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Mumakore gumi apfuura, gene sequencing tekinoroji yakashandiswa zvakanyanya mukutsvagisa kenza uye tsika yekiriniki, ichiva chishandiso chakakosha kuburitsa mamorekuru maitiro egomarara. Kufambira mberi mukuongororwa kwema molecular uye kurapwa kwakanangwa kwakasimudzira kuvandudzwa kwe tumor precision therapy concepts uye kwakaunza shanduko huru kumunda wese wekuongororwa uye kurapwa. Kuongororwa kwemajini kunogona kushandiswa kunyevera njodzi yegomarara, kutungamira sarudzo dzekurapa uye kuongorora fungidziro, uye chishandiso chakakosha chekuvandudza mhedzisiro yekiriniki yemurwere. Pano, tinopfupikisa zvinyorwa zvichangoburwa zvakaburitswa muCA Cancer J Clin, JCO, Ann Oncol nemamwe majenari kuti aongorore mashandisirwo ekuongorora genetic mukuongorora uye kurapwa kwegomarara.

Somatic mutations uye germline mutations. Kazhinji, kenza inokonzerwa neDNA mutations inogona kugarwa nhaka kubva kuvabereki (germline mutations) kana kuwanikwa nezera (somatic mutations). Germ line mutations iripo kubva pakuzvarwa, uye mutator inowanzo takura shanduko muDNA yesero rese riri mumuviri uye inogona kupfuudzwa kuvana. Somatic mutations inowanikwa nevanhu vari mumasero asiri-gametic uye kazhinji haipfuudzirwe kuvana. Ose ari maviri germline uye somatic mutations anogona kuparadza yakajairika basa basa remaseru uye kutungamirira kukuchinja kwakashata kwemaseru. Somatic mutations ndiwo mutyairi akakosha wehuipi uye inonyanya kufanotaura biomarker mune oncology; zvisinei, angangoita gumi kusvika 20 muzana yevarwere vebundu vanotakura germline mutations inowedzera zvakanyanya njodzi yavo yegomarara, uye mamwe ekuchinja aya anorapawo.
Kuchinja kwemutyairi uye kuchinja kwevatyairi. Haasi ese akasiyana eDNA anokanganisa kushanda kwesero; paavhareji, zvinotora zvishanu kusvika gumi zviitiko zve genomic, zvinozivikanwa se "mutyairi mutations," kukonzeresa zvakajairika sero degeneration. Kuchinja kwemutyairi kunowanzoitika mumajini ane hukama zvakanyanya nemabasa ehupenyu hwesero, senge majini anobatanidzwa mukutonga kwekukura kwesero, kugadzirisa kweDNA, kudzora kutenderera kwesero uye mamwe maitiro ehupenyu, uye ane mukana wekushandiswa sechinangwa chekurapa. Nekudaro, huwandu hwese hwekuchinja mune chero cancer yakakura, kubva pazviuru zvishoma mune mamwe mazamu egomarara kusvika kune anopfuura zana mune mamwe akasiyana-siyana colorectal uye endometrial cancers. Kuchinja kwakawanda hakuna kana kushomeka kwebhayoloji yakakosha, kunyangwe shanduko ikaitika munharaunda yekodha, zviitiko zvisina kukosha zvakadaro zvinodaidzwa kuti "vatambi vanochinja". Kana jini rakasiyana mune imwe bundu rudzi richifanotaura mhinduro yaro kana kuramba kurapwa, musiyano unoonekwa seunoshanda mukiriniki.
Oncogenes uye tumor suppressor majini. Majini anowanzo shandurwa mugomarara anogona kukamurwa kuita zvikamu zviviri, oncogenes uye tumor suppressor genes. Mumasero akajairwa, puroteni yakavharidzirwa neoncogenes inonyanya kuita basa rekusimudzira kuwanda kwesero uye kuvharidzira sero apoptosis, nepo protein yakavharidzirwa neoncosuppressor genes inonyanya kuita basa rekudzora kupatsanurwa kwesero zvisina kunaka kuchengetedza kushanda kwesero. Mune yakashata shanduko maitiro, genomic mutation inotungamira mukusimudzirwa kweiyo oncogene chiitiko uye kudzikira kana kurasikirwa kweoncosuppressor gene chiitiko.
