. Consis en wi h hem, T uong e al.
28
iden i ied 3
ch omosomal egions a 15q25, 5q15 and 6p21 and B enne e al.
25
obse ed his associa ion wi h he 15q25 egion, ela ing SNPs such
as s12914385 (CHRNA3) and s3813565 (LOC105370913) wi h
an inc eased isk o SCLC. On he con a y, hey ound SNPs
wi h a p o ec i e e ec s8034191 (LOC123688) and s1051730
(CHRNA3), which is in disco dance wi h he da a obse ed in o he
s udies.
21 , 22 , 26 Cheng e al.
24 associa ed 15q25 wi h lung cance
oo in Han Chinese popula ion. They obse ed ha s6495304
(HYKK) is a SCLC isk ac o , ha ing an impo an associa ion
wi h smoking habi , wi h a mul iplica i e in e ac ion wi h gende ,
hough his may be due o he di e en smoking habi s among sexes
in hei s udy popula ion.
No only genes ela ed wi h ASCL1 we e obse ed in ou e ision,
O´
B ien e al.
30 iden i ied 5 genes ela ed wi h SCLC isk, and
Clinical Lung Cance Janua y 2024 15
Genome Wide Associa ion S udies in Small-Cell Lung Cance
some o hem o e lap o he lung cance his ological ypes, such
as CHRNA5, PSMA4, RP11-650 L12.2, MYL4, and RPRML,
being he i s 2 only associa ed wi h lung cance .
27 I is in e es -
ing ha his esea ch obse ed ha he ocal adhesion pa hway has
an impo an ole in SCLC, which is ele an in cance me as-
asis because i is in ol ed in he epi helial-mesenchymal ansi-
ion.
38
In addi ion, Deng e al.
23
iden i ied s2282987 (CDK6) and
s2706748 (SH3RF1) as a isk ac o o SCLC in Chinese Han
popula ion. I is ema kable ha CDK6 ake an impo an ole in
ca cinogenesis egula ing he G1
phase p og ession
39
and i is known
ha SH3RF1 is a p oapop o ic p o ein ha can in e ac when an
apop o ic s imulus appea s.
A ending o he unique speci ic GWAS de eloped o SCLC and
adjus ed by indoo adon exposu e,
18
CHRNA5/A3/B4 gene clus e
o he ch omosome 15 we e no iden i ied as a isk ac o o his
his ologic sub ype, may be due o he small sample. On he o he
hand, new SNPs we e iden i ied like s47363076 loca ed in Mic o-
ubule associa ed p o ein 4 (MAP4), being co ela ed wi h p ogno-
sis in NSCLC pa ien s ea ed wi h a ezolizumab
40
o s48185972
loca ed in CDC25A, a gene o e exp essed in SCLC samples.
41 In
addi ion o MAP4 and CDC25A, his GWAS ela es al e a ions
a he ch omosome 3 a s47363076 loca ed in Kelch like amily
membe 18 (KLHL18) and s47546915 in elonga o ace yl ans-
e ase complex subuni 6 (ELP6) adding new SNPs in compa ison
wi h o he s udies included in ou e iew.
Byun e al.
19
iden i ied s141178913 (IL17RC) and s191133092
(LINC01556, HCG15) as a isk ac o o SCLC, bo h desc ibed o
he i s ime.
Finally, Hu e al.
17
iden i ied s2736100 (TERT) as a isk ac o
o SCLC bu Timo ee a e al.
26
and B enne e al.
25
ela ed i wi h
adenoca cinoma. I is ema kable because he gene TERT o e ex-
p ession is also ela ed wi h NSCLC-EGFR mu a ed ans o ma-
ion in o SCLC, p edisposing TP53 and RB1 al e a ions,
10 , 11 , 13 , 42
in cong uence wi h Mc Lee e al.
42 Ano he SNP iden i ied is
s17728461 (HORMAD2), which was ela ed wi h NSCLC in Han
Chinese popula ion.
43
On he o he hand, hey iden i ied s465498
(CLPTM1L) as a p o ec i e ac o , in con as wi h Timo ee a
e al.
26
who iden i ied o he SNP o his gene as a isk ac o .
This s udy has se e al ad an ages. To ou knowledge, i is he i s
sys ema ic e iew ocused exclusi ely on GWAS on SCLC. A u he
ad an age is ha we ha e used common c i e ia o include di e -
en a ailable s udies and he e o e he s udies included sha e some
simila esul s. Ne e heless, he e a e some disad an ages, such as
he sca ce numbe o speci ic GWAS o SCLC, which o ced us o
include s udies wi h di e en me hodologies and designs based on
p e ious lung cance GWAS ha ex end he in o ma ion o SCLC,
he low numbe o women included and he impossibili y o di e -
en ia ing he cha ac e is ics o smoke s and ne e -smoke s. Ano he
limi a ion is he he e ogenei y o he included s udies. Finally, he
low sample size in mos o hese s udies may limi he obus ness o
ou esul s.
Conclusion
We obse ed ha he e is a lack o GWAS pe o med speci ically
o SCLC and he esul s ob ained a e he e ogeneous. The mos
impo an clus e o genes ound, in acco dance wi h he di e -
en s udies included, is CHRNA5/A3/B4 bu he mechanism o
he ole o hese genes is unclea . I is in e es ing ha in he Kyo o
Encyclopedia o Genes and Genome (KEGG) hese ecep o s we e
ound o be o e exp essed whe e nico ine, NNK and NNN ac s,
in ol ing di e en ou es in SCLC ca cinogenesis such as PI3K-
Ak signaling pa hway and MAPK signaling pa hway among o he s.
Mo e s udies a e clea ly needed o disen angle he complex gene ics
o Small Cell Lung Cance . Among hem, i could be in e es ing o
de elop s udies o alida e he di e en SNPs iden i ied and y o
ecognize oncogenic ou es in ol ing CHARNA5/A3/B4 clus e o
ch omosome 15. Finally, a ending o he SCLC cance classi ica-
ion, i could be in e es ing s udy he ou es o he di e en SCLC
g oups, especially ASCL1.
Disclosu e
Ka l Kelsey is a ounde and scien i ic ad iso o Cellin ec, which
had no ole in his esea ch. The o he au ho s decla e no o ha e
any con lic o in e es .
Acknowledgmen s
This wo k was suppo ed by PI15/01211 –ISCIII – co- inanced
FEDER .
Re e ences
1. Sung H, Fe lay J, Siegel RL, e al. Global Cance S a is ics 2020: GLOBOCAN
es ima es o incidence and mo ali y wo ldwide o 36 cance s in 185 coun ies.
CA Cance J Clin . 2021;71(3):209–249. doi: 10.3322/caac.21660 .
2. Enjo-Ba ei o JR, Ruano-Ra ina A, Pé ez-Ríos M, Radon, e al. obacco exposu e
and non-small cell lung cance isk ela ed o BER and NER gene ic polymo -
phisms. A ch B onconeumol . 2021;58(4):311–322. doi: 10.1016/j.a b es.2021.07.
006 .
3. Zeeb H, Shannoun F. WHO Handbook on Indoo Radon: A Public Heal h Pe spec-
i e . Wo ld Heal h O ganiza ion; 2009 . [Accessed: Feb ua y 23, 2023]; A aliable
a : h ps://apps.who.in /i is/handle/10665/44149 .
4. Schaba h MB, Co e ML. Cance p og ess and p io i ies: lung cance . Cance
Epidemiol Bioma ke s P e . 2019;28(10):1563–1579. doi: 10.1158/1055-9965.
EPI- 19- 0221 .
5. Vikis HG. Mouse models o chemically-induced lung ca cinogenesis. F on Biosci .
2013;E5(3):939–946. doi: 10.2741/e673 .
