Ci a ion: Rome o-Ga mendia, I.;
Ga cia-E xeba ia, K. F om Omic
Laye s o Pe sonalized Medicine in
Colo ec al Cance : The Road Ahead.
Genes 2023,14, 1430. h ps://
doi.o g/10.3390/genes14071430
Academic Edi o : Lucio Be a io
Recei ed: 25 May 2023
Re ised: 5 July 2023
Accep ed: 10 July 2023
Published: 11 July 2023
Copy igh : © 2023 by he au ho s.
Licensee MDPI, Basel, Swi ze land.
This a icle is an open access a icle
dis ibu ed unde he e ms and
condi ions o he C ea i e Commons
A ibu ion (CC BY) license (h ps://
c ea i ecommons.o g/licenses/by/
4.0/).
genes
G C A T
T A C G
G C A T
Re iew
F om Omic Laye s o Pe sonalized Medicine in Colo ec al
Cance : The Road Ahead
I a i Rome o-Ga mendia 1and Koldo Ga cia-E xeba ia 2,3,*
1Depa men o Gene ics, Physical An h opology and Animal Physiology, Uni e si y o he Basque
Coun y (Uni e sidad del País Vasco/Euskal He iko Unibe si a ea), 48940 Leioa, Spain;
i a i. ome [email p o ec ed]
2Biodonos ia, Gas oin es inal Gene ics G oup, 20014 San Sebas ián, Spain
3Cen o de In es igación Biomédica en Red de En e medades Hepá icas y Diges i as (CIBERehd),
08036 Ba celona, Spain
*Co espondence: koldo.ga [email p o ec ed]g
Abs ac :
Colo ec al cance is a majo heal h conce n since i is a highly diagnosed cance and he
second cause o dea h among cance s. Thus, he mos sui able bioma ke s o i s diagnosis, p ognosis,
and ea men ha e been s udied o imp o e and pe sonalize he p e en ion and clinical managemen
o colo ec al cance . The eme gence o omic echniques has p o ided a g ea oppo uni y o be e
s udy CRC and make pe sonalized medicine easible. In his e iew, we will y o summa ize how
he analysis o he omic laye s can be use ul o pe sonalized medicine and he exis ing di icul ies. We
will discuss how single and mul iple omic laye analyses ha e been used o imp o e he p edic ion
o he isk o CRC and i s ou comes and how o o e come he challenges in he use o omic laye s in
pe sonalized medicine.
Keywo ds:
colo ec al cance ; gene ics; genomics; ansc ip omics; mic obio a; pe sonalized medicine
1. In oduc ion
Wo ldwide, app oxima ely 10% o diagnosed cance s a e colo ec al cance (CRC), and
i is he second cause o dea h among cance s [
1
,
2
]. Mo eo e , 500,000 cases o CRC a e
diagnosed and 242,000 pe sons die as a consequence o CRC each yea in Eu ope alone [
3
].
CRC a ec s bo h sexes and Eu opean coun ies simila ly: In emales, i is he second mos
diagnosed cance and he hi d cause o dea h, and in males, i is he hi d mos diagnosed
cance and he second cause, and he majo i y o Eu opean coun ies show his end [
3
]. All
o hese numbe s sugges ha CRC has a high bu den in de eloped coun ies and is a majo
conce n o heal h sys ems. To add ess he bu den ha is CRC, sc eening s a egies ha e
been de eloped o acili a e i s de ec ion, and he sea ch o bioma ke s o mo e accu a e
diagnosis, p ognosis, and success o ea men o CRC is in cons an de elopmen [
4
].
The e is no doub ha he be e known he biological ac o s ha con ibu e o he isk and
e iology o CRC a e, he be e he bioma ke s ha will be ound.
CRC shows a g ea he e ogenei y since he majo i y o CRC cases a e spo adic and
he mino i y a e gene ically inhe i ed. Lynch synd ome (2–4% o diagnosed CRCs) and
polyposis synd omes (e.g., adenoma ous polyps, Peu z–Jeghe s polyps, o se a ed polyps)
a e he wo main inhe i ed synd omes [
5
]. Hype mu a ed cance s wi h mic osa elli e
ins abili y and non-hype mu a ed cance s wi h copy numbe al e a ions a e he main
classes o spo adic umo s [
6
]. In addi ion, spo adic CRCs a e de eloped in wo main
ways [
7
]: In app oxima ely 66% o spo adic CRC, con en ional adenomas (lesions wi h
ubula , ubulo illous, o illous his ology) can p og ess o CRC ( he con en ional way); in
he es o he cases, se a ed adenomas (lesions wi h he s ella e a chi ec u e o he c yp
epi helium) can p og ess o CRC (se a ed way).
Genes 2023,14, 1430. h ps://doi.o g/10.3390/genes14071430 h ps://www.mdpi.com/jou nal/genes
Genes 2023,14, 1430 2 o 11
Li es yle and he en i onmen a e among he isk ac o s o CRC, since i s de elop-
men is in luenced by die and physical ac i i y [
8
]. In addi ion, he p e ious diseases
su e ed by pa ien s a e ano he sou ce o isk, since in lamma o y p ocesses can lead o
he de elopmen o CRC [9,10], especially in he case o in lamma o y bowel disease [11].
Al hough “pe sonalized medicine” has been used wi h di e en meanings, i can be
de ined as he igh ea men o he igh pe son a he igh ime [
12
]. The de elopmen
o omic echnologies has made possible he iden i ica ion o indi idual suscep ibili y o
some diseases and he esponse o he apies and, he e o e, be e p edic ion, p e en ion,
diagnosis, and ea men o diseases could be eached [
12
]. In cance , he use o pe sonalized
medicine app oaches can be used o sc eening pe sons wi h a highe isk o de eloping
he disease using gene ic es s ha can iden i y isks o de e mine he bes ea men o a
pa ien based on he molecula cha ac e iza ion o cance o o esee he disease p og ession
and he esponse o he ea men [12].
In his e iew, we will y o summa ize how he analysis o he omic laye s can be
use ul o pe sonalized medicine and exis ing di icul ies. Fi s , we will b ie ly summa ize
he analysis o a single omic laye ca ied ou in CRC; hen, we will e iew he analyses
ca ied ou combining mo e han one omic laye , and we will inish wi h he conclusions
and he possible s eps o o e come he di icul ies ha we a e acing when we wan o
implemen pe sonalized medicine in CRC.