Kusiyanisa kuduku uye kuchinja kwemaitiro. Aya ndiwo marudzi maviri makuru ekuchinja mujenome. Zvikamu zvidiki zvinoshandura DNA nekuchinja, kudzima, kana kuwedzera nhamba shoma yezvigadziko, kusanganisira kuisa hwaro, kudzima, frameshift, kutanga kurasikirwa kwekodon, kumisa kuparara kwekodon, etc. Structural variation is a big genome rearrangement, inosanganisira zvikamu zvemagene kubva pakukura kubva kuzviuru zvishoma zvigadziko kusvika kuhuwandu hwechromosome, kudhinda nhamba yekromosome, kudhinda nhamba yekromosome. inversion kana translocation. Kuchinja uku kunogona kukonzera kudzikiswa kana kukwidziridzwa kwebasa remapuroteni. Pamusoro pekuchinja padanho remajini ega ega, masiginecha egenomic zvakare chikamu chemishumo yekutevedzana kwekiriniki. Genomic siginicha inogona kuoneka seakaomesesa mapatani ediki uye/kana maumbirwo akasiyana, kusanganisira tumor mutation load (TMB), microsatellite instability (MSI), uye homologous recombination defects.

Clonal mutation uye subclonal mutation. Kuchinja kweClonal kunowanikwa mune ese bundu masero, aripo pakuongororwa, uye anoramba aripo mushure mekufambira mberi kwekurapa. Naizvozvo, clonal shanduko ine mukana wekushandiswa sebundu kurapa zvinangwa. Subclonal mutations iripo mune chete subset yekenza maseru uye inogona kuonekwa pakutanga kwekuongororwa, asi inonyangarika nekudzoka kunotevera kana kuoneka chete mushure mekurapwa. Cancer heterogeneity inoreva kuvapo kweakawanda subclonal mutations mune imwe kenza. Zvikuru, ruzhinji rwekiriniki yakakosha shanduko yekutyaira mune ese akajairwa kenza mhando shanduko uye inoramba yakagadzikana mukati mekukura kwegomarara. Kupikisa, iyo inowanzopindirana ne-subclones, inogona kusaonekwa panguva yekuongororwa asi inoonekwa kana ichidzoka mushure mekurapa.

Nzira yechinyakare FISH kana sero karyotype inoshandiswa kuona shanduko pachikamu chechromosomal. FISH inogona kushandiswa kuona kusanganiswa kwemajini, kudzima, uye kukwidziridzwa, uye inonzi "yegoridhe mwero" yekuona zvakasiyana-siyana zvakadaro, nehuchenjeri hwepamusoro uye kunzwisiswa asi hushoma. Mune dzimwe hematologic malignancies, kunyanya acute leukemia, karyotyping ichiri kushandiswa kutungamira kuongororwa uye kufungidzira, asi nzira iyi inotsiviwa zvishoma nezvishoma neanotariswa ma molecular assays akadai seFISH, WGS, uye NGS.
Shanduko mumajini ega ega dzinogona kuwonekwa nePCR, zvese zviri zviviri-chaiyo-nguva PCR uye dijitari inodonha PCR. Aya maitiro ane kunzwisiswa kwepamusoro, anonyanya kukodzera pakuona uye kuongorora zvipembenene zviduku zvakasara, uye zvinogona kuwana migumisiro munguva shoma shoma, kukanganisa ndechokuti chiyero chekutsvaga chinogumira (kazhinji chinongoona kuchinja kwemajini mune imwe kana kuti mashoma), uye kukwanisa kune miedzo yakawanda kunogumira.
Immunohistochemistry (IHC) iprotein-based monitoring tool inowanzoshandiswa kuona mataurirwo ezvinyorwa zvakadai seERBB2 (HER2) uye estrogen receptors. IHC inogona zvakare kushandiswa kuona mapuroteni akachinja (akadai seBRAF V600E) uye chaiwo majene fusions (akadai seALK fusions). Kubatsira kweIHC ndeyekuti inogona kubatanidzwa nyore nyore mune yakajairwa tishu yekuongorora maitiro, saka inogona kusanganiswa nemimwe bvunzo. Mukuwedzera, IHC inogona kupa ruzivo pane subcellular protein localization. Izvo zvisingabatsiri ndezvishoma scalability uye yakakwirira yehurongwa zvido.
Kutevedzana kwechizvarwa chechipiri (NGS) NGS inoshandisa nzira dzepamusoro-soro dzakafanana dzekutevedzana kuti dzione kusiyana kweDNA uye / kana RNA level. Iyi tekinoroji inogona kushandiswa kuteedzera ese ese genome (WGS) uye gene matunhu anofarira. WGS inopa ruzivo rwakakwana rwe genomic mutation, asi pane zvipingamupinyi zvakawanda pakushandiswa kwayo kwekiriniki, kusanganisira kudiwa kwemasamples etishu yemamota matsva (WGS haisati yave yakakodzera kuongororwa formalin-immobilized samples) uye mutengo wakakwirisa.
Yakatemerwa NGS sequencing inosanganisira yakazara exon sequencing uye inonangwa gene panhi. Miedzo iyi inopfumisa nzvimbo dzinofarirwa neDNA probes kana PCR amplification, zvichidzikamisa huwandu hwekutevedzana kunodiwa (iyo exome yese inoita 1 kusvika 2 muzana yegenome, uye kunyange mapaneru makuru ane mazana mashanu emajini anongoita 0.1 muzana chete yejenome). Kunyangwe yese exon sequencing ichiita zvakanaka mu-formalin-yakagadziriswa tishu, mutengo wayo unoramba wakakwira. Misanganiswa yemajini inovavarirwa ine mari shoma uye inobvumira kuchinjika mukusarudza majini anoedzwa. Uye zvakare, kutenderera yemahara DNA (cfDNA) iri kubuda senzira nyowani yekuongorora genomic yevarwere vegomarara, inozivikanwa semvura biopsies. Maseru ese ekenza nemaseru akajairwa anogona kuburitsa DNA muropa, uye DNA yakadururwa kubva kumaseru egomarara inonzi inotenderera bundu DNA (ctDNA), iyo inogona kuongororwa kuti ione angangoita shanduko mumamota masero.
Kusarudzwa kwekuedzwa kunoenderana nedambudziko rekiriniki rinofanirwa kugadziriswa. Mazhinji emabiomarker ane hukama neakatenderwa marapirwo anogona kuwonekwa neFISH, IHC, uye PCR maitiro. Idzi nzira dzine musoro pakuona kwezvishoma zvishoma zvezvinyorwa, asi hazvigadzirisi kushanda kwekutsvaga nekuwedzera kwekuwedzera, uye kana mabhii akawandisa akaonekwa, panogona kunge pasina matishu akakwana ekuona. Mune mamwe magomarara chaiwo, akadai sekenza yemapapu, uko masamples ematishu anonetsa kuwana uye kune akawanda biomarkers ekuongorora, kushandisa NGS isarudzo iri nani. Mukupedzisa, kusarudzwa kwekuongororwa kunoenderana nehuwandu hwema biomarkers kuti aongororwe kumurwere wega wega uye nhamba yevarwere kuti vaongororwe iyo biomarker. Mune zvimwe zviitiko, kushandiswa kweIHC / FISH kunokwana, kunyanya kana chinangwa chave chichionekwa, zvakadai sekuonekwa kweesrogen receptors, progesterone receptors, uye ERBB2 muvarwere vekenza yemazamu. Kana kuongororwa kwakadzama kwekuchinja kwegenomic uye kutsvaga kwezvingangonangwa zvekurapa kuchidikanwa, NGS inonyanya kurongeka uye inodhura. Pamusoro pezvo, NGS inogona kutariswa mune zviitiko apo IHC/FISH mhedzisiro isinganzwisisiki kana isingaite.

Nhungamiro dzakasiyana dzinopa gwara rekuti varwere vanofanirwa kuve vanokodzera kuongororwa majini. Muna 2020, ESMO Precision Medicine Working Group yakapa yekutanga NGS yekuyedza kurudziro yevarwere vane gomarara repamusoro, ichikurudzira ongororo yeNGS yemhando yepamusoro isiri-squamous isiri diki kenza yemapapu, kenza yeprostate, colorectal cancer, bile duct cancer, uye ovarian cancer tumor samples, uye muna 2024, ESMO yakagadziridzwa mune iri rebundu. Senge gastrointestinal stromal tumors, sarcomas, thyroid gomarara uye kenza isingazivikanwe kwakabva.