6. Liang J, Guan X, Bao G, Yao Y, Zhong X. Molecula sub yping o small cell lung
cance . Semin Cance Biol . 2022;86(P 2):450–462. doi: 10.1016/j.semcance .2022.
05.010 .
7. Lommel AV. Pulmona y neu oendoc ine cells (PNEC) and neu oepi helial bodies
(NEB): chemo ecep o s and egula o s o lung de elopmen . Paedia Respi Re .
2001;2(2):171–176. doi: 10.1053/p .2000.0126 .
8. Linnoila RI. Func ional ace s o he pulmona y neu oendoc ine sys em. Lab In es .
2006;86(5):425–444. doi: 10.1038/labin es .3700412 .
9. Rudin CM, Poi ie JT, Bye s LA, e al. Molecula sub ypes o small cell lung cance :
a syn hesis o human and mouse model da a. Na Re Cance . 2019;19(5):289–
297. doi: 10.1038/s41568- 019- 0133- 9 .
10. Yin X, Li Y, Wang H, e al. Small cell lung cance ans o ma ion: om pa ho-
genesis o ea men . Semin Cance Biol . 2022;86(P 2):595–606. doi: 10.1016/j.
semcance .2022.03.006 .
11. Ose MG, Niede s MJ, Sequis LV, Engelman JA. T ans o ma ion om non-
small-cell lung cance o small-cell lung cance : molecula d i e s and cells
o o igin. Lance Oncol . 2015;16(4):e165–e172. doi: 10.1016/S1470-2045(14)
71180-5 .
12. Li JH, Mazu CA, Be isa T, Pick ell JK. Low-pass sequencing inc eases he powe
o GWAS and dec eases measu emen e o o polygenic isk sco es compa ed o
geno yping a ays. Genome Res . 2021;31(4):529–537. doi: 10.1101/g .266486.120 .
13. Semeno a EA, Nagel R, Be ns A. O igins, gene ic landscape, and eme ging he a-
pies o small cell lung cance . Genes De . 2015;29(14):1447–1462. doi: 10.1101/
gad.263145.115 .
14. Page MJ, McKenzie JE, Bossuy PM, e al. The PRISMA 2020 s a emen : an
upda ed guideline o epo ing sys ema ic e iews. BMJ . 2021;372:n71. doi: 10.
1136/bmj.n71 .
15. Rod íguez-Ma ínez Á, To es-Du án M, Ba os-Dios JM, Ruano-Ra ina A.
Residen ial adon and small cell lung cance . A sys ema ic e iew. Cance Le .
2018;426:57–62. doi: 10.1016/j.canle .2018.04.003 .
16. To es-Du án M, Ba os-Dios JM, Fe nández-Villa A, Ruano-Ra ina A. Residen-
ial adon and lung cance in ne e smoke s. A sys ema ic e iew. Cance Le .
2014;345(1):21–26. doi: 10.3109/09553002.2015.1047985 .
16 Clinical Lung Cance Janua y 2024
José Ramón Enjo-Ba ei o e al
17. Hu Z, Wu C, Shi Y, e al. A genome-wide associa ion s udy iden i ies wo new lung
cance suscep ibili y loci a 13q12.12 and 22q12.2 in Han Chinese. Na Gene .
2011;43(8):792–796. doi: 10.1038/ng.875 .
18. Enjo-Ba ei o JR, Ruano-Ra ina A, Diz-de-Almeida S, e al. A genome-wide associ-
a ion s udy o small cell lung cance . A ch B onconeumol . 2023;59(10):645–650.
doi: 10.1016/j.a b es.2023.07.008 .
19. Byun J, Han Y, Li Y, e al. C oss-ances y genome-wide me a-analysis o 61,047
cases and 947,237 con ols iden i ies new suscep ibili y loci con ibu ing o
lung cance . Na Gene . 2022;54(8):1167–1177. doi: 10.1038/s41588- 022- 01115-
x .
