Malo olimbana ndi khansa: zolembera za khansa yapadziko lonse

KUONA KWA MINI

Malo olimbana ndi khansa: zolembera za khansa yapadziko lonse

Chengchen Qian1, Xiaolong Zou2, Wei Li1,3, Yinshan Li4, Wenqiang Yu5

1Shanghai Epiprobe Biotechnology Co., Ltd, Shanghai 200233, China;2 Dipatimenti ya Opaleshoni Yambiri, Chipatala Chothandizira Choyamba cha Harbin Medical University, Harbin 150001, China;3Shandong Epiprobe Medical Laboratory Co., Ltd, Heze 274108, China;Chipatala cha 4 cha People's cha Ningxia Hui Autonomous Region, Ningxia Medical University, Yinchuan 750002, China;5Shanghai Public Health Clinical Center & Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Laboratory of RNA Epigenetics, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China

ABSTRACT

Khansara ndiyomwe imayambitsa imfa padziko lonse lapansi.Kuzindikira khansara msanga kungachepetse kufa kwa mitundu yonse ya khansa;komabe, ma biomarker ozindikira mwachangu akusowa mitundu yambiri ya khansa.DNA methylation nthawi zonse yakhala chandamale chachikulu chifukwa DNA methylation nthawi zambiri imachitika zisanachitike kusintha kwina kwa majini.Pofufuza zomwe zimachitika kawirikawiri za khansa pogwiritsa ntchito kalozera wa kalozera wa DNA methylation, zolembera za khansa yapadziko lonse (UCOMs) zatulukira ngati ofuna amphamvu kuti azindikire khansara mwachangu komanso molondola.Ngakhale kufunikira kwachipatala kwamankhwala amakono a khansa kumachepetsedwa ndi kukhudzika kochepa komanso / kapena kutsika pang'ono, mawonekedwe apadera a UCOM amatsimikizira zotsatira zachipatala.Kutsimikizika kwa kuthekera kwachipatala kwa ma UCOM m'mapapo, khomo lachiberekero, endometrial, ndi khansa ya urothelial kumathandiziranso kugwiritsa ntchito ma UCOM mumitundu ingapo ya khansa komanso zochitika zosiyanasiyana zachipatala.M'malo mwake, kugwiritsa ntchito ma UCOM pakali pano akufufuzidwa mwachangu ndikuwunikiridwa koyambirira kwa khansa, kuzindikira kothandizira, kuthandizira kwamankhwala, komanso kuyang'anira kuyambiranso.Njira zamamolekyu zomwe UCOMs amazindikira khansa ndiyo mitu yofunika kufufuzidwa.Kugwiritsa ntchito ma UCOM pazochitika zenizeni padziko lapansi kumafunanso kukhazikitsidwa ndi kukonzanso.

MAWU AKUTI

Kuzindikira khansa;kuyezetsa khansa;DNA methylation;khansa epigenetics;khansa biomarkers

Chifukwa chake timafunikira zatsopano biomarkers?

Pambuyo polimbana ndi khansa kwa zaka zopitirira 100, khansa idakali chiwopsezo chakupha kwambiri kwa anthu.Khansara ikadali nkhawa padziko lonse lapansi chifukwa cha anthu 19.3 miliyoni omwe adadwala komanso kufa pafupifupi 10 miliyoni mchaka cha 20201.Kuphatikiza apo, anthu pafupifupi 3 miliyoni amafa chifukwa cha khansa ku China mu 2020, omwe anali 30% ya kufa padziko lonse lapansi chifukwa cha khansa.Ziwerengerozi zikuwonetsa kuti China ili pamalo oyamba pachiwonetsero komanso kufa kwa khansa.Kuphatikiza apo, chiwopsezo cha kupulumuka kwa khansa kwazaka 5 ndi 40.5%, chomwe ndi chotsika nthawi 1.5 kuposa chiwopsezo chazaka 5 ku United States2,3.Kutsika kocheperako komanso kufa kwachiwopsezo ku China kuposa mayiko omwe ali ndi ziwonetsero zapamwamba zachitukuko cha anthu kukuwonetsa kuti njira yothandiza komanso yotsika mtengo yopewera khansa komanso yowunika ndiyofunika mwachangu.Kuzindikira khansara koyambirira ndi chimodzi mwazinthu zofunika kwambiri pazachipatala.Kuzindikira khansara koyambirira kumatha kupangitsa kuti munthu azitha kudwala khansa komanso kupulumuka adakali aang'ono pafupifupi mitundu yonse ya khansa4.Njira zowunikira bwino zapangitsa kuti chiwerengero cha anthu odwala matenda a khansa ya pachibelekero, m'mawere, colorectal, ndi prostate chichepe kwambiri.

Komabe, kuti muzindikire khansara msanga si ntchito yophweka.Kufufuza zamoyo ndi momwe mungadziwire khansa yoyambirira, kuzindikira ndi kutsimikizira zolembera zodalirika zodziwira msanga, ndikupanga matekinoloje opezeka komanso olondola ozindikira msanga nthawi zonse zakhala zopinga zazikulu kwambiri pakuchitapo4.Kuzindikira bwino khansa kumatha kusiyanitsa zowopsa ndi zotupa, zomwe zimathandiza kupewa njira zosafunikira komanso kumathandizira kuwongolera matenda.Njira zamakono zodziwira msanga zikuphatikiza ma biopsies opangidwa ndi endoscope, kujambula kwachipatala, cytology, immunoassays, ndi mayeso a biomarker5-7.Pokhala olowerera komanso okwera mtengo, ma biopsies opangidwa ndi endoscope amanyamula katundu wolemetsa monga njira yayikulu yachipatala yodalira akatswiri.Monga cytology, njira zonse zowunikira zimadalira akatswiri azachipatala ndipo zimatengera kuweruza kwanu ndikuchita komwe sikuli koyenera8.Mosiyana ndi izi, kuyesa kwa ma immunoassays ndikolakwika kwambiri, chifukwa cha kuchuluka kwabodza.Kujambula kwachipatala, monga njira yowunikira, kumafunikira zida zodula komanso akatswiri apadera.Chifukwa chake, kujambula kwachipatala kumakhala kochepa kwambiri chifukwa cha kupezeka kochepa.Pazifukwa zonsezi, ma biomarkers amawoneka ngati njira yabwino yodziwira khansa.

Kulumikizana ndi: Yinshan Li ndi Wenqiang Yu

Email: liyinshan@nxrmyy.com and wenqiangyu@fudan.edu.cn

ORCID ID: https://orcid.org/0009-0005-3340-6802 ndi

https://orcid.org/0000-0001-9920-1133

Adalandira Ogasiti 22, 2023;anavomereza October 12, 2023;

yosindikizidwa pa intaneti Novembala 28, 2023.

Ipezeka pa www.cancerbiomed.org

©2023 Cancer Biology & Medicine.Creative Commons

Attribution-NonCommerce 4.0 International License

Ma biomarkers pakadali pano ali m'gulu la mapuloteni, zolembera za kusintha kwa DNA, zolembera epigenetic, zolakwika za chromosomal, zolembera za RNA zomwe zimachokera mwachindunji ku zotupa, kapena zidutswa za chotupa zomwe zimapezeka mwachindunji kuchokera kumadzi am'thupi.Zolemba zamapuloteni ndizomwe zimagwiritsidwa ntchito kwambiri pakuwunika khansa komanso kuzindikira.Ma protein biomarker, monga zowunikira zowunikira, amakhala ochepa chifukwa cha chizolowezi chokhudzidwa ndi zotupa zosawoneka bwino, zomwe zimatsogolera ku matenda opitilira muyeso komanso kumwa mopitirira muyeso, monga zanenedwa za α-fetoprotein ndi prostate-specific antigen (PSA)9,10.Zolemba za RNA zimaphatikizapo mawonekedwe a ma genetic ndi zolembera zina za RNA zosalemba. Kuphatikiza kwa zolembera za RNA zitha kudziwika pogwiritsa ntchito zitsanzo za mkodzo, kukhudzika kwake sikunali kokwanira (60%) kwa zotupa zoyambirira, komanso kuzindikira komwe kungathe. kukhudzidwa ndi kuwonongeka kosavuta kwa RNA mu chilengedwe11.Zolemba za genetic ndi epigenetic onse amakumana ndi vuto la kuchuluka kwa zotupa komanso kuchepetsa mitundu ya khansa.

DNA methylation yakhala ikudziwika kwambiri ngati njira yodziwira khansa kuyambira pamene Feinberg adalumikizidwa ndi khansa mu 198312. Kusokonezeka kwa DNA methylation kumawonedwa m'magawo onse a khansa, kumayambiriro kwa kansa.Aberrant DNA hypermethylation nthawi zambiri imachitika pazilumba za CpG mu olimbikitsa majini kuti athane ndi zotupa zotupa13,14.Kafukufuku wasonyezanso kuti DNA hypermethylation yachilendo imapangitsa kuti pakhale ndondomeko zoyendetsera chitukuko15.DNA methylation Valley, yomwe nthawi zambiri imagwirizanitsidwa ndi owongolera chitukuko ndi khansa ya hypermethylated, ikhoza kusintha mawonekedwe a jini kukhala njira yokhazikika yodalira DNA methylation ndi kuchepetsa kugwirizana kwa methylated histone H3K27me3 ndi mapuloteni ogwirizana ndi polycomb16,17.

Pakati pazolemba zambiri za DNA methylation zosindikizidwa, angapo adachita bwino pamsika;Komabe, zolembera zaposachedwa za DNA methylation ndi mapanelo owunikira sanatsegule mokwanira kuthekera kozindikira khansa pazifukwa zingapo18.Ngakhale nthawi zambiri amawonetsa magwiridwe antchito ovomerezeka pogwiritsa ntchito zidziwitso zapa database, ma biomarker awa nthawi zambiri samachita bwino mdziko lenileni chifukwa chakuti zitsanzo zenizeni nthawi zambiri zimakhala zovuta kwambiri ndipo sizimayimilira ngati zomwe zimasankhidwa pazosungidwa.Kuzindikira koyambirira kwa khansa ya m'badwo wotsatira kwawonetsedwa kuti kumangokhala ndi 16.8% ndi 40.4% kukhudzidwa mu gawo I ndi II khansa, motsatana19.Mayesero ozindikira msanga amafunikira kukhazikika kwakukulu komanso zolembera zolondola kwambiri.