2. Single Omic Laye Analyses
Since i is a opic o high in e es , he a ailable omic echnologies o analyses and hei
con ibu ion o CRC s udies ha e been ex ensi ely e iewed be o e [
13
,
14
]. The ocus o
his e iew is no o e-summa ize wha in o ma ion each omic laye can o e ; he e o e,
in his sec ion, we will y o summa ize wha in o ma ion om each omic laye has been
used owa ds pe sonalized medicine.
2.1. Genome
Genome-wide associa ion s udies (GWASs) ha e been used o ind he single nu-
cleo ide polymo phisms (SNPs) in ol ed in he isk o de eloping CRC. In a me a-analysis
o 16 s udies, 34,626 CRC cases and 71,379 we e analyzed and 623 SNPs om 79 loci we e
signi ican ly associa ed wi h CRC isk in a popula ion wi h Eu opean ances y [
15
]. Based
on some o hose GWASs and addi ional GWAS analyses ha ha e been ca ied ou in
ecen yea s, polygenic isk sco es (PRSs) ha e been de eloped o calcula e he isk o an
indi idual de eloping CRC [
16
–
24
]. Howe e , he pe o mance o he PRS is dependen on
each model and he popula ion in which i is applied [
25
]. Thus, esea che s should e alu-
a e wha is he mos app op ia e PRS model o pe o m an op imal isk s a i ica ion in a
gi en popula ion, bo h in popula ions o he same ances y and di e en ances ies [
25
,
26
].
Mo eo e , i has been obse ed ha he SNPs in ol ed in he isk o igh colon
cance and le colon cance a e pa ly di e en [
27
]. The s a i ica ion o he analyses is
he only way o de ec he e ec o some SNPs ha could be in ol ed in he de elopmen
o CRC since hey seem o be associa ed wi h he loca ion o he umo [
25
,
27
]. Thus,
isk-s a i ica ion s a egies should inco po a e he di e ences in he gene ic a chi ec u e
acco ding o he loca ion and pe sonalize acco dingly he sc eenings.
GWASs ha e been ca ied ou o ind SNPs associa ed wi h me as a ic colo ec al cance
su i al in ea men wi h chemo he apy plus biologics [
28
], su i al in ec al cance [
29
],
p og ession- ee su i al in me as a ic colo ec al cance in di e en ea men s [
30
], and
su i al in colo ec al cance [
31
]. Thus, he e a e a ailable ma ke s ha could be help ul o
p edic he success o he ea men and ailo he clinical op ions, al hough he alida ion
o hose ma ke s in di e en popula ions is pending.
2.2. Epigenome
DNA me hyla ion, his one modi ica ions, and non-coding RNAs ha e been analyzed
in CRC o ind easible bioma ke s o di e en ea u es o CRC.
Genes 2023,14, 1430 3 o 11
The CpG island me hyla o pheno ype, whe e he p omo e s o se e al genes (e.g.,
hMLH1,CDKN2A,MINT,CACNA1G,CRABP1,IGF2,NEUROG1,RUNX3, and SOCS1)
show highe hype me hyla ion, has been p oposed as a use ul p edic o o CRC [
32
–
34
]. In
addi ion, he me hyla ion s a us o SEPT9 has been p oposed o CRC diagnosis, al hough
i s pe o mance is a iable depending on he s age [35].
In he case o his one modi ica ions, se e al modi ica ions ha e been epo ed, al-
hough he mos ele an modi ica ions in CRC we e ace yla ion and me hyla ion [
36
,
37
].
In addi ion, H4K12ac and H3K18ac modi ica ions inc eased in CRC [37,38].
Finally, he ole o mic o RNAs (miRNAs) and long non-coding RNAs (lncRNAs)
in CRC could be ele an since hei exp ession could a ec oncogenic genes [
39
]. The
exp ession o miRNAs was use ul o dis inguish be ween subg oups [
40
,
41
] and hey ha e
been p oposed o help in inding new he apeu ic a ge s [
42
]. In addi ion, he exp ession
o lncRNAs has been used o dis inguish be ween s ages and p og ession [43–45].
I has o be highligh ed ha based on epigene ic ma ke s, se e al bioma ke s ha e
been comme cialized and p oposed o clinical use o guidelines [
46
]. Thus, he epigenome
seems o be an app op ia e laye o ind use ul bioma ke s.
2.3. T ansc ip ome
T ansc ip ome da a we e used o de ine he consensus molecula sub ypes o CRC,
a classi ica ion ha is widely used [
47
]. Based on he gene-exp ession p o iles o se e al
ansc ip ome s udies, ou sub ypes we e de ined [
47
]: CMS1, which showed mic osa elli e
ins abili y and immune il a ion and ac i a ion; CMS2, which was de ined as canonical;
CMS3, which showed me abolic de egula ion; and CMS4, which showed s omal in il-
a ion. Recen ly, he use o single-cell ansc ip ome analysis was used o e ine his
classi ica ion, he in insic sub ypes [
48
]. Two in insic sub ypes we e de ined based on he
ansc ip ome o epi helial cells [
48
]: iCMS2, which showed a mu a ion in APC and TP53
and g ea e Wn /b-ca enin and MYC ac i i y; and iCMS3, which showed KRAS, PIK3CA,
and BRAM mu a ions and highe in lamma ion esponse.
Mo eo e , he ansc ip ome da a o CRC a ailable h ough TCGA [
49
] has been
eanalyzed o ind ele an genes ela ed o di e en ea u es o CRC. A di e en ially
exp essed gene analysis o CRC s ages ound 11 genes (NEK4,RNF34,HIST3H2BB,NUDT6,
LRCh4,GLB1L,HIST2H4A,TMEM79,AMIGO2,C20o 135, and SPSB3) ha change hei
exp ession depending on he s age [
50
]. Fo example, he NEK4 gene, which is in ol ed
in he senescence o cells, showed highe exp ession in s age I and he lowes exp ession
in s age IV [
50
]. Howe e , he whole gene exp ession pa e n o he CRC pa ien s was
no di e en be ween s ages since he p incipal componen analysis was no able o show
clea pa e ns [
50
]. In addi ion, TCGA da a we e used o ind genes associa ed wi h o e all
su i al [
51
]. I was concluded ha he exp ession pa e n o six genes (ART5,FOXD1,
HIST3H2BB,TIMP1,EPHA6, and IRX6) was able o disc imina e be ween CRC pa ien s
wi h poo diagnos ic ou comes and good diagnos ic ou comes and ha he model was
independen o o he clinical ea u es [51].
Fu he mo e, he ole o genes in ol ed in DNA damage and epai mechanisms in
colon cance was in e oga ed [
52
]. Fi s , pa o he TCGA exp ession da a was used o
build a 12-gene model (CCNB3,ISY1,CDC25C,SMC1B,MC1R,LSP1P4,RIN2,TPM1,ELL3,
POLG,CD36, and NEK4) ha was able o di e en ia e low- isk and high- isk g oups [
52
].
Then, he 12-gene model was applied o he emaining TCGA exp ession da a, and he
abili y o classi y 5 yea s o su i al eached an a ea unde he cu e (AUC) o he ecei e
ope a ing cha ac e is ic (ROC) o 0.79 [
52
]. In addi ion, he model was applied o wo
da ase s a ailable in he GEO da abase [
52
]; in one o he da ase s, he AUC o su i al o
5 yea s was 0.65, and in he o he , i was 0.72.
Conside ing ha he o e lap o genes be ween s udies is limi ed and he pe o mance
o he models is no ideal, i could be di icul o ansla e he esul s o he ansc ip ome
in o clinical p ac ice.
Genes 2023,14, 1430 4 o 11
2.4. P o eome
P o eome analysis has been used in di e en issues (CRC biopsies, pa a in-embedded
CRC biopsies, se um, and plasma) o ind diagnos ic bioma ke s using se e al me hods.
Fo example, a s udy whe e wo-dimensional gel elec opho esis coupled o mass
spec ome y was used on CRC biopsies and adjacen no mal issue ound he up egula ion
o ACTBL2 [
53
]. In ano he s udy, Fou ie ans o m mass spec ome y was used o analyze
CRC biopsies and adjacen no mal issue, and he up egula ion o DPEP1 was ound [
54
].
Using liquid ch oma og aphy-mass andem mass spec ome y on pa a ine-embedded
issues, a s udy ound ha OLFM4, KNG1, and Sec24C ha e di e en ial exp ession in he
ea ly CRC s ages han in no mal and p emalignan issues [
55
]. In ano he s udy, using he
same me hod, CyPA, ANXA2, and ALDOA we e ound o be up egula ed in CRC [56].
Mo eo e , ano he s udy, in which a ge ed liquid ch oma og aphy- andem mass
spec ome y was used on blood samples, p oposed a model based on LRG1, EGFR, ITIH4,
Hpx, and SOD3 p o eins ha had a good pe o mance o CRC de ec ion [
57
]. Ano he
s udy, whe e liquid ch oma og aphy/mul iple- eac ion moni o ing-mass spec ome y
was used on plasma samples, p oposed a di e en model o CRC de ec ion based on
MASP-1, SPP1, PON3, T R1, and AREG [
58
]. In a s udy whe e ma ix-assis ed lase -
deso p ion/ioniza ion ime-o - ligh was used on se um samples, i was de ec ed ha he
down egula ion o STK4 was a good p edic o o CRC diagnosis and possibly o dis an
me as asis [
59
]. In addi ion, he combina ion o high-pe o mance liquid ch oma og aphy
and mass spec ome y on se um samples ound ha MRC1 and S100A9 we e up egula ed
in CRC [60].
As happened wi h he ansc ip ome, he o e lap o p o eins be ween s udies is
limi ed, and, he e o e, hei use o pe sonalized medicine could ace di icul ies.
2.5. Me abolome
Se e al s udies ha e analyzed he me abolome o ind easible candida es o CRC
p og ession de ec ion.
Fo example, ecal samples o CRC, adenoma, and heal hy con ols we e examined o
ind me aboli es ha could di e en ia e be ween he h ee s a uses [
61
]. In o al, 105 me abo-
li es we e e alua ed, and 18 o hem we e al e ed in CRC [
61
]. In addi ion, a p edic i e
model was cons uc ed using se en me aboli es, and he AUC o he model was 0.821 [
61
].
The inclusion o sex and age imp o ed he model (AUC = 0.848) and he esul s o he
ecal occul blood es (AUC = 0.885) [
61
]. In addi ion, 1380 me aboli es we e analyzed
in CRC, adenoma, and heal hy con ols, and 25 me aboli es we e ound o di e en ia e
CRC and adenomas om heal hy con ols. Among hose me aboli es, sphingomyelins,
lac osylce amides, and seconda y bile acids we e de ec ed [
62
]. The combina ion o i e
me aboli es showed an accu acy o 91.67% [62].
Mo eo e , 50 lipids we e ound o be good bioma ke s o he adenoma- o-CRC se-
quence, especially phospha idylcholines and iacylglyce ols [
63
]. The use o ou me abo-
li es showed a good pe o mance in di e en ia ing he di e en s a uses (adenoma om no -
mal, AUC = 0.879; CRC om no mal, AUC = 0.817; CRC om adenoma, AUC = 0.805) [
63
].
In ano he s udy, 79 lipids we e ound o ha e di e en ial abundance be ween CRC and
con ols, he majo i y o which we e phospha idylcholines and iacylglyce ols [
64
]. F om
hose lipids, 12 lipids showed an AUC > 0.95 [64].
Conside ing he pe o mance o he models, me aboli es seem o be easible bioma ke s
o CRC, al hough he de ec ed me aboli es could no be he same in di e en s udies.
2.6. Mic obiome
Mic obiome has been ex ensi ely in es iga ed o ind ma ke s ha could be use ul
o p edic he de elopmen o CRC, especially in ecal samples since i is he less in asi e
me hod [
65
]. In CRC, some axa a e di e en compa ed wi h heal hy samples, al hough
he e is a iabili y among s udies [
66
–
68
]. In addi ion, he axa p esen in CRC we e
di e en depending on he CRC s age [
66
,
67
]. As happened wi h o he omic laye s, he e
Genes 2023,14, 1430 5 o 11
ha e been di e ences de ec ed in he mic obiome composi ion be ween igh -colon and
le -colon cance [
69
,
70
]. Thus, he mic obiome signa u e could be used o p edic di e en
ea u es o CRC.
3. Combina ion o he Analysis o Mul iple Omic Laye s
The combina ion o mul iple omic laye s allows he s udy o he in e ac ion o he
analyzed laye s and he e ec o ha in e ac ion on he ai , in his case, CRC. In his way,
eliable and ep esen a i e bioma ke s can be in e ed om each omic laye ha can be
use ul o pe sonalize he diagnos ic o he ea men .
The analysis and in eg a ion o da a om he genome (single-nucleo ide a ian
and copy numbe a ia ion), epigenome (DNA me hyla ion), and ansc ip ome (mRNA)
allowed he disco e y o 12 genes ha we e use ul o p ognosis in I and II s ages o
CRC [
71
]. In addi ion, among hose genes, he exp ession o REP15 and LRRC26 genes
showed he bes p ognosis in he ea ly s ages o CRC [
71
]. In ano he s udy, he combina ion
o he genome (copy numbe a ia ion), ansc ip ome (gene and miRNA exp ession), and
me abolome ( om se um and u ea) we e used o ind he molecula p o iling o he
elapse in I and II s ages CRC [
72
]. Fi s , each omic laye was analyzed o ob ain he
mos in o ma i e ea u es (16 copy numbe a ia ions, 12 genes, 25 miRNAs, 24 se um
me aboli es, and 7 u ine me aboli es) and hen hose ea u es we e combined o ob ain
he mos in o ma i e da a and emo e edundan in o ma ion, gaining 31 in o ma i e
ea u es (2 copy numbe a ia ions, 8 genes, 1 miRNA, 13 se um me aboli es, and 7 u ine
me aboli es) as p edic o s o elapse [
72
]. Thus, he use o di e en omic laye s could be
use ul o ind bioma ke s o p ognosis and, he e o e, o adjus he ea men .
Mo eo e , ano he s udy used s emness ( he capaci y o sel - enewal and epopu-
la ion o umo ous cells) o classi y he umo s and link ha classi ica ion o a ious
omic laye s [
73
]. Fi s , he ansc ip ome was used o classi y he umo s in o low- and
high-s emness g oups, which ha e be e and wo se p ognoses, espec i ely [
73
]. They
concluded ha nine genes (GFPT1,PTMAP9,MOGAT3,DPM3,S100A12,PGM5,FUT6,
SEMA3C, and ADAM33) could be use ul o pe o m he p edic ion o he g oups, and
hey assessed hei p ognos ic alue [
73
]. The pe o mance o classi ying hose genes
was high in he i e da ase s hey used o he alida ion [
73
]. Finally, he genomic laye
( umo mu a ion bu den, SNPs, inse ions and dele ions, genome al e a ions, and copy
numbe a ia ions) was used o cha ac e ize he g oups [
73
]: The g oup wi h he be e
p ognosis was mu a ion-d i en and he g oup wi h he wo s p ognosis was copy numbe
dele ion-d i en. Thus, as ele an ea u es o umo s a e in es iga ed and inco po a ed,
s a i ica ion will become mo e e ined, and he e o e, mul i-laye ed analyses can be used
o ind use ul new ma ke s.
Mo eo e , in a s udy compa ing sho - e m and long- e m su i al o CRC, he ex-
p ession o mRNA and miRNA and he bac e ial composi ion we e analyzed al oge he o
measu e hei abili y o p edic su i al. The mic obiome was he bes omic laye p edic ing
he su i al o CRC pa ien s (AUC o 0.755), ollowed by mRNA (AUC o 0.702), while
miRNA showed he wo s pe o mance (AUC o 0.546) [
74
]. In ano he s udy, genome,
me abolome, and mic obiome da a we e used o assess he isk ac o s o CRC and, when
analyzed al oge he , he con ibu ion o each laye was di e en [
75
]: The mic obiome
a ec ed he mos a iance, he me abolome showed a smalle e ec , and he con ibu ion o
he genome o he a iance was limi ed. In addi ion, he co a iance be ween he di e en
laye s was limi ed, and he use o ea u es om he h ee laye s showed be e pe o mance
o p edic CRC isk han using only wo laye s [
68
,
75
]. Howe e , some ea u es om he
me abolome and mic obiome ha we e use ul o p edic CRC isk could be in luenced by
he genome [
68
,
75
]. Thus, a pa o he isk cap u ed by each laye could be independen
and ano he pa could be edundan , depending on he biological mechanism in ol ed.
Genes 2023,14, 1430 6 o 11
4. Di icul ies and Fu u e S eps
We ha e e iewed how o ake ad an age o omic laye s owa ds pe sonalized
medicine and i is clea ha , al hough ema kable p og ess has been made, we a e no ye
he e. In his sec ion, we will discuss he di icul ies ha we ha e o ace and he possible
s eps o o e come hem.
Al hough he da a om a ious omics laye s om CRC samples ha e been a ailable
o some ime and i was sugges ed ha his would se e o imp o e knowledge abou
CRC [
49
], i seems ha hei use in clinical p ac ice has no been as gene al as we would
expec . Fo example, he sea ch o non-in asi e bioma ke s has led o he inding o
bioma ke s om he blood ha seems p omising [
76
]. Those bioma ke s we e om he
epigenome laye (DNA me hyla ion and mic oRNA) and hei combina ion is necessa y
o each an op imal pe o mance [
76
]. In addi ion, he con ibu ion, in ol emen , and
collabo a ion o di e en s akeholde s a e needed o he success o he applica ion o hose
bioma ke s in sc eening p og ams [76].
I has o be highligh ed ha he e ec o each omic laye can be inhe i ed om he
p e ious omic laye (e.g., he e ec o a gi en ansc ip can be a consequence o a mu a ion
o he genome), he e ec can eme ge in ha omic laye , and he e ec can be in a di e en
di ec ion (Figu e 1). In o he wo ds, he pheno ype could be a consequence o a linea
a ia ion o he omic laye , o i could be he combina ion o he a ia ion o each omic
laye [
77
]. Thus, depending on he omic laye s analyzed and he biological mechanisms
in ol ed, he bioma ke s p oposed may no accu a ely ep esen all he a ia ion, and
hei pe o mance would no be op imal. P e iously, we ha e discussed ha some ma ke s
o each laye can be edundan [
72
] and o he s complemen a y [
68
,
75
], since pa o he
isk o CRC o i s ou comes seems o be inhe i ed om a p e ious omic laye and ano he
pa o he isk seems o eme ge in one omic laye [
68
,
75
]. Thus, one mus e alua e he
con ibu ion o each omic laye and each ma ke o a oid o e laps o losing in o ma ion.