20. Bossé Y, Li Z, Xia J, e al. T ansc ip ome-wide associa ion s udy e eals candida e
causal genes o lung cance . In J Cance . 2020;146(7):1862–1878 1 de ab il de.
doi: 10.1002/ijc.32771 .
21. Niu X, Chen Z, Shen S, e al. Associa ion o he CHRNA3 locus wi h lung cance
isk and p ognosis in Chinese Han popula ion. J Tho ac Oncol O Publ In Assoc
S udy Lung Cance . 2010;5(5):658–666. doi: 10.1097/JTO.0b013e3181d5e447 .
22. Shi aishi K, Kohno T, Kuni oh H, e al. Con ibu ion o nico ine ace yl-
choline ecep o polymo phisms o lung cance isk in a smoking-independen
manne in he Japanese. Ca cinogenesis . 2009;30(1):65–70. doi: 10.1093/ca cin/
bgn257 .
23. Deng Q, Guo H, Dai J, e al. Impu a ion-based associa ion analyses iden i y
new lung cance suscep ibili y a ian s in CDK6 and SH3RF1 and hei in e -
ac ions wi h smoking in Chinese popula ions. Ca cinogenesis . 2013;34(9):2010–
2016. doi: 10.1093/ca cin/bg 145 .
24. Cheng Y, Wang C, Zhu M, e al. Ta ge ed sequencing o ch omosome 15q25
iden i ied no el a ian s associa ed wi h isk o lung cance and smoking beha io
in Chinese. Ca cinogenesis . 2017;38(5):552–558. doi: 10.1093/ca cin/bgx025 .
25. B enne DR, Amos CI, B hane Y, e al. Iden i ica ion o lung cance his ology-
speci ic a ian s applying Bayesian amewo k a ian p io i iza ion app oaches
wi hin he TRICL and ILCCO conso ia. Ca cinogenesis . 2015;36(11):1314–
1326. doi: 10.1093/ca cin/bg 128 .
26. Timo ee a MN, Hung RJ, Ra na T, e al. In luence o common gene ic a ia ion
on lung cance isk: me a-analysis o 14 900 cases and 29 485 con ols. Hum Mol
Gene . 2012;21(22):4980–4995. doi: 10.1093/hmg/dds334 .
27. Imp ogo MRD, Schlich ing NA, Co es RY, Zhao-Shea R, Tappe AR,
Ga dne PD. ASCL1 egula es he exp ession o he CHRNA5/A3/B4 lung
cance suscep ibili y locus. Mol Cance Res MCR . 2010;8(2):194–203. doi: 10.
1158/1541- 7786.MCR- 09- 0185 .
28. T uong T, Hung RJ, Amos CI, e al. Replica ion o lung cance suscep ibili y
loci a ch omosomes 15q25, 5p15, and 6p21: a pooled analysis om he In e -
na ional Lung Cance Conso ium. J Na l Cance Ins . 2010;102(13):959–971.
doi: 10.1093/jnci/djq178 .
29. Han S, Gao F, Yang W, e al. Iden i ica ion o an SCLC suscep ibili y
s7963551 gene ic polymo phism in a p e iously GWAS-iden i ied 12p13.33
RAD52 lung cance isk locus in he Chinese popula ion. In J Clin Exp Med .
2015;8(9):16528–16535 .
30. O’B ien TD, Jia P, Capo aso NE, Landi MT, Zhao Z. Weak sha ing o
gene ic associa ion signals in h ee lung cance sub ypes: e idence a he SNP,
gene, egula ion, and pa hway le els. Genome Med . 2018;10(1):16. doi: 10.1186/
s13073- 018- 0522- 9 .
31. Bo omeo MD, Sa age TK, Kollipa a RK, e al. ASCL1 and NEUROD1 e eal
he e ogenei y in pulmona y neu oendoc ine umo s and egula e dis inc gene ic
p og ams. Cell Rep . 2016;16(5):1259–1272. doi: 10.1016/j.cel ep.2016.06.081 .