Muna 2022, ASCO's Clinical Opinion pane somatic genome bvunzo mune varwere vane metastatic kana advanced cancer inoti kana biomarker ine chekuita nekurapa ikabvumidzwa muvarwere vane metastatic kana advanced solid solid tumors, genetic test inokurudzirwa kune varwere ava. Semuenzaniso, kuongororwa kwegenomic kunofanirwa kuitwa muvarwere vane metastatic melanoma kuratidza BRAF V600E shanduko, sezvo RAF neMEK inhibitors zvichitenderwa chiratidzo ichi. Mukuwedzera, kuongororwa kwemajini kunofanirawo kuitwa kana pane chiratidzo chakajeka chekuramba kuti mushonga upiwe kumurwere. Egfrmab, semuenzaniso, haishande muKRAS mutant colorectal cancer. Paunenge uchifunga nezvekukodzera kwemurwere pakutevedzana kwemajini, chimiro chemuviri wemurwere, comorbidities, uye nhanho yebundu inofanira kubatanidzwa, nekuti nhevedzano yematanho anodiwa pakutevedzana kwegenome, kusanganisira mvumo yemurwere, kugadzirwa kwerabhoritari, uye kuongororwa kwekutevedzana kwemhedzisiro, zvinoda kuti murwere ave nehunyanzvi hwemuviri hwakakwana uye tarisiro yehupenyu.
Pamusoro pekuchinja kwe somatic, mamwe magomarara anofanirwawo kuongororwa majini ejemu. Kuongororwa kwe germ line mutations kunogona kukanganisa sarudzo dzekurapa kwegomarara senge BRCA1 uye BRCA2 kuchinja kwezamu, ovarian, prostate, uye pancreatic cancers. Germline mutations inogonawo kuve nezvainoreva kune ramangwana rekuongorora kenza nekudzivirira muvarwere. Varwere vangangove vakakodzera kuongororwa kushanduka kwegermline vanofanirwa kusangana nemamwe mamiriro, ayo anosanganisira zvinhu zvakaita senhoroondo yemhuri yegomarara, zera rekuongororwa, uye rudzi rwegomarara. Nekudaro, varwere vazhinji (kusvika 50%) vakatakura pathogenic mutations mumutsara wejemisi havazadzise maitiro echinyakare ekuongororwa kwe germ line shanduko zvichienderana nenhoroondo yemhuri. Naizvozvo, kuti kuwedzere kuzivikanwa kwevatakuri vanotakura, National Comprehensive Cancer Network (NCCN) inokurudzira kuti vese kana vazhinji varwere vane mazamu, ovarian, endometrial, pancreatic, colorectal, kana prostate cancer vaongororwe kana germ line mutations.
Nezve nguva yekuongororwa kwemajini, nekuti ruzhinji rwemakiriniki akakosha ekuchinja kwemutyairi ari clonal uye akagadzikana mukati mekufamba kwegomarara, zvine musoro kuita genetic test pavarwere panguva yekuongororwa kwegomarara repamusoro. Kune kunotevera kuongororwa kwemajini, kunyanya mushure mekunangwa kwema molecular therapy, ctDNA kuongororwa kunobatsira kupfuura tumor tishu DNA, nekuti DNA yeropa inogona kuve neDNA kubva kune ese maronda maronda, izvo zvinonyanya kubatsira kuwana ruzivo nezve bundu heterogeneity.
Ongororo yectDNA mushure mekurapwa inogona kufanotaura mhinduro yebundu pakurapwa uye kuona kufambira mberi kwechirwere pamberi pemaitiro akajairwa ekufungidzira. Nekudaro, maprotocol ekushandisa aya data kutungamira sarudzo dzekurapa haasati agadzwa, uye ctDNA kuongororwa haikurudzirwe kunze kwekunge kuri mukuyedza kwekiriniki. ctDNA inogona zvakare kushandiswa kuongorora zvidiki zvakasara maronda mushure mekuvhiyiwa kwakanyanya bundu. Kuongororwa kwectDNA mushure mekuvhiyiwa ndiyo fungidziro yakasimba yekuenderera mberi kwechirwere uye inogona kubatsira kuona kana murwere achizobatsirwa neadjuvant chemotherapy, asi haisati yakurudzirwa kushandisa ctDNA kunze kwemiedzo yekiriniki kutungamira adjuvant chemotherapy sarudzo.

Kugadziriswa kwedata Nhanho yekutanga mukutevedzana kwegenome ndeyekubvisa DNA kubva kuvarwere samples, kugadzirira maraibhurari, uye kugadzira mbishi kutevedzana data. Iyo mbishi data inoda kumwe kugadziridzwa, kusanganisira kusefa yakaderera-mhando data, kuienzanisa nereferensi genome, kuzivisa marudzi akasiyana ekuchinja kuburikidza neakasiyana analytical algorithms, kuona mhedzisiro yekuchinja uku pashanduro yeprotein, uye kusefa germ line mutations.
Mutyairi gene annotation yakagadzirirwa kusiyanisa mutyairi uye mutyairi shanduko. Shanduko dzemutyairi dzinotungamira mukurasikirwa kana kukwidziridzwa kwe tumor suppressor gene chiitiko. Misiyano midiki inotungamira mukusashanda kwe tumor suppressor genes zvinosanganisira kusachinja-chinja, furemu shanduko, uye kiyi splicing saiti shanduko, pamwe nekushomeka kwekutanga kudzima codon, kumisa kudzima codon, uye kuwanda kwekuisa / kudzima shanduko. Uye zvakare, missense shanduko uye diki intron yekuisa / kudzima shanduko inogona zvakare kutungamira mukurasikirwa kwebundu suppressor gene chiitiko kana ichikanganisa akakosha anoshanda madomasi. Zvimiro zvakasiyana zvinotungamira mukurasikirwa kwebundu suppressor gene chiitiko zvinosanganisira chikamu kana chakazara kudzima gene uye mamwe ma genomic akasiyana anotungamira mukuparadzwa kwejini kuverenga furemu. Misiyano midiki inotungamira mukukwidziridzwa kushanda kweoncogenes inosanganisira missense mutations uye apo neapo intron kuiswa / kudzima kunonangana akakosha mapuroteni anoshanda madomasi. Muzviitiko zvisingawanzoitiki, protein truncation kana splicing site mutations inogona kutungamira kune activation ye oncogenes. Misiyano yezvimiro inotungamira kune oncogene activation inosanganisira gene fusion, kudzima majini, uye kudzokorora kwemajini.
Tsanangudzo yekiriniki ye genomic variation inoongorora kukosha kwekiriniki kwekuchinja kwakaonekwa, kureva kugona kwavo kuongororwa, kufungidzira, kana kukosha kwekurapa. Kune akati wandei ehumbowo-hwakavakirwa magiredhi masisitimu anogona kushandiswa kutungamira kududzira kwekiriniki kwekusiyana kwegenomic.
Chirangaridzo Sloan-Kettering Cancer Center's Precision Medicine Oncology Database (OncoKB) inoronga kusiyana kwemajini mumatanho mana zvichienderana nekufanotaura kukosha kwekushandisa zvinodhaka: Nhamba 1/2, FDA-yakatenderwa, kana kliniki-yakajairwa biomarkers inofanotaura mhinduro yechiratidzo chaicho kune chinodhaka chinotenderwa; Level 3, FDA-inotenderwa kana isina-yakatenderwa biomarkers inofanotaura mhinduro kune itsva yakanangwa mishonga yakaratidza kuvimbiswa mumiedzo yekiriniki, uye Level 4, isiri-FDA-inobvumidzwa biomarkers inofanotaura mhinduro kune novel yakanangana nemishonga iyo yakaratidza inogutsa humbowo hwehupenyu mumakiriniki ekuedzwa. Chikamu chechishanu chakabatana nekuramba kurapwa chakawedzerwa.
IAmerican Society for Molecular Pathology (AMP)/American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) mirayiridzo yekududzirwa kwe somatic variation inokamura somatic variation muzvikamu zvina: Giredhi I, ine kliniki yakakosha yakakosha; Giredhi II, ine zvingave zvakakosha zvekiriniki; Giredhi III, kukosha kwekiriniki kusingazivikanwe; Giredhi IV, isingazivikanwe kuve yakakosha muchipatara. Chete giredhi I uye II akasiyana akakosha pasarudzo dzekurapa.
ESMO's Molecular Target Clinical Operability Scale (ESCAT) inoronga kusiyana kwemajini mumatanho matanhatu: Level I, zvinangwa zvakakodzera kushandiswa kwemazuva ose; Phase II, chinangwa chichiri kudzidzwa, chingangoshandiswa kuongorora huwandu hwevarwere vanogona kubatsirwa nemushonga wavanoda, asi data rakawanda rinodiwa kuitsigira. Giredhi III, zvakanangwa magene akasiyana izvo zvakaratidza kubatsirwa kwekiriniki mune mamwe marudzi egomarara; Giredhi IV, inongotarirwa magene akasiyana anotsigirwa nehumbowo hwepreclinical; Mugiredhi V, pane humbowo hunotsigira kukosha kwekiriniki yekunangidzira kushanduka, asi kurapa kwemishonga imwe chete kunopesana nechinangwa hachiwedzere kupona, kana nzira yekurapa yakasanganiswa inogona kugamuchirwa; Giredhi X, kushaya kukosha kwekiriniki.