Al hough he echnologies o sequence and analyze omic laye s ha e been imp o ed,
we s ill ha e se e al challenges when inco po a ing omic in o ma ion in o pe sonalized
medicine [
78
]: The cos o hose echnologies is no a o dable o e e yone, and he s o age,
p ocess, in eg a ion, and in e p e a ion o he da a could be a limi a ion. These issues a e
o conce n in some omic laye s. Fo example, in mic obiome analyses, he concilia ion
o di e en s udies is di icul , no only because o he biological a iabili y be ween
popula ions bu also due o me hodological a iabili y [
65
]. In addi ion, he alida ion o
he ma ke s in di e en popula ions is no as widesp ead as would be expec ed, maybe
because i is no a o dable o possible o analyze all he ele an omic ea u es in he
samples ha a e a ailable.
Mo eo e , we canno o ge he e ec o he en i onmen [
8
] and socioeconomic
s a us [
79
] on he isk and de elopmen o CRC (Figu e 1). In addi ion, he use o clinical
da a can imp o e he p edic ion capabili y o omic ma ke s [
68
,
75
]. The inco po a ion o
hese da a will be necessa y o imp o e omic analyses and a oid biases due o con ounding
ac o s ha a e no usually conside ed.
Howe e , we ha e an exci ing oad ahead. The de elopmen o single-cell echnologies,
he imp o emen o compu a ional capabili ies, he a ailabili y o open me hods and da a,
and he ad ancemen o medical ca e and de ices a e an oppo uni y o o e come he
limi a ions. In addi ion, we will need he inco po a ion o new popula ions o be possible
o he alida ion o ma ke s o o ind ma ke s ha a e ele an o hose popula ions o
p edic ing and pe sonalizing CRC diagnosis, p ognosis, and ea men .
Genes 2023,14, 1430 7 o 11
Genes 2023, 14, x FOR PEER REVIEW 7 o 11
da a, and he ad ancemen o medical ca e and de ices a e an oppo uni y o o e come
he limi a ions. In addi ion, we will need he inco po a ion o new popula ions o be pos-
sible o he alida ion o ma ke s o o ind ma ke s ha a e ele an o hose popula-
ions o p edic ing and pe sonalizing CRC diagnosis, p ognosis, and ea men .
Figu e 1. In e ac ions be ween omic laye s and he en i onmen ha could lead o colo ec al cance
de elopmen .
5. Conclusions
The in o ma ion om omic laye s can be used o ob ain biological ma ke s ha could
imp o e and pe sonalize he diagnosis, p ognosis, and ea men o colo ec al cance . As
mo e omic in o ma ion has been inco po a ed, we ha e ealized ha he e ec o each
omic laye and i s ea u es could be edundan o complemen a y. In addi ion, as mo e
popula ions ha e been analyzed, we ha e ealized ha he pe o mance o he omic ma k-
e s can be a iable. Thus, he omic ma ke s should be e alua ed in e ms o u ili y o a
popula ion and non- edundancy. We will need esh ideas o ex ac he maximum in o -
ma ion om each omic laye , in eg a e he omic laye s, and alida e he mo e easible
omic ma ke s in a wide ange o popula ions, o make pe sonalized medicine use ul and
accessible o all CRC pa ien s.
Au ho Con ibu ions: Concep ualiza ion, I.R.-G. and K.G.-E.; w i ing—o iginal d a p epa a ion,
K.G.-E.; w i ing— e iew and edi ing, I.R.-G. and K.G.-E.; isualiza ion, K.G.-E.; supe ision, K.G.-
E. All au ho s ha e ead and ag eed o he published e sion o he manusc ip .
Funding: This esea ch ecei ed no ex e nal unding.
Da a A ailabili y S a emen : No applicable.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Figu e 1.
In e ac ions be ween omic laye s and he en i onmen ha could lead o colo ec al cance
de elopmen .
5. Conclusions
The in o ma ion om omic laye s can be used o ob ain biological ma ke s ha could
imp o e and pe sonalize he diagnosis, p ognosis, and ea men o colo ec al cance .
As mo e omic in o ma ion has been inco po a ed, we ha e ealized ha he e ec o
each omic laye and i s ea u es could be edundan o complemen a y. In addi ion, as
mo e popula ions ha e been analyzed, we ha e ealized ha he pe o mance o he omic
ma ke s can be a iable. Thus, he omic ma ke s should be e alua ed in e ms o u ili y
o a popula ion and non- edundancy. We will need esh ideas o ex ac he maximum
in o ma ion om each omic laye , in eg a e he omic laye s, and alida e he mo e easible
omic ma ke s in a wide ange o popula ions, o make pe sonalized medicine use ul and
accessible o all CRC pa ien s.
Au ho Con ibu ions:
Concep ualiza ion, I.R.-G. and K.G.-E.; w i ing—o iginal d a p epa a ion,
K.G.-E.; w i ing— e iew and edi ing, I.R.-G. and K.G.-E.; isualiza ion, K.G.-E.; supe ision, K.G.-E.
All au ho s ha e ead and ag eed o he published e sion o he manusc ip .
Funding: This esea ch ecei ed no ex e nal unding.
Da a A ailabili y S a emen : No applicable.
Con lic s o In e es : The au ho s decla e no con lic o in e es .
Re e ences
1. S ewa , B.; Wild, C. Wo ld Cance Repo 2014; IARC Publica ions: Lyon, F ance, 2014.
2.
Fe lay, J.; Soe joma a am, I.; Dikshi , R.; Ese , S.; Ma he s, C.; Rebelo, M.; Pa kin, D.M.; Fo man, D.; B ay, F. Cance Incidence and
Mo ali y Wo ldwide: Sou ces, Me hods and Majo Pa e ns in GLOBOCAN 2012. In . J. Cance
2015
,136, E359–E386. [C ossRe ]
[PubMed]
Genes 2023,14, 1430 8 o 11
3.
Fe lay, J.; Colombe , M.; Soe joma a am, I.; Dyba, T.; Randi, G.; Be io, M.; Ga in, A.; Visse , O.; B ay, F. Cance Incidence
and Mo ali y Pa e ns in Eu ope: Es ima es o 40 Coun ies and 25 Majo Cance s in 2018. Eu . J. Cance
2018
,103, 356–387.
[C ossRe ] [PubMed]
4.
Le in, B.; Liebe man, D.A.; McFa land, B.; Smi h, R.A.; B ooks, D.; And ews, K.S.; Dash, C.; Gia diello, F.M.; Glick, S.; Le in, T.R.;
e al. Sc eening and Su eillance o he Ea ly De ec ion o Colo ec al Cance and Adenoma ous Polyps, 2008: A Join Guideline
om he Ame ican Cance Socie y, he US Mul i-Socie y Task Fo ce on Colo ec al Cance , and he Ame ican College o Radiology.
CA Cance J. Clin. 2008,58, 130–160. [C ossRe ]
5.
Ma, H.; B osens, L.A.A.; O e haus, G.J.A.; Gia diello, F.M.; de Leng, W.W.J.; Mon gome y, E.A. Pa hology and Gene ics o
He edi a y Colo ec al Cance . Pa hology 2018,50, 49–59. [C ossRe ] [PubMed]
6.
Mülle , M.F.; Ib ahim, A.E.K.; A ends, M.J. Molecula Pa hological Classi ica ion o Colo ec al Cance . Vi chows A ch.
2016
,469,
125–134. [C ossRe ]
7.
Nakanishi, Y.; Diaz-Meco, M.T.; Mosca , J. Se a ed Colo ec al Cance : The Road Less T a elled? T ends Cance
2019
,5, 742–754.
[C ossRe ]
8.
C oss, A.J.; Fe ucci, L.M.; Risch, A.; G auba d, B.I.; Wa d, M.H.; Pa k, Y.; Hollenbeck, A.R.; Scha zkin, A.; Sinha, R. A La ge
P ospec i e S udy o Mea Consump ion and Colo ec al Cance Risk: An In es iga ion o Po en ial Mechanisms Unde lying This
Associa ion. Cance Res. 2010,70, 2406–2414. [C ossRe ]
9.
Las y, A.; Zinge , A.; Ben-Ne iah, Y. In lamma o y Ne wo ks Unde lying Colo ec al Cance . Na . Immunol.
2016
,17, 230–240.
[C ossRe ]
10. Lucas, C.; Ba nich, N.; Nguyen, H. Mic obio a, In lamma ion and Colo ec al Cance . In . J. Mol. Sci. 2017,18, 1310. [C ossRe ]
11.
Axel ad, J.E.; Lich ige , S.; Yajnik, V. In lamma o y Bowel Disease and Cance : The Role o In lamma ion, Immunosupp ession,
and Cance T ea men . Wo ld J. Gas oen e ol. 2016,22, 4794. [C ossRe ]
12.
Di Sanzo, M.; Cipolloni, L.; Bo o, M.; La Russa, R.; San u o, A.; Scope i, M.; Simmaco, M.; F a i, P. Clinical Applica ions o
Pe sonalized Medicine: A New Pa adigm and Challenge. Cu . Pha m. Bio echnol. 2017,18, 194–203. [C ossRe ] [PubMed]
13.
Alo da-Cla a, M.; To ens-Mas, M.; Mo la-Ba celo, P.M.; Ma inez-Be nabe, T.; Sas e-Se a, J.; Roca, P.; Pons, D.G.; Oli e , J.;
Reyes, J. Use o Omics Technologies o he De ec ion o Colo ec al Cance Bioma ke s. Cance s
2022
,14, 817. [C ossRe ] [PubMed]
14.
Ullah, I.; Yang, L.; Yin, F.-T.; Sun, Y.; Li, X.-H.; Li, J.; Wang, X.-J. Mul i-Omics App oaches in Colo ec al Cance Sc eening and
Diagnosis, Recen Upda es and Fu u e Pe spec i es. Cance s 2022,14, 5545. [C ossRe ]
15.
Law, P.J.; Timo ee a, M.; Fe nandez-Rozadilla, C.; B ode ick, P.; S udd, J.; Fe nandez-Tajes, J.; Fa ing on, S.; S in i, V.; Palles,
C.; O lando, G.; e al. Associa ion Analyses Iden i y 31 New Risk Loci o Colo ec al Cance Suscep ibili y. Na . Commun.
2019
,
10, 2154. [C ossRe ]
16.
Jia, G.; Lu, Y.; Wen, W.; Long, J.; Liu, Y.; Tao, R.; Li, B.; Denny, J.C.; Shu, X.-O.; Zheng, W. E alua ing he U ili y o Polygenic
Risk Sco es in Iden i ying High-Risk Indi iduals o Eigh Common Cance s. JNCI Cance Spec .
2020
,4, pkaa021. [C ossRe ]
[PubMed]
17.
Hsu, L.; Jeon, J.; B enne , H.; G ube , S.B.; Schoen, R.E.; Be nd , S.I.; Chan, A.T.; Chang-Claude, J.; Du, M.; Gong, J.; e al. A
Model o De e mine Colo ec al Cance Risk Using Common Gene ic Suscep ibili y Loci. Gas oen e ology
2015
,148, 1330–1339.
[C ossRe ]
18.
F i sche, L.G.; Pa il, S.; Beesley, L.J.; VandeHaa , P.; Sal a o e, M.; Ma, Y.; Peng, R.B.; Taliun, D.; Zhou, X.; Mukhe jee, B. Cance
PRSweb: An Online Reposi o y wi h Polygenic Risk Sco es o Majo Cance T ai s and Thei E alua ion in Two Independen
Biobanks. Am. J. Hum. Gene . 2020,107, 815–836. [C ossRe ]
19.
Huyghe, J.R.; Bien, S.A.; Ha ison, T.A.; Kang, H.M.; Chen, S.; Schmi , S.L.; Con i, D.V.; Qu, C.; Jeon, J.; Edlund, C.K.; e al.
Disco e y o Common and Ra e Gene ic Risk Va ian s o Colo ec al Cance . Na . Gene . 2019,51, 76–87. [C ossRe ]
20.
Kachu i, L.; G a , R.E.; Smi h-By ne, K.; Meye s, T.J.; Rashkin, S.R.; Zi , E.; Wi e, J.S.; Johansson, M. Pan-Cance Analysis
Demons a es Tha In eg a ing Polygenic Risk Sco es wi h Modi iable Risk Fac o s Imp o es Risk P edic ion. Na . Commun.
2020
,
11, 6084. [C ossRe ]
21.
Shi, Z.; Yu, H.; Wu, Y.; Lin, X.; Bao, Q.; Jia, H.; Pe schon, C.; Duggan, D.; Hel and, B.T.; Zheng, S.L.; e al. Sys ema ic E alua ion
o Cance -Speci ic Gene ic Risk Sco e o 11 Types o Cance in he Cance Genome A las and Elec onic Medical Reco ds and
Genomics Coho s. Cance Med. 2019,8, 3196–3205. [C ossRe ]
22.
G a , R.E.; Ca azos, T.B.; Thai, K.K.; Kachu i, L.; Rashkin, S.R.; Ho man, J.D.; Alexee , S.E.; Bla chins, M.; Meye s, T.J.; Leong, L.;
e al. C oss-Cance E alua ion o Polygenic Risk Sco es o 16 Cance Types in Two La ge Coho s. Na . Commun.
2021
,12, 970.
[C ossRe ] [PubMed]
23.
A chambaul , A.N.; Su, Y.-R.; Jeon, J.; Thomas, M.; Lin, Y.; Con i, D.V.; Win, A.K.; Sakoda, L.C.; Lansdo p-Vogelaa , I.; Pe e se,
E.F.; e al. Cumula i e Bu den o Colo ec al Cance –Associa ed Gene ic Va ian s Is Mo e S ongly Associa ed wi h Ea ly-Onse s.
La e-Onse Cance . Gas oen e ology 2020,158, 1274–1286. [C ossRe ] [PubMed]
24.
Schmi , S.L.; Edlund, C.K.; Schumache , F.R.; Gong, J.; Ha ison, T.A.; Huyghe, J.R.; Qu, C.; Melas, M.; Van Den Be g, D.J.; Wang,
H.; e al. No el Common Gene ic Suscep ibili y Loci o Colo ec al Cance . J. Na l. Cance Ins . 2019,111, 146–157. [C ossRe ]
25.
Ga cia-E xeba ia, K.; E xa , A.; Ba e o, M.; Na ia, B.; Segues Me ino, N.M.; Rome o-Ga mendia, I.; F anke, A.; D’Ama o, M.;
Bujanda, L. Pe o mance o he Use o Gene ic In o ma ion o Assess he Risk o Colo ec al Cance in he Basque Popula ion.
Cance s 2022,14, 4193. [C ossRe ] [PubMed]
Genes 2023,14, 1430 9 o 11
26.
Ho, P.J.; Tan, I.B.; Chong, D.Q.; Kho , C.C.; Yuan, J.-M.; Koh, W.-P.; Do ajoo, R.; Li, J. Polygenic Risk Sco es o he P edic ion o
Common Cance s in Eas Asians: A Popula ion-Based P ospec i e Coho S udy. eLi e 2023,12, e82608. [C ossRe ] [PubMed]
27.
Huyghe, J.R.; Ha ison, T.A.; Bien, S.A.; Hampel, H.; Figuei edo, J.C.; Schmi , S.L.; Con i, D.V.; Chen, S.; Qu, C.; Lin, Y.; e al.
Gene ic A chi ec u es o P oximal and Dis al Colo ec al Cance A e Pa ly Dis inc . Gu 2021,70, 1325–1334. [C ossRe ]
28.
Innocen i, F.; Sibley, A.B.; Pa il, S.A.; E he idge, A.S.; Jiang, C.; Ou, F.-S.; Howell, S.D.; Plumme , S.J.; Casey, G.; Be agnolli,
M.M.; e al. Genomic Analysis o Ge mline Va ia ion Associa ed wi h Su i al o Pa ien s wi h Colo ec al Cance T ea ed wi h
Chemo he apy Plus Biologics in CALGB/SWOG 80405 (Alliance). Clin. Cance Res. 2021,27, 267–275. [C ossRe ]
29.
Xu, W.; Xu, J.; Shes opalo , K.; Dicks, E.; G een, J.; Pa ey, P.; G een, R.; Sa as, S. A Genome Wide Associa ion S udy on
New oundland Colo ec al Cance Pa ien s’ Su i al Ou comes. Bioma k. Res. 2015,3, 6. [C ossRe ]
30.
Pande , J.; an Huis-Tanja, L.; Böh inge , S.; an de S aa en, T.; Gelde blom, H.; Pun , C.; Guchelaa , H.-J. Genome Wide
Associa ion S udy o P edic o s o P og ession F ee Su i al in Pa ien s on Capeci abine, Oxalipla in, Be acizumab and
Ce uximab in Fi s -Line The apy o Me as a ic Colo ec al Cance . PLoS ONE 2015,10, e0131091. [C ossRe ]
31.
Phipps, A.I.; Passa elli, M.N.; Chan, A.T.; Ha ison, T.A.; Jeon, J.; Hu e , C.M.; Be nd , S.I.; B enne , H.; Caan, B.J.; Campbell, P.T.;
e al. Common Gene ic Va ia ion and Su i al a e Colo ec al Cance Diagnosis: A Genome-Wide Analysis. Ca cinogenesis
2016
,
37, 87–95. [C ossRe ]
32.
Bae, J.M.; Kim, J.H.; Kang, G.H. Epigene ic Al e a ions in Colo ec al Cance : The CpG Island Me hyla o Pheno ype. His ol.
His opa hol. 2013,28, 585–595. [PubMed]
33.
Jia, M.; Gao, X.; Zhang, Y.; Ho meis e , M.; B enne , H. Di e en De ini ions o CpG Island Me hyla o Pheno ype and Ou comes
o Colo ec al Cance : A Sys ema ic Re iew. Clin. Epigene . 2016,8, 1–14. [C ossRe ] [PubMed]
34.
Rhee, Y.-Y.; Kim, K.-J.; Kang, G.H. CpG Island Me hyla o Pheno ype-High Colo ec al Cance s and Thei P ognos ic Implica ions
and Rela ionships wi h he Se a ed Neoplasia Pa hway. Gu Li e 2017,11, 38. [C ossRe ] [PubMed]
35.
Chu ch, T.R.; Wandell, M.; Lo on-Day, C.; Mongin, S.J.; Bu ge , M.; Payne, S.R.; Cas años-Vélez, E.; Blumens ein, B.A.; Rösch, T.;
Osbo n, N.; e al. P ospec i e E alua ion o Me hyla ed SEPT9 in Plasma o De ec ion o Asymp oma ic Colo ec al Cance . Gu
2014,63, 317–325. [C ossRe ]
36.
Binde , H.; S eine , L.; P zybilla, J.; Rohl , T.; P ohaska, S.; Galle, J. T ansc ip ional Regula ion by His one Modi ica ions: Towa ds
a Theo y o Ch oma in Re-O ganiza ion du ing S em Cell Di e en ia ion. Phys. Biol. 2013,10, 026006. [C ossRe ]
37.
Nakazawa, T.; Kondo, T.; Ma, D.; Niu, D.; Mochizuki, K.; Kawasaki, T.; Yamane, T.; Iino, H.; Fujii, H.; Ka oh, R. Global His one
Modi ica ion o His one H3 in Colo ec al Cance and I s P ecu so Lesions. Hum. Pa hol. 2012,43, 834–842. [C ossRe ]
38.
S ypula-Cy us, Y.; Damania, D.; Kun e, D.P.; C uz, M.D.; Sub amanian, H.; Roy, H.K.; Backman, V. HDAC Up-Regula ion in Ea ly
Colon Field Ca cinogenesis Is In ol ed in Cell Tumo igenici y h ough Regula ion o Ch oma in S uc u e. PLoS ONE
2013
,8,
e64600. [C ossRe ]
39.
Luo, X.; Bu winkel, B.; Tao, S.; B enne , H. Mic oRNA Signa u es: No el Bioma ke o Colo ec al Cance ? Cance Epidemiol.
Bioma k. P e . 2011,20, 1272–1286. [C ossRe ]
40.
Mosakhani, N.; Sa hadi, V.K.; Bo ze, I.; Ka jalainen-Lindsbe g, M.-L.; Sunds öm, J.; Ris amäki, R.; Ös e lund, P.; Knuu ila,
S. Mic oRNA P o iling Di e en ia es Colo ec al Cance Acco ding o KRAS S a us. Genes Ch omosomes Cance
2012
,51, 1–9.
[C ossRe ]
41.
Balague , F.; Mo ei a, L.; Lozano, J.J.; Link, A.; Rami ez, G.; Shen, Y.; Cua ecasas, M.; A nold, M.; Mel ze , S.J.; Syngal, S.;
e al. Colo ec al Cance s wi h Mic osa elli e Ins abili y Display Unique MiRNA P o iles. Clin. Cance Res.
2011
,17, 6239–6249.
[C ossRe ]
42.
Xu, P.; Zhu, Y.; Sun, B.; Xiao, Z. Colo ec al Cance Cha ac e iza ion and The apeu ic Ta ge P edic ion Based on Mic oRNA
Exp ession P o ile. Sci. Rep. 2016,6, 20616. [C ossRe ] [PubMed]
43.
Ge, X.; Chen, Y.; Liao, X.; Liu, D.; Li, F.; Ruan, H.; Jia, W. O e exp ession o Long Noncoding RNA PCAT-1 Is a No el Bioma ke
o Poo P ognosis in Pa ien s wi h Colo ec al Cance . Med. Oncol. 2013,30, 1–6. [C ossRe ] [PubMed]
44.
Kogo, R.; Shimamu a, T.; Mimo i, K.; Kawaha a, K.; Imo o, S.; Sudo, T.; Tanaka, F.; Shiba a, K.; Suzuki, A.; Komune, S.; e al. Long
Noncoding RNA HOTAIR Regula es Polycomb-Dependen Ch oma in Modi ica ion and Is Associa ed wi h Poo P ognosis in
Colo ec al Cance s. Cance Res. 2011,71, 6320–6326. [C ossRe ] [PubMed]
45.
Ling, H.; Spizzo, R.; A lasi, Y.; Nicoloso, M.; Shimizu, M.; Redis, R.S.; Nishida, N.; Ga à, R.; Song, J.; Guo, Z.; e al. CCAT2,
a No el Noncoding RNA Mapping o 8q24, Unde lies Me as a ic P og ession and Ch omosomal Ins abili y in Colon Cance .
Genome Res. 2013,23, 1446–1461. [C ossRe ]
46.
Jung, G.; He nández-Illán, E.; Mo ei a, L.; Balague , F.; Goel, A. Epigene ics o Colo ec al Cance : Bioma ke and The apeu ic
Po en ial. Na . Re . Gas oen e ol. Hepa ol. 2020,17, 111–130. [C ossRe ] [PubMed]
47.
Guinney, J.; Diens mann, R.; Wang, X.; De Reyniès, A.; Schlicke , A.; Soneson, C.; Ma isa, L.; Roepman, P.; Nyamundanda, G.;
Angelino, P.; e al. The Consensus Molecula Sub ypes o Colo ec al Cance . Na . Med. 2015,21, 1350–1356. [C ossRe ]
48.
Joani o, I.; Wi apa i, P.; Zhao, N.; Nawaz, Z.; Yeo, G.; Lee, F.; Eng, C.L.P.; Macalinao, D.C.; Kah aman, M.; S ini asan, H.; e al.
Single-Cell and Bulk T ansc ip ome Sequencing Iden i ies Two Epi helial Tumo Cell S a es and Re ines he Consensus Molecula
Classi ica ion o Colo ec al Cance . Na . Gene . 2022,54, 963–975. [C ossRe ]
49.
Zhu, J.; Shi, Z.; Wang, J.; Zhang, B. Empowe ing Biologis s wi h Mul i-Omics Da a: Colo ec al Cance as a Pa adigm. Bioin o ma ics
2015,31, 1436–1443. [C ossRe ]