32. Baine MK, Hsieh MS, Lai WV, e al. SCLC sub ypes de ined by ASCL1,
NEUROD1, POU2F3, and YAP1: a comp ehensi e immunohis ochemical and
his opa hologic cha ac e iza ion. J Tho ac Oncol . 2020;15(12):1823–1835. doi: 10.
1016/j.j ho.2020.09.009 .
33. Gay CM, S ewa CA, Pa k EM, e al. Pa e ns o ansc ip ion ac o p og ams
and immune pa hway ac i a ion de ine ou majo sub ypes o SCLC wi h dis inc
he apeu ic ulne abili ies. Cance Cell . 2021;39(3):346–360.e7.. doi: 10.1016/j.
lungcan.2022.01.008 .
34. To es-Du án M, Cu iel-Ga cía MT, Ruano-Ra ina A, e al. Small-cell lung cance
in ne e -smoke s. ESMO Open . 2021;6(2):100059 ab il de. doi: 10.1016/j.esmoop.
2021.100059 .
35. Takayama S, Reed JC. Molecula chape one a ge ing and egula ion by
BAG amily p o eins. Na Cell Biol . 2001;3(10):E237–E241. doi: 10.1038/
ncb1001-e237 .
36. Sasaki T, Gan EC, Wakeham A, Ko nblu h S, Mak TW, Okada H. HLA-B-
associa ed ansc ip 3 (Ba 3)/Scy he is essen ial o p300-media ed ace yla ion o
p53. Genes De . 2007;21(7):848–861. doi: 10.1101/gad.1534107 .
37. Hoka i S, Tamu a Y, Kaneda A, e al. Compa a i e analysis o TTF-1 binding
DNA egions in small-cell lung cance and non-small-cell lung cance . Mol Oncol .
2020;14(2):277–293. doi: 10.1002/1878-0261.12608 .
38. Das V, Bha acha ya S, Chikkapu aiah C, Haz a S, Pal M. The basics o epi helial–
mesenchymal ansi ion (EMT): a s udy om a s uc u e, dynamics, and unc ional
pe spec i e. J Cell Physiol . 2019;234(9):14535–14555. doi: 10.1002/jcp.28160 .
39. Malumb es M, Ba bacid M. Cell cycle, CDKs and cance : a changing pa adigm.
Na Re Cance . 2009;9(3):153–166. doi: 10.1038/n c2602 .
40. Qian J, Nie W, Lu J, e al. Racial di e ences in cha ac e is ics and p ognoses
be ween Asian and whi e pa ien s wi h nonsmall cell lung cance ecei ing
a ezolizumab: An ancilla y analysis o he POPLAR and OAK s udies. In J Cance .
2020;146(11):3124–3133. doi: 10.1002/ijc.32717 .
41. Ma C, Zhao J, Wu Y, Wang J, Wang H. Diagnos ic alue o abno mal ch omosome
3p genes in small–cell lung cance . Oncol Le . 2022;24(1):209. doi: 10.3892/ol.
2022.13330 .
42. Mc Lee A, Foll M, B e e M, e al. De ec ion o acqui ed TERT ampli ica ion
in addi ion o p edisposing p53 and Rb pa hways al e a ions in EGFR-mu an
lung adenoca cinomas ans o med in o small-cell lung cance s. Lung Cance .
2022;167:98–106 mayo de. doi: 10.1016/j.lungcan.2022.01.008 .
43. Dong Y, Chen J, Chen Z, e al. E alua ing he associa ion o eigh polymo -
phisms wi h cance suscep ibili y in a Han Chinese Popula ion. PloS One .
2015;10(7):e0132797. doi: 10.1371/jou nal.pone.0132797 .
Clinical Lung Cance Janua y 2024 17