Carcinogenesis

Carcinogenesis
Description (en)
Iri	disease of cellular proliferation (en) pathogenesis (en)
Specialty (en)	oncology
Identifier (en)
MeSH	D063646

Carcinogenesis, wanda kuma ake kira oncogenesis ko tumorigenesis, shine samuwar ciwon daji, inda kwayoyin halitta suka canza zuwa kwayoyin cutar kansa . Tsarin yana halin canje-canje a salon salula, kwayoyin halitta, da matakan epigenetic da rarraba kwayoyin halitta mara kyau. Rarraba tantanin halitta tsari ne na ilimin lissafi wanda ke faruwa a kusan dukkanin kyallen takarda kuma a ƙarƙashin yanayi iri-iri. Yawanci, ma'auni tsakanin yaduwa da tsarin mutuwar kwayar halitta, a cikin nau'i na apoptosis, ana kiyaye shi don tabbatar da kuma amincin kyallen takarda da gabobin . Bisa ga ka'idar da aka yarda da ita ta carcinogenesis, ka'idar maye gurbi na somatic, maye gurbi a cikin DNA da epimutations wanda ke haifar da ciwon daji ya rushe waɗannan matakai masu tsari ta hanyar tsoma baki tare da shirye-shiryen da ke tsara tsarin tafiyar matakai, tada ma'auni na yau da kullum tsakanin yaduwa da mutuwar kwayar halitta. Wannan yana haifar da rarrabuwar tantanin halitta mara sarrafawa da haɓakar waɗannan sel ta zaɓin yanayi a cikin jiki. Wasu maye gurbi ne kawai ke haifar da ciwon daji yayin da yawancin maye gurbi ba sa.

Bambance-bambancen kwayoyin halittar da aka gada na iya sa mutane su kamu da cutar kansa. Bugu da ƙari, abubuwan muhalli kamar su carcinogens da radiation suna haifar da maye gurbi wanda zai iya taimakawa wajen bunkasa ciwon daji. A ƙarshe kuskuren bazuwar a cikin kwafin DNA na yau da kullun na iya haifar da ciwon daji da ke haifar da maye gurbi. ^[1] Ana buƙatar jerin maye gurbi da yawa zuwa wasu nau'ikan kwayoyin halitta kafin tantanin halitta ta al'ada ya canza zuwa kwayar cutar kansa .^{[2][3][4][5][6]} A matsakaita, alal misali, 15 "maye gurbin direba" da "fasinja" 60 ana samun su a cikin ciwon daji na hanji.^[2] Maye gurbi a cikin kwayoyin halittar da ke daidaita rabon tantanin halitta, apoptosis (mutuwar tantanin halitta), da gyaran DNA na iya haifar da yaduwar kwayar halitta da ciwon daji.

Ciwon daji ya kasan ce shi ne asalin cuta na ƙayyadaddun ci gaban nama. Domin tantanin halitta ta al'ada ya canza zuwa kwayar cutar daji, dole ne a canza kwayoyin halittar da ke daidaita girma da bambance-bambancen kwayar halitta.^[7] Canje-canje na kwayoyin halitta da na epigenetic na iya faruwa a matakai da yawa, daga riba ko asarar dukkanin chromosomes, zuwa maye gurbin da ya shafi DNA nucleotide guda ɗaya, ko don yin shiru ko kunna microRNA wanda ke sarrafa bayanin kwayoyin 100 zuwa 500.^[8][9] Akwai manyan nau'ikan kwayoyin halitta guda biyu waɗanda waɗannan canje-canjen suka shafa. Oncogenes na iya zama kwayoyin halitta na yau da kullun waɗanda aka bayyana a manyan matakan da ba su dace ba, ko kuma canjin kwayoyin halitta waɗanda ke da sabbin abubuwa. A kowane hali, bayyanar da waɗannan kwayoyin halitta suna haɓaka mummunan yