nkhani

M'zaka khumi zapitazi, ukadaulo wotsata ma gene wakhala ukugwiritsidwa ntchito kwambiri pakufufuza za khansa komanso machitidwe azachipatala, kukhala chida chofunikira chowululira mawonekedwe a khansa. Kupita patsogolo pakuzindikira kwa ma cell ndi chithandizo chomwe chaperekedwa kwalimbikitsa kukhazikitsidwa kwa malingaliro ochiritsira chotupa ndikubweretsa kusintha kwakukulu pagawo lonse la matenda ndi chithandizo cha chotupa. Kuyeza kwa majini kungagwiritsidwe ntchito kuchenjeza za chiopsezo cha khansa, kutsogolera zosankha za chithandizo ndikuwunika momwe matendawa angakhalire, ndipo ndi chida chofunikira chothandizira kusintha zotsatira zachipatala za odwala. Apa, tikufotokozera mwachidule nkhani zaposachedwa zomwe zafalitsidwa mu CA Cancer J Clin, JCO, Ann Oncol ndi magazini ena kuti awonenso momwe kuyezetsa ma genetic pakuzindikira ndi kuchiza khansa.

Kusintha kwa Somatic ndi kusintha kwa majeremusi. Nthawi zambiri, khansa imayamba chifukwa cha kusintha kwa DNA komwe kumatha kutengera makolo (kusintha kwa majeremusi) kapena kupezeka ndi zaka (somatic mutations). Kusintha kwa majeremusi kumakhalapo kuyambira kubadwa, ndipo mutator nthawi zambiri amanyamula masinthidwe a DNA a selo lililonse m'thupi ndipo amatha kuperekedwa kwa ana. Masinthidwe a Somatic amapezedwa ndi anthu omwe ali m'maselo omwe si a gametic ndipo nthawi zambiri samaperekedwa kwa ana. Kusintha kwa majeremusi ndi somatic kumatha kuwononga magwiridwe antchito a cell ndikupangitsa kusintha koyipa kwa maselo. Kusintha kwa Somatic ndiye dalaivala wamkulu wa zoyipa komanso zolosera zam'tsogolo kwambiri mu oncology; komabe, pafupifupi 10 mpaka 20 peresenti ya odwala chotupa amanyamula masinthidwe a majeremusi omwe amawonjezera kwambiri chiopsezo cha khansa, ndipo ena mwa masinthidwewa ndi achire.
Kusintha kwa oyendetsa ndi kusintha kwa okwera. Sikuti mitundu yonse ya DNA imakhudza magwiridwe antchito a cell; pafupifupi, zimatengera zisanu kapena khumi zochitika genomic, otchedwa "madalaivala masinthidwe," kuyambitsa yachibadwa alibe selo. Kusintha kwa madalaivala nthawi zambiri kumachitika m'majini ogwirizana kwambiri ndi zochitika za moyo wa maselo, monga majini omwe amakhudzidwa ndi kayendetsedwe ka kukula kwa maselo, kukonza DNA, kuwongolera kayendedwe ka maselo ndi njira zina zamoyo, ndipo amatha kugwiritsidwa ntchito ngati zochizira. Komabe, chiwerengero chonse cha masinthidwe a khansa iliyonse ndi yayikulu kwambiri, kuyambira masauzande angapo a khansa ya m'mawere mpaka 100,000 mu khansa ya colorectal ndi endometrial. Zosintha zambiri zimakhalabe kapena zilibe tanthauzo lachilengedwe, ngakhale masinthidwewo achitika m'chigawo cholembera, zochitika zosafunikira zotere zimatchedwa "kusintha kwapaulendo". Ngati kusintha kwa majini mumtundu wina wa chotupa kuneneratu kuyankha kwake kapena kukana chithandizo chamankhwala, kusiyanako kumawonedwa kuti ndi kothandiza.
Oncogenes ndi chotupa suppressor majini. Majini omwe amasinthidwa pafupipafupi mu khansa amatha kugawidwa m'magulu awiri, ma oncogenes ndi genes suppressor chotupa. M'maselo abwinobwino, mapuloteni omwe amapangidwa ndi ma oncogene makamaka amathandizira kulimbikitsa kuchuluka kwa ma cell ndikuletsa ma cell apoptosis, pomwe puloteni yomwe imapangidwa ndi jini ya oncosuppressor imayang'anira molakwika kugawikana kwa ma cell kuti maselo azikhala bwino. Pakusintha koyipa, kusintha kwa ma genomic kumabweretsa kupititsa patsogolo ntchito ya oncogene komanso kuchepa kapena kutayika kwa jini ya oncosuppressor.
Kusintha kwakung'ono ndi kusiyanasiyana kwamapangidwe. Awa ndi mitundu iwiri ikuluikulu ya masinthidwe mu genome. Mitundu yaying'ono imasintha DNA posintha, kufufuta, kapena kuwonjezera zoyambira pang'ono, kuphatikiza kuyika maziko, kufufutidwa, kufufuta, kuyambitsa kutayika kwa kodon, kuyimitsa kutayika kwa ma codon, ndi zina zambiri. kutembenuka kapena kusamutsa. Kusintha kumeneku kungayambitse kuchepetsa kapena kupititsa patsogolo ntchito ya mapuloteni. Kuphatikiza pa kusintha pamlingo wa majini amtundu uliwonse, ma signature a genomic nawonso ndi gawo la malipoti otsatizana azachipatala. Ma signature a genomic amatha kuwonedwa ngati njira zovuta zamitundu yaying'ono komanso/kapena yamagulu, kuphatikiza chotupa mutation load (TMB), microsatellite instability (MSI), ndi zolakwika za homologous recombination.

Kusintha kwa Clonal ndi subclonal mutation. Kusintha kwa ma clonal kumachitika m'maselo onse a chotupa, amapezeka pakuzindikiridwa, ndipo amakhalabepo chithandizo chikapita patsogolo. Chifukwa chake, kusintha kwa ma clonal kumatha kugwiritsidwa ntchito ngati zochizira zotupa. Ma subclonal masinthidwe amapezeka m'magulu ang'onoang'ono a khansa ndipo amatha kudziwika kumayambiriro kwa matenda, koma amatha ndi kubwereza kapena kuwonekera pambuyo pa chithandizo. Cancer heterogeneity imatanthawuza kukhalapo kwa masinthidwe angapo a subclonal mu khansa imodzi. Zachidziwikire, kusintha kwakukulu komwe kumayambitsa khansa pamitundu yonse ya khansa ndikusintha kwamtundu wa clonal ndipo kumakhala kosasunthika panthawi yonse ya khansa. Kukaniza, komwe nthawi zambiri kumalumikizidwa ndi ma subclones, sikungadziwike panthawi ya matendawa koma kumawoneka ngati kuyambiranso pambuyo pa chithandizo.

Njira yachikhalidwe FISH kapena cell karyotype imagwiritsidwa ntchito kuzindikira kusintha kwa chromosomal. NSOMBA zitha kugwiritsidwa ntchito kuzindikira kuphatikizika kwa majini, kufufutidwa, ndi kukulitsa, ndipo imatengedwa ngati "golide" wozindikira mitundu yotere, yolondola kwambiri komanso yachidziwitso koma kutulutsa kochepa. M'matenda ena a hematologic, makamaka acute leukemia, karyotyping imagwiritsidwabe ntchito kutsogolera matenda ndi matenda, koma njira iyi imasinthidwa pang'onopang'ono ndi kuyesa kwa maselo monga FISH, WGS, ndi NGS.
Kusintha kwa majini pawokha kumatha kuzindikirika ndi PCR, PCR yeniyeni yeniyeni ndi PCR drop drop. Njirazi zimakhala ndi chidziwitso chapamwamba, ndizoyenera kwambiri kuti zizindikire ndi kuyang'anira zilonda zazing'ono zotsalira, ndipo zimatha kupeza zotsatira mu nthawi yochepa kwambiri, choyipa ndi chakuti chiwerengero chodziwikiratu chimakhala chochepa (kawirikawiri amangozindikira kusintha kwa jini imodzi kapena pang'ono), ndipo kuthekera kwa mayesero angapo ndi ochepa.
Immunohistochemistry (IHC) ndi chida chowunikira chomwe chimagwiritsidwa ntchito ndi mapuloteni omwe amagwiritsidwa ntchito kwambiri kuti azindikire mawonekedwe a biomarkers monga ERBB2 (HER2) ndi ma estrogen receptors. IHC itha kugwiritsidwanso ntchito kuzindikira mapuloteni osinthika (monga BRAF V600E) ndi ma gene fusions (monga ma ALK fusions). Ubwino wa IHC ndikuti ukhoza kuphatikizidwa mosavuta mu ndondomeko yowunikira minofu, kotero ikhoza kuphatikizidwa ndi mayesero ena. Kuphatikiza apo, IHC ikhoza kupereka zambiri pazambiri zama protein a subcellular. Zoyipa zake ndizochepa scalability ndi zofuna mkulu bungwe.
Sequencing wachiwiri (NGS) NGS amagwiritsa ntchito njira zotsatizana zotsatizana kwambiri kuti azindikire kusiyana kwa DNA ndi / kapena RNA. Njirayi ingagwiritsidwe ntchito kutsata ma genome onse (WGS) ndi madera osangalatsa a jini. WGS imapereka chidziwitso chokwanira kwambiri cha kusintha kwa ma genomic, koma pali zopinga zambiri pakugwiritsa ntchito kwake kuchipatala, kuphatikiza kufunikira kwa zitsanzo zatsopano za chotupa (WGS sinali yoyenera kusanthula zitsanzo za formalin-immobilized) komanso kukwera mtengo.
Kutsata kotsata kwa NGS kumaphatikizapo kutsatizana kwa exon ndi gulu la jini. Mayeserowa amalemeretsa zigawo zochititsa chidwi pogwiritsa ntchito DNA probes kapena PCR amplification, motero kuchepetsa kuchuluka kwa kutsatizana kofunikira (exome yonse imapanga 1 mpaka 2 peresenti ya genome, ndipo ngakhale mapanelo akuluakulu okhala ndi majini 500 amapanga 0.1 peresenti yokha ya genome). Ngakhale kutsatizana konse kwa exon kumachita bwino m'magulu okhazikika a formalin, mtengo wake umakhalabe wokwera. Kuphatikizika kwa ma jini omwe amatsata ndikosavuta ndipo kumalola kusinthasintha posankha majini kuti ayesedwe. Kuphatikiza apo, kufalikira kwa DNA yaulere (cfDNA) ikutuluka ngati njira yatsopano yowunikira odwala omwe ali ndi khansa, omwe amadziwika kuti liquid biopsies. Maselo onse a khansa ndi maselo abwinobwino amatha kutulutsa DNA m'magazi, ndipo DNA yokhetsedwa kuchokera ku maselo a khansa imatchedwa circulating chotupa DNA (ctDNA), yomwe imatha kufufuzidwa kuti izindikire kusintha komwe kungachitike m'maselo otupa.
Kusankhidwa kwa mayeso kumadalira vuto lachipatala lomwe liyenera kuthetsedwa. Zambiri mwazomwe zimagwirizanitsidwa ndi njira zochiritsira zovomerezeka zimatha kuzindikirika ndi njira za FISH, IHC, ndi PCR. Njirazi ndi zomveka kuti zizindikire zolembera zazing'ono, koma sizimapangitsa kuti zidziwitso zitheke ndi kuwonjezereka, ndipo ngati zizindikiro zowonjezereka zapezeka, sipangakhale minofu yokwanira kuti izindikire. M'makhansa ena enieni, monga khansa ya m'mapapo, pomwe zitsanzo za minofu zimakhala zovuta kupeza ndipo pali zolembera zingapo zoyesera, kugwiritsa ntchito NGS ndi chisankho chabwinoko. Pomaliza, kusankha kuyesedwa kumadalira kuchuluka kwa ma biomarkers omwe amayenera kuyesedwa kwa wodwala aliyense komanso kuchuluka kwa odwala omwe amayenera kuyesedwa kwa biomarker. Nthawi zina, kugwiritsa ntchito IHC / FISH ndikokwanira, makamaka pamene chandamale chadziwika, monga kuzindikira kwa estrogen receptors, progesterone receptors, ndi ERBB2 odwala khansa ya m'mawere. Ngati kufufuzidwa mozama za kusintha kwa ma genomic ndi kufunafuna njira zochizira zomwe zingatheke, NGS imakhala yokonzekera bwino komanso yotsika mtengo. Kuphatikiza apo, NGS ikhoza kuganiziridwa ngati zotsatira za IHC/FISH zimakhala zosamveka kapena zosamveka.

Malangizo osiyanasiyana amapereka chitsogozo cha odwala omwe akuyenera kuyezetsa majini. Mu 2020, ESMO Precision Medicine Working Group idapereka malingaliro oyamba oyesa a NGS kwa odwala omwe ali ndi khansa yapamwamba, ndikulimbikitsa kuyezetsa kwanthawi zonse kwa NGS kwa khansa ya m'mapapo yopanda squamous, khansa ya prostate, khansa ya colorectal, khansa ya ndulu, ndi zotupa za khansa ya ovarian, ndipo mu 2024, ESMO idasinthidwa pazifukwa izi, ndikulimbikitsa khansa ya m'mawere. Monga zotupa za m'mimba stromal, sarcoma, khansa ya chithokomiro ndi khansa yosadziwika bwino.
Mu 2022, ASCO's Clinical Opinion pa kuyezetsa ma genome kwa odwala omwe ali ndi khansa ya metastatic kapena yapamwamba akuti ngati chithandizo chokhudzana ndi biomarker chivomerezedwa kwa odwala omwe ali ndi zotupa za metastatic kapena zolimba kwambiri, kuyezetsa majini kumalimbikitsidwa kwa odwalawa. Mwachitsanzo, kuyezetsa ma genomic kuyenera kuchitidwa mwa odwala omwe ali ndi melanoma ya metastatic kuti awone kusintha kwa BRAF V600E, popeza zoletsa za RAF ndi MEK ndizovomerezeka kuti ziziwonetsa izi. Kuonjezera apo, kuyesa kwa majini kuyeneranso kuchitidwa ngati pali chizindikiro chodziwika bwino cha kukana kuti mankhwalawa aperekedwe kwa wodwalayo. Mwachitsanzo, Egfrmab sigwira ntchito ku khansa yapakhungu ya KRAS. Poganizira kuti wodwalayo ali woyenera kutsata ma jini, mawonekedwe a thupi la wodwalayo, comorbidities, ndi siteji ya chotupa ayenera kuphatikizidwa, chifukwa mndandanda wa masitepe ofunikira kuti ma genome atsatidwe, kuphatikizapo kuvomereza kwa odwala, kukonza ma laboratory, ndi kusanthula zotsatira zotsatizana, zimafuna kuti wodwalayo akhale ndi mphamvu zokwanira za thupi komanso moyo wautali.
Kuphatikiza pa masinthidwe a somatic, makhansa ena amayeneranso kuyezetsa majini a majeremusi. Kuyeza kusintha kwa majeremusi kungakhudze zosankha za chithandizo cha khansa monga BRCA1 ndi BRCA2 masinthidwe am'mawere, ovarian, prostate, ndi pancreatic cancer. Kusintha kwa ma Germline kungakhalenso ndi zotsatira pakuwunika khansa yamtsogolo komanso kupewa kwa odwala. Odwala omwe ali oyenerera kuyezetsa kusintha kwa majeremusi amayenera kukwaniritsa zinthu zina, zomwe zimaphatikizapo zinthu monga mbiri ya khansa ya m'banja, zaka zozindikiridwa, ndi mtundu wa khansa. Komabe, odwala ambiri (mpaka 50%) omwe ali ndi masinthidwe amtundu wa majeremusi samakwaniritsa zofunikira zoyesa kusintha kwa majeremusi kutengera mbiri yabanja. Chifukwa chake, kuti adziwe zambiri zonyamula masinthidwe, bungwe la National Comprehensive Cancer Network (NCCN) limalimbikitsa kuti onse kapena odwala ambiri omwe ali ndi khansa ya m'mawere, ovarian, endometrial, pancreatic, colorectal, kapena prostate ayesedwe ngati majeremusi asintha.
Pankhani ya nthawi yoyezetsa majini, chifukwa chakuti kusintha kwakukulu kwa dalaivala kumakhala kokhazikika komanso kosasunthika panthawi ya kukula kwa khansa, ndizomveka kuyesa chibadwa pa odwala panthawi yomwe akudwala khansa yapamwamba. Pakuyesa kwa majini kotsatira, makamaka pambuyo pa chithandizo cha maselo, kuyezetsa kwa ctDNA ndikopindulitsa kuposa DNA ya chotupa, chifukwa DNA yamagazi imatha kukhala ndi DNA kuchokera ku zotupa zonse za chotupa, zomwe zimathandiza kudziwa zambiri za chotupacho.
Kuwunika kwa ctDNA pambuyo pa chithandizo kumatha kuneneratu kuyankha kwa chotupa pamankhwala ndikuzindikira momwe matenda akupitira patsogolo kuposa njira zojambulira. Komabe, ndondomeko zogwiritsira ntchito detayi kuti zitsogolere zosankha za chithandizo sizinakhazikitsidwe, ndipo kusanthula kwa ctDNA sikuvomerezeka pokhapokha ngati mayesero achipatala. ctDNA itha kugwiritsidwanso ntchito kuyesa zilonda zazing'ono zotsalira pambuyo pa opaleshoni yoopsa ya chotupa. Kuyezetsa kwa ctDNA pambuyo pa opaleshoni ndikowonetseratu kwambiri za kukula kwa matenda ndipo kungathandize kudziwa ngati wodwala angapindule ndi adjuvant chemotherapy, komabe sikuvomerezeka kugwiritsa ntchito ctDNA kunja kwa mayesero a zachipatala kuti atsogolere zosankha za adjuvant chemotherapy.

Kukonza deta Gawo loyamba pakutsatizana kwa ma genome ndikuchotsa DNA kuchokera ku zitsanzo za odwala, kukonza malo osungiramo mabuku, ndi kupanga zotsatizana zosaphika. Deta yaiwisi imafunika kukonzedwanso, kuphatikiza kusefa zomwe zili zotsika mtengo, kuzifanizitsa ndi ma genome, kuzindikira mitundu yosiyanasiyana ya masinthidwe kudzera mu ma aligorivimu amawunikidwe osiyanasiyana, kudziwa zotsatira za masinthidwewa pakumasulira kwa mapuloteni, ndi kusefa mizere ya majeremusi.
Kafotokozedwe ka jini ya oyendetsa adapangidwa kuti azisiyanitsa masinthidwe a oyendetsa ndi okwera. Kusintha kwa madalaivala kumabweretsa kutayika kapena kukulitsa ntchito ya jini ya chotupa. Zosintha zing'onozing'ono zomwe zimapangitsa kuti chibadwa cha chotupa chisagwire ntchito ndi monga masinthidwe opanda pake, masinthidwe amtundu, ndi masinthidwe amtundu wapamalo, komanso kufufutika kocheperako koyambira koyambira, kuyimitsa ma codon, komanso kusintha kosiyanasiyana kwa intron / kuchotsa. Kuphatikiza apo, masinthidwe a missense ndi kusintha kwakung'ono kwa intron / kuchotsa kungayambitsenso kutayika kwa chotupa suppressor gene zochita zikakhudza madera ofunikira. Zosintha zamapangidwe zomwe zimapangitsa kuti ntchito ya jini ya chotupa iwonongeke imaphatikizapo kuchotsa pang'onopang'ono kapena kotheratu kwa majini ndi mitundu ina ya ma genomic yomwe imayambitsa kuwonongeka kwa mawonekedwe owerengera jini. Zosintha zing'onozing'ono zomwe zimapangitsa kuti ma oncogene azigwira ntchito bwino ndikusintha masinthidwe olakwika komanso zoyikapo nthawi zina / zochotsa zomwe zimayang'ana magawo ofunikira a protein. Nthawi zina, kuchepa kwa mapuloteni kapena kuphatikizika kwamasamba kungayambitse kuyambitsa kwa oncogenes. Kusiyanasiyana kwamapangidwe komwe kumayambitsa kuyambitsa kwa oncogene kumaphatikizapo kuphatikizika kwa majini, kufufutidwa kwa majini, ndi kubwereza kwa majini.
Kutanthauzira kwachipatala kwa kusintha kwa ma genomic kumayang'ana tanthauzo lachipatala la masinthidwe ozindikirika, mwachitsanzo, momwe angadziwire matenda, kulosera, kapena chithandizo chamankhwala. Pali machitidwe angapo otengera umboni omwe angagwiritsidwe ntchito kutsogolera kutanthauzira kwachipatala kwa kusintha kwa ma genomic.
Bungwe la Memorial Sloan-Kettering Cancer Center's Precision Medicine Oncology Database (OncoKB) limayika mitundu yosiyanasiyana ya majini m'magulu anayi kutengera mtengo wawo wolosera kuti agwiritse ntchito mankhwala osokoneza bongo: Level 1/2, FDA-approved, kapena clinically-standard biomarkers zomwe zimalosera kuyankha kwa chisonyezero chapadera cha mankhwala ovomerezeka; Level 3, ma biomarkers ovomerezeka a FDA kapena osavomerezeka omwe amalosera kuyankha kwa mankhwala omwe akuwongoleredwa omwe awonetsa lonjezano m'mayesero azachipatala, ndi Level 4, ma biomarker ovomerezeka omwe si a FDA omwe amalosera kuyankha kwa mankhwala omwe akuwunikira omwe awonetsa umboni wokhutiritsa wachilengedwe m'mayesero azachipatala. Kagulu kakang'ono kachisanu kokhudzana ndi kukana chithandizo chinawonjezeredwa.
The American Society for Molecular Pathology (AMP)/American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) malangizo otanthauzira kusinthasintha kwa somatic amagawanitsa kusiyana kwa somatic m'magulu anayi: Gulu loyamba, lokhala ndi tanthauzo lolimba lachipatala; Gulu lachiwiri, lomwe lingakhale ndi tanthauzo lachipatala; Gulu la III, tanthauzo lachipatala losadziwika; Gulu la IV, lomwe silikudziwika kuti ndilofunika kwambiri pazachipatala. Mitundu ya giredi I ndi II yokha ndiyomwe ndiyofunikira pakusankha chithandizo.
ESMO's Molecular Target Clinical Operability Scale (ESCAT) imayika mitundu yosiyanasiyana ya majini m'magulu asanu ndi limodzi: Level I, mipherezero yoyenera kugwiritsidwa ntchito mwachizolowezi; Phase II, cholinga chomwe chikuphunziridwabe, chikhoza kugwiritsidwa ntchito poyang'ana chiwerengero cha odwala omwe angapindule ndi mankhwala omwe akugwiritsidwa ntchito, koma deta yambiri ikufunika kuti iwathandize. Gulu la III, mitundu yosiyanasiyana ya majini yomwe yawonetsa kupindula kwachipatala mu mitundu ina ya khansa; Gulu la IV, mitundu yokhayo ya majini yomwe imayang'aniridwa ndi umboni wotsimikizira; M'kalasi ya V, pali umboni wotsimikizira kuti chithandizo chamankhwala chimayang'ana kusintha, koma chithandizo cha mankhwala amodzi motsutsana ndi cholingacho sichimawonjezera kupulumuka, kapena njira yophatikizira yothandizira ikhoza kutengedwa; Gulu X, kusowa kwa chipatala.