Kupezeka kwa kansa ya Universal kokha (UCOM) pogwiritsa ntchito kalozera kalozera (GPS)

Ngakhale zaka makumi ambiri za kafukufuku wa khansa, kupewa ndi kuchiza kogwira mtima sikunachitike.Njira zatsopano zimafunikira kuti ofufuza athe kuunika bwinobwino khansa.Pazaka 23 zapitazi, zizindikiro 6 za khansa, monga kuthamangitsa apoptosis, kuukira kwa minofu & metastasis, ndi zina zambiri, zakulitsidwa mpaka 14 pophatikiza zinthu monga nonmutational epigenetic reprogramming ndi polymorphic microbiomes20,21.Pomwe zambiri zokhudzana ndi khansa zikuwululidwa, malingaliro ambiri amayambika pa kafukufuku wa khansa.Kafukufuku wa khansa pang'onopang'ono wayamba kukhala watsopano m'njira ziwiri (zachikhalidwe komanso payekha).Ndi chitukuko cha oncology yolondola m'zaka zaposachedwa, chidwi cha kafukufuku wa khansa chikutsamira pa chithandizo chamunthu payekha komanso kusiyanasiyana kwa khansa22.Chifukwa chake, zodziwika za khansa zomwe zadziwika posachedwa zayang'ana kwambiri mitundu ina ya khansa, monga PAX6 forcervical cancer23 ndi BMP3 ya colorectal cancer24.Kachitidwe ka ma biomarker awa okhudzana ndi mitundu ya khansa imasiyanasiyana, komabe sizingatheke kuti anthu omwe ali pachiwopsezo athe kuyezetsa makhansa onse nthawi imodzi chifukwa chochepetsa kutenga zitsanzo zamoyo komanso kukwera mtengo kwake.Zingakhale zabwino ngati titha kuzindikira chizindikiro chimodzi cholimba chomwe chili chothandiza pamitundu yonse ya khansa posachedwa.

Kuti mukwaniritse cholinga choyenera chotere, wochita bwino wa biomarker ayenera kusankhidwa pamndandanda wamitundu yomwe ingachitike.DNA methylation aberrations, pakati pa ma genetic ndi epigenetic mbiri, amadziwika kuti ndi okhudzana ndi khansa ndipo ndi ena mwazovuta zoyambirira, ngati si zoyambirira, zokhudzana ndi khansa zomwe zimachitika motsatira nthawi.Kufufuza kwa DNA methylation kunayamba msanga, koma kwalepheretsa kusowa kwa njira zofufuzira.Pakati pa malo 28 miliyoni omwe angakhale ndi methylated CpG mu genome, chiwerengero chotheka chiyenera kuzindikiridwa ndikugwirizana ndi genome kuti mumvetse bwino tumorigenesis.Whole genome bisulfite sequencing (WGBS), yomwe imatengedwa kuti ndi golide muyeso wa DNA methylation sequencing, imatha kuphimba 50% ya Cs m'maselo a khansa chifukwa chamankhwala a bisulfite omwe amaphwanya zidutswa za DNA ndikuchepetsa zovuta za genome panthawiyi. Kusintha kwa mtengo wa Cs-to-Ts25.Njira zina, monga tchipisi 450k, zimangophimba 1.6% ya genome methylation.Kutengera ndi data ya 450k, gulu la DNA methylation detection lili ndi 35.4% kukhudzidwa kwa mitundu 6 ya khansa ya siteji I26.Kuchepa kwa mitundu ya khansa, kusagwira bwino ntchito, komanso phokoso lomwe limapangidwa ndi njira zodziwira posanthula zakhala zopinga zazikulu kwambiri zamapulogalamu ozindikira khansa ya pan-cancer.

Kuti tifufuze bwino mawonekedwe a epigenetic a ma cell panthawi ya tumorigenesis ndi metastasis, tinapanga GPS yapadera yozindikira ma genome-wide DNA methylation, yomwe imakhudza mpaka 96% ya masamba a CpG mu 0.4 biliyoni owerenga25.GPS ndi njira yotsatizana yomwe imagwiritsa ntchito 3 ′ mapeto a DNA fragment ya non-convertible methyl-cytosines pambuyo pa mankhwala a bisulfite omwe amawongolera kuyanjanitsa kwa DNA methylation calculation of the 5′ end through pair-end sequencing (Chithunzi 1)25.Ulusi wotsogolera wa methyl-cytosine, womwe umakhala ngati chingwe cha template, umathandizira kulumikizana kwa chigawo chapamwamba cha GC chomwe chimapezanso deta yosiyidwa kwambiri mu WGBS yachikhalidwe.Mawonekedwe apamwamba a GPS amapereka chidziwitso chochuluka cha DNA methylation, chomwe chimatilola kufufuza mbiri ya khansa ya methylation ndi kusamvana kwakukulu m'madera omwe sanafufuzidwepo kale.

GPS imatipatsa chida champhamvu chofufuzira kuchuluka kwa khansa, zomwe zimatha kufewetsa kafukufuku wa khansa komanso kupeza kufotokozera kwapadziko lonse lapansi za tum- genesis ndi metastasis.Pamene tikusanthula deta ya GPS ya ma cell a khansa, chodabwitsa chapadera chinkachitika kawirikawiri.Panali zigawo zingapo zomwe zimawoneka ngati zachilendo hypermethylated m'mitundu ingapo ya zitsanzo za khansa.Zotsatira zosayembekezerekazi zidatsimikiziridwa kuti zikhale ngati ma UCOM.Zoposa 7,000 zitsanzo kuchokera ku mitundu 17 ya khansa mu nkhokwe ya Cancer Genome Atlas (TCGA) yawunikidwa, yomwe tidazindikira UCOM, HIST1H4F yoyamba, jini yokhudzana ndi histone yomwe imakhala ndi hypermethylated mumitundu yonse ya khansa27.Ma UCOM angapo adapezeka ndikutsimikiziridwa munkhokwe ya TCGA, database ya Gene Expression Omnibus (GEO), ndi zitsanzo zenizeni zachipatala.Pofika pano, HIST1H4F, PCDHGB7, ndi SIX6 zapezeka ndikutsimikiziridwa ngati UCOM.Kupezeka kosayembekezereka kwa ma UCOM kumapereka yankho lamphamvu pakufunika kozindikira khansa.Ma UCOM amapereka yankho pakuzindikiritsa chizindikiro chimodzi cha khansa zingapo.

Makhalidwe a UCOMs

Potsimikiziridwa, ma UCOM awonetsedwa kuti akuwonetsa zinthu zinayi zazikulu zomwe zimathandiza ma UCOM kupitilira mphamvu zama biomarkers apano (Chithunzi 2).

Wapadera ku malignancy

Ma UCOM ndi apadera ku zilonda za khansa kapena zisanachitike khansa ndipo samakhudzidwa ndi kusintha koyenera kwa thupi.Zina mwazolemba zaposachedwa zokhudzana ndi khansa zomwe zakhala zikugwiritsidwa ntchito kwambiri pakuzindikiridwa koyambirira komanso / kapena kuwunika zapangitsa kuti adziwe zambiri.Miyezo yokwera ya PSA, chida chovomerezeka chachipatala, imapezekanso m'mikhalidwe yabwino, monga prostate hyperplasia ndi prostatitis10.Kuzindikira mopitirira muyeso ndi kuchitiridwa mankhwala mopambanitsa kumabweretsa kutsika kwa moyo chifukwa cha matumbo, mkodzo, ndi zovuta zogonana28.Ma biomarker ena opangidwa ndi mapuloteni komanso omwe amagwiritsidwa ntchito kwambiri m'chipatala, monga CA-125, sanabweretse phindu lililonse pomwe akuyambitsa matenda opitilira muyeso komanso kumwa mopitirira muyeso29.Kukhazikika kwamphamvu kwa ma UCOM pamatenda owopsa kumapewa zoperewerazi.UCOM, PCDHGB7, imasiyanitsa bwino zotupa za squamous intraepithelial (HSILs) ndi khansa ya khomo pachibelekero kuchokera ku zitsanzo zabwinobwino komanso zotupa zotsika kwambiri za squamous intraepithelial (LSILs), pomwe zolembera zina zambiri zimatha kusiyanitsa khansa ya khomo lachiberekero ndi zitsanzo zanthawi zonse30.Ngakhale PCDHGB7 sizindikira kusiyana kwakukulu pakati pa endometrium yachibadwa ndi endometrial hyperplasia, kusiyana kwakukulu kumadziwika pakati pa endometrium wamba ndi atypical hyperplasia, ndipo kusiyana kwakukulu kumazindikirika pakati pa endometrium ndi khansa ya endometrial (EC) yotengera PCDHGB731.Ma UCOM ndi apadera ku zotupa zowopsa m'malo osungira komanso zitsanzo zachipatala.Malinga ndi momwe wodwalayo amaonera, ma UCOM apadera amachepetsa mwayi womvetsetsa zovuta zamitundu yosiyanasiyana yosakhazikika yosakhazikika komanso nkhawa zomwe zimayenderana pakuwunika.Malinga ndi chipatala, ma UCOM apadera amasiyanitsa matenda owopsa ndi zilonda zam'mimba, zomwe zimathandiza pakuyesa odwala ndikuchepetsa njira zamankhwala zosafunikira komanso kuchulukitsa.Chifukwa chake, ma UCOM apadera amachepetsa kuchepetsedwa kwa machitidwe azachipatala, kuchepetsa kupsinjika kwa dongosolo, ndikupangitsa kuti chithandizo chamankhwala chipezeke kwa omwe akufunika.

Chithunzi 1 Schematic of GPS workflow for DNA methylation discovery25.Mzere wotuwa: kulowetsa kwa DNA;mzere wofiira: DNA yothandizidwa ndi T4 DNA polymerase, m'malo mwa cytosine ndi 5'-methylcytosine pamapeto a 3';blue C ndi Ine: methylated cytosine;blue C: unmethylated cytosine;yellow T: thymine25.

Zonse kapena ayi

Ma UCOM amapezeka m'maselo a khansa ndipo amapezeka pafupifupi pafupifupi ma cell onse a khansa.HIST1H4F idatsimikiziridwa kuti ndi hypermethylated pafupifupi mitundu yonse ya chotupa koma osati mu zitsanzo zabwinobwino27.Mofananamo, PCDHGB7 ndi SIX6 zasonyezedwanso kuti ndi hypermethylated mu zitsanzo zonse za chotupa koma osati mu zitsanzo zabwinobwino30-32.Makhalidwe apaderawa amathandizira kwambiri magwiridwe antchito a UCOM pokhudzana ndi malire a kuzindikira ndi kuzindikira.Ochepa ngati 2% ya maselo a khansa amatha kusiyanitsidwa ndi zitsanzo, zomwe zimapangitsa ma UCOM kukhala ozindikira kwambiri kuposa ma biomarker ambiri omwe alipo30. Monga chizindikiro chomwe chimagwiritsidwa ntchito pozindikira khansa yapakhungu, masinthidwe a KRAS amapezeka pafupifupi 36% ya khansa yapakhungu. kuwonetsa kuthekera koperewera kwa matenda33.Kuchepa kwa kusintha kwa KRAS mu khansa ya colorectal kumalepheretsa KRAS kuphatikiza ndi ma biomarker ena.M'malo mwake, kuphatikiza kwa ma biomarker kumatha kuwoneka ngati kolimbikitsa poyambilira, koma sikuti nthawi zonse kumabweretsa zotsatira zokhutiritsa pomwe kukuwonetsa phokoso lalikulu pakuwunika kozindikira ndipo nthawi zambiri kumafuna njira zoyesera zovuta.Mosiyana ndi izi, PCDHGB7 ndi ma UCOM ena amapezeka m'makhansa onse.Ma UCOM amazindikira omwe ali ndi khansa m'mitundu yosiyanasiyana ya khansa mwatsatanetsatane kwinaku akuchotsa njira zovuta zowunikira phokoso-kuletsa.Sizovuta kuzindikira khansa mu zitsanzo zambiri, koma ndizovuta kwambiri kuzindikira khansara pang'ono.Ma UCOM amatha kuzindikira zocheperako za khansa.

Chithunzi 2 Makhalidwe a UCOMs.

Kuzindikira khansa kusanachitike kusintha kwa pathological

Ma UCOM amatha kudziwika panthawi ya khansa isanayambe kusintha kwa ma pathological.Monga epigenetic biomarkers, zolakwika za UCOM zimachitika m'mbuyomu kuposa zovuta za phenotypic ndipo zimawonekera mu tumorigenesis, kupita patsogolo, ndi metastasis34,35.Kukhudzika kwa UCOM pakapita nthawi kumakulitsa magwiridwe antchito a UCOM pozindikira khansa yoyambirira komanso zotupa za khansa.Kuzindikira khansa yoyambirira yotengera biopsies ndi cytology kungakhale kovuta kwa ngakhale akatswiri odziwa bwino za matenda.Biopsy imodzi yopezedwa kudzera mu colposcopy yanenedwa kuti ndi yabwino mu 60.6% ya zitsanzo za HSIL+.Ma biopsies owonjezera amafunikira kuti zilonda zambiri ziwonjezere kukhudzidwa36.Mosiyana ndi izi, UCOM, PCDHGB7, ili ndi mphamvu ya 82% ya zitsanzo za HSIL +, kupitirira kukhudzidwa kwa biopsies ndi biomarkers30.Chizindikiro cha methylation, FAM19A4, chili ndi kukhudzika kwa 69% kwa CIN2 +, komwe kuli kofanana ndi cytology, koma sikungathe kusiyanitsa CIN1 kuchokera ku zitsanzo zabwinobwino37.Ma UCOM awonetsedwa kuti ndiwodziwika kwambiri pozindikira msanga.Poyerekeza ndi akatswiri odziwa zachipatala, ma UCOMs ali ndi chidziwitso chodziwika bwino cha khansa yoyambilira, zomwe zimapangitsa kuti pakhale chitukuko cha khansa komanso kupulumuka30.Kuphatikiza apo, ma UCOMs amapereka nsanja yodziwira yomwe imapezeka kumadera opanda akatswiri odziwa za matenda ndipo imathandizira kwambiri kuzindikira.Pogwiritsa ntchito zitsanzo zofanana ndi njira zodziwira, kuzindikira kwa UCOM kumabweretsa zotsatira zokhazikika komanso zosavuta kumasulira zomwe zimagwirizana bwino ndi ndondomeko yowunikira yomwe imafuna akatswiri ochepa komanso azachipatala.

Zosavuta kuzizindikira

Njira zamakono zodziwira DNA methylation ndizovuta komanso zimatenga nthawi.Njira zambiri zimafuna kusintha kwa bisulfite, zomwe zimayambitsa kutayika kwa khalidwe lachitsanzo ndipo mwinamwake zimapanga zotsatira zosakhazikika komanso zolakwika.Kusabereka bwino komwe kumachitika chifukwa cha chithandizo cha bisulfite kungayambitse chisokonezo kwa madokotala ndi odwala ndikusokonezanso njira zotsatiridwa ndi / kapena chithandizo.Chifukwa chake, tidasinthanso njira yodziwira UCOM kuti tipewe zovuta za mankhwala a bisulfite a zitsanzo, kutengera zofunikira zachipatala, ndikuwonjezera kupezeka.Tinapanga njira yatsopano yogwiritsira ntchito ma methylation-sensitive restriction enzymes kuphatikiza ndi nthawi yeniyeni ya fluorescent quantitative PCR (Me-qPCR) kuti tidziwe momwe ma UCOM ali ndi methylation mkati mwa 3 h pogwiritsa ntchito njira zosavuta (Chithunzi 3).Me-qPCR imatha kukhala ndi mitundu ingapo, monga kusonkhanitsa kwachipatala kwa matenda a chimfine ndi mikodzo yodzitolera yokha.Zitsanzo zachipatala zomwe zasonkhanitsidwa zitha kukonzedwa, kusungidwa, ndikupitilirabe kuzizindikira pogwiritsa ntchito DNA yokhazikika komanso yodzipangira yokha.DNA yochotsedwayo imatha kugwiritsidwa ntchito mwachindunji papulatifomu ya Me-qPCR kuti ipangitse mphika umodzi ndi zotsatira za kuchuluka kwa zotsatira.Pambuyo pa kusanthula kosavuta kwa zotsatira pogwiritsa ntchito njira zodziwira matenda zomwe zimayikidwa ndikutsimikiziridwa ku mitundu ina ya khansa, kutsimikiza komaliza kwa zotsatira zodziwika za UCOM kumatanthauziridwa ndikuwonetsedwa ngati mtengo wochepa.Pulatifomu ya Me-qPCR imaposa njira yachikhalidwe ya bisulfite-pyrosequencing pozindikira UCOM ndikusunga 3 h ofbisulfite kutembenuka, malinga ndi EZ DNA Methylation-Gold kit protocol.Njira yatsopano yodziwira methylation imapangitsa kuzindikira kwa UCOM kukhala kokhazikika, kolondola, komanso kupezeka30.

Chithunzi 3 Njira yodziwira ma UCOM.Mitundu ya zitsanzo imaphatikizapo BALF, burashi ya Pap, ndi/kapena mkodzo wodzitolera wokha.Njira yochotsera DNA imatha kukhala ndi chotsitsa chodziwikiratu, chomwe chimatha kudziwika mwachindunji ndi qPCR.

Kugwiritsa ntchito ma UCOM

Khansa ya m'mapapo

Khansara ya m'mapapo ndi khansa yachiwiri yomwe imapezeka kawirikawiri komanso yakupha kwambiri padziko lonse lapansi, yomwe imapangitsa 11.4% ya odwala atsopano ndi 18.0% ya imfa zatsopano1.Pakati pa matenda onse, 85% ndi khansa ya m'mapapo yosakhala yaying'ono (NSCLC) ndipo 15% ndi khansa yaing'ono ya m'mapapo (SCLC), yomwe ili ndi matenda ambiri38.Kusanthula kwa mlingo wochepa wa computed tomography (LDCT) ndiyo njira yomwe ikulimbikitsidwa pakali pano yowunikira khansa ya m'mapapo ndipo yasonyezedwa kuti imathandizira kuzindikira msanga ndi kuchepetsa imfa6;komabe, chifukwa chochepa kwambiri komanso kusapezeka bwino, LDCT sinakhalebe njira yokhutiritsa yoyezetsa, monganso zizindikiro zina za khansa, monga CEA39.Mtengo ndi kuthekera kwa matenda omwe adaphonya komanso kusazindikira bwino kwa njira yowunikira ya LDCT kumalepheretsa kupita patsogolo kwa kuyezetsa khansa ya m'mapapo40.HIST1H4F, UCOM, ili ndi kuthekera kokulirapo ngati chodziwikiratu msanga mu zitsanzo za bronchoalveolar fluid (BALF)27.HIST1H4F ndi hypermethylated mu lung adenocarcinoma ndi lung squamous cell carcinoma, yodziwika bwino ya 96.7% ndi kukhudzika kwa 87.0% (Chithunzi 4A), ndi ntchito yapadera ya khansa ya siteji I27.HIST1H4F ili ndi chidziwitso cha 96.5% ndi kukhudzika kwa 85.4% kwa NSCLC, ndi 96.5% ndi 95.7%, motero, kwa SCLC27.Kuphatikiza apo, zitsanzo za mitundu ina isanu ndi itatu ya khansa, kuphatikiza khansa ya kapamba ndi colorectal, zatsimikizira kuti HIST1H4F ndi hypermethylated m'mitundu yonse eyiti27.

Khansa ya khomo lachiberekero

Khansara ya pachibelekero inali yachinayi yomwe imapezeka kawirikawiri ndi khansa komanso yachinayi yomwe imayambitsa kufa kwa khansa mwa amayi mu 2020, yomwe ikuwerengera 3.1% ya odwala atsopano ndi 3.4% ya imfa zokhudzana ndi khansa padziko lonse1.Pofuna kuthetsa khansa ya khomo lachiberekero pofika chaka cha 2030, monga momwe bungwe la WHO linanenera, kutulukira msanga kwa khansa ya pachibelekero ndikofunikira.Ngati atadziwika adakali aang'ono, kupulumuka kwa zaka 5 kumafika 92% ndi khansa ya pachibelekero41.Malangizo a American Cancer Society (ACS) akuwonetsa mayeso a cervical cytology, mayeso oyambira a HPV, kapena mayeso owunika42.Cervical cytology ndi yosokoneza ndipo imatha kuzindikira 63.5% ya CIN2+ kesi37.

PCDHGB7, mosiyana, yachita bwino kwambiri pogwiritsa ntchito mayeso a Pap ndi ukazi, ndipo imatha kusiyanitsa bwino HSIL ndi LSIL poyambirira kwambiri.PCDHGB7 yokha ili ndi mphamvu ya 100.0% ndi 88.7% ya khansa ya khomo lachiberekero (Chithunzi 4B), ndi 82.1% sensitivity ndi 88.7% yeniyeni ya HSIL + zitsanzo30.PCDHGB7 ilinso ndi 90.9% sensitivity ndi 90.4% yeniyeni mu zitsanzo za ukazi wa khansa ya khomo lachiberekero, zomwe zimakhala zosavuta kuzisonkhanitsa30.Ikaphatikizidwa ndi mayeso owopsa kwambiri (hr) HPV kapena Thinprep Cytology Test (TCT), PCDHGB7 imakhala ndi chidwi chowonjezeka cha 95.7% ndi kutsimikizika kwa 96.2%, kupitilira kuyesa kwa hrHPV (20.3%),TCT (51.2% ), ndi awiriwo pamodzi (57.8%) a khansa ya pachibelekero30.PCDHGB7 yasonyezedwanso kuti ili ndi hypermethylated mu mitundu ya khansa ya 17 kuchokera ku database ya TCGA, kusonyeza kuyenerera kwake mu banja la UCOM30.

Chithunzi 4 UCOMs zatsimikiziridwa mu mitundu inayi ya khansa mu maphunziro akuluakulu azachipatala.A. Kuchita kwa HIST1H4F, UCOM, pozindikira khansa ya m'mapapo ya zitsanzo 508.B. Magwiridwe a PCDHGB7, UCOM, pozindikira khansa ya chiberekero cha 844 zitsanzo.C. Magwiridwe a PCDHGB7, UCOM, pozindikira khansa ya endometrial ya 577 endometrial Pap ndi Tao brush zitsanzo.D. Magwiridwe a SIX6, UCOM, mu kuzindikira khansa ya urothelial ya zitsanzo za 177.

EC

EC ndi imodzi mwamatenda a khansa omwe amapezeka kwambiri padziko lonse lapansi, ndipo akuti pafupifupi 4.2 miliyoni amadwaladwala ndi 1% ya matenda obwera chifukwa cha khansa chaka chilichonse.Ndi matenda odziwika bwino atangotsala pang'ono, EC ndi yochiritsika ndipo imakhala ndi zaka 5 za moyo wa 95% pa khansa ya siteji yoyamba.Odwala omwe ali ndi zizindikiro, monga kutuluka kwa magazi m'chiberekero, amapimidwa nthawi ndi nthawi ndikuchitidwa njira zopweteka komanso zowawa za biopsy, ngakhale 5% -10% yokha imayamba kupanga EC43.Transvaginal ultra-sound, monga njira yodziwikiratu, ndiyosadalirika kwambiri chifukwa cholephera kusiyanitsa zowopsa ndi kusintha koyipa kwa endometrical ndi kuchuluka kwabodza kwabodza44.

Kuyerekeza kofananira kwa seramu CA-125, EC biomarker yogwiritsidwa ntchito kwambiri, ndi PCDHGB7 idachitidwa.Seramu ya CA-125 inali ndi chidwi cha 24.8%, zomwe zikusonyeza kuti CA-125 ndi chizindikiro chosakwanira cha EC ngakhale kuti 92.3% 31 ndi yeniyeni.Kuzindikira kwa PCDHGB7 pogwiritsa ntchito zitsanzo za burashi ya Pap kunapangitsa chidwi cha 80.65% komanso kutsimikizika kwa 82.81% kwa magawo a ECatall, pomwe burashi ya Tao inali ndi mphamvu ya 61.29% ndi 95.31% 31.PCDHGB7 diagnostic model, yochokera ku Me-qPCR, inapereka mphamvu ya 98.61%, yeniyeni ya 60.5%, ndi kulondola kwathunthu kwa 85.5%, pogwiritsa ntchito zitsanzo za Pap ndi Tao brush (Chithunzi 4C)31.

Khansara ya urothelial

Khansara ya urothelial, yopangidwa ndi chikhodzodzo, aimpso, ndi khansa ya mkodzo, inali khansa yachisanu ndi chiwiri yomwe imapezeka kawirikawiri mu 2020 padziko lonse lapansi, kuchititsa 5.2% ya milandu yatsopano ndi 3.9% yakufa1.Makhansa a urothelial, opitilira 50% omwe ndi khansa ya m'chikhodzodzo, anali khansa yachinayi yomwe idapezeka pafupipafupi ku United States mu 2022, zomwe zidapangitsa 11.6% ya omwe adapezeka kumene.Pafupifupi 75% ya khansa ya m'chikhodzodzo imatchedwa khansa ya m'chikhodzodzo yopanda minofu yomwe imangokhala mucosa kapena submucosa45.cystoscopy biopsy ndiye muyeso wagolide wozindikira khansa ya urothelial yokhazikitsidwa ndi fluorescence in situ hybridization (FISH) ndi mayeso a cytology.NSOMBA ndi cytology zimakhala ndi matenda osadziwika bwino, ndipo cystoscopy ndi intrusive ndipo imakhala ndi chiopsezo chachikulu chosowa ma microlesions, kutanthauzira molakwika zilonda, komanso zomwe zingayambitse kufalikira kapena kubwereranso kwa khansa46.UCOM, PCDHGB7 yomwe idatsimikiziridwa kale, idawonetsedwanso kuti ili ndi hypermethylated mu khansa ya urothelial, yomwe ili pansi pa 0.86, zomwe zikuwonetsa kuthekera kozindikira30.Pofuna kutsimikiziranso ma UCOM ochulukirapo komanso kutengera mitundu yambiri ya zitsanzo, SIX6, buku la UCOM, idawunikidwa ndikuwonetsa kuthekera kodziwikiratu koyambirira kwa khansa ya urothelial pogwiritsa ntchito zitsanzo za mkodzo papulatifomu ya Me-qPCR.Kuzindikira kwa SIX6 pogwiritsa ntchito zitsanzo za mkodzo kunawonetsa kukhudzika kwa 86.7% ndi kutsimikizika kwa 90.8% (Chithunzi 4D), pomwe kunali kosasokoneza komanso kosavuta kupeza32.Kuthekera kwa SIX6 pakuwunika kwa metastasis ndikuwunika momwe chithandizo chikuyendera chikufufuzidwa.

Tsogolo ndi zovuta

Ma UCOM achita bwino kwambiri pakuzindikira matenda a khansa angapo, koma pali ntchito yambiri yoti ichitike.Takhala tikukulitsa mndandanda wa ma UCOM ndipo takhala tikutsimikizira mwachangu ma UCOM mumitundu yambiri ya khansa, kuphatikiza zomwe mwachizolowezi zimakhala zovuta kuzizindikira.Zotsatira zotsimikizika kuchokera ku nkhokwe za TCGA zatsimikiziranso kagwiritsidwe ntchito ka ma UCOM pamitundu yambiri ya khansa ndi zina zambiri.Pakufufuza koyambirira, ma UCOM awonetsedwa kuti ali ndi kuthekera kodziwikiratu kwa cholangiocarcinomas ndi pancreatic adenocarcinomas, zomwe ndizosatheka kuzizindikira posachedwa ndi njira zowonera32,47.Kutha kuzindikira makhansa osowa ndi ma UCOM atha kugwiritsidwa ntchito ndi chotupa chozungulira DNA (ctDNA) ndi nsanja yamadzimadzi ya biopsy48.Kafukufuku wokhudza gulu lozindikira khansa ya plasma ya DNA adawonetsa chidwi cha 57.9% 49.Ngakhale kuti ndizodziwika kwambiri, ntchito yonseyi imasonyeza kuti pali malo oti asinthe.

Makhalidwe apadera a UCOM athandiziranso kufufuzidwa kwa kuthekera kwa UCOM pakuwunika momwe chithandizo chikuyendera komanso kuyang'anira mobwerezabwereza.Malinga ndi Response Evaluation Criteria in Solid Tumors (RECIST), kuyerekeza kwachipatala ndi njira yovomerezeka yowunika kachiromboka komanso kuwunika momwe chithandizo chamankhwala chikugwirira ntchito, pomwe zolembera zotupa zimagwiritsidwa ntchito paokha pakuwunika50.Zoona zake, komabe, njira zowonera zimakhudzidwa kwambiri ndi kuchuluka kwa nthawi komanso nthawi, motero zimayika odwala pachiwopsezo chachikulu komanso mtengo51,52.SIX6 yatsimikiziridwa kuti ikhale yolosera za khansa ya m'mawere metastasis32.Liquid biopsy-based ctDNA monitoring imathandizira kuyang'anira nthawi yeniyeni pamatenda otsalira ochepa miyezi ingapo isanadziwike ndi radiologic, kuchedwetsa ndikupewa kufalikira kwa khansa yokhudzana ndi kuyambiranso53.Zotsatira zoyambira zikuwonetsa kuti ma UCOM amawonetsa kuchuluka kwa hypermethylation ya khansa munthawi yeniyeni atangochitidwa opaleshoni ndi chithandizo32.Kukhudzika kwakukulu komwe kumawonetsedwa ndi ma UCOM komanso kugwiritsa ntchito mitundu ingapo yosaphatikizika kumalola ma UCOM kukhala ngati njira yowunikira momwe zinthu zikuyendera ndikusungabe kumvera kwa odwala.

Panthawi imodzimodziyo, kupezeka kwa anthu ku mayesero ndi nkhani ina yaikulu yomwe imafuna khama lowonjezera.Ngakhale kuti mgwirizano wodziwikiratu wa UCOM wavomerezedwa m'zipatala zambiri ndikuyembekeza kupindulitsa odwala ambiri, kuzindikira ndi kuwunika kwa pro bono kwachitika mwachangu kumidzi yaku China.Ma UCOM amafunikira kuti athe kupezeka mosavuta kuti akhale chida chowunikira, makamaka kumadera osatukuka.

Ngakhale ntchito ya UCOM imapangitsa kuti anthu adziwike koyambirira ndikulonjeza, zambiri zosadziwika za UCOM zilipo.Ndi kufufuza mwakhama, kufufuza kwina kuli koyenera chifukwa chake ma UCOM amapezeka mu khansa.Njira zoyendetsera epigenetic zomwe zimakhazikitsidwa ndi UCOM ndizoyenera kufufuzidwanso, zomwe zingapangitse njira yatsopano yochizira khansa.Kubwereranso kumasewera pakati pa tumor homogeneity ndi heterogeneity, tili ndi chidwi chifukwa chomwe ma UCOM atha kukhala osiyana ndi ambiri a khansa omwe amalumikizana kwambiri ndi mitundu ina ya khansa.Udindo wa UCOM-identified DNA methylation aberrations mu tumorigenesis, kukula kwa chotupa, ndi metastasis sichinadziwike pakutaya ndi kubwezeretsanso kudziwika kwa maselo ndipo kumafunika kuunika bwino.Chidwi chinanso chagona pakukula kwa kuphatikizika kwa ma UCOM okhala ndi zolembera zapadera za minofu ndikuyembekeza kuyandikira kuzindikirika bwino kwa kansalu ndikuzindikiritsa komwe minofu ya chotupa imayambira.Ma UCOM amatha kukhala chida chabwino chopewera khansa, kuzindikira khansa, komanso kuteteza ndikuchotsa khansa.

Perekani thandizo

Ntchitoyi inathandizidwa ndi National Key R&D Programme ya China (Grant No. 2022BEG01003), National Natural Science Foundation of China (Grant Nos. 32270645 ndi 32000505), Grant kuchokera ku Heilongjiang Provincial Health Commission (Grant No. 2020-111) , ndi Ndalama yochokera ku Heze Science and Technology Institute (Grant No. 2021KJPT07).

Kutsutsana kwa chiwongola dzanja

Wei Li ndi Mtsogoleri wa R&D wa Shanghai Epiprobe Biotechnology Co., Ltd. Wenqiang Yu amagwira ntchito ku Scientific Advisory Board ya Epiprobe.W. Yu ndi Epiprobe avomereza ma patent omwe akudikirira okhudzana ndi ntchitoyi.Olemba ena onse amalengeza kuti palibe zokonda zopikisana.

Zopereka za olemba

Anapanga ndi kupanga polojekitiyi: Chengchen Qian ndi Wenqiang Yu.

Analemba pepala: Chengchen Qian.

Anapanga mafanizo: Chengchen Qian.

Adawunikiranso ndikusintha zolemba: Xiaolong Zou, Wei Li, Yinshan Li ndi Wenqiang Yu.

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doi: 10.20892/j.issn.2095-3941.2023.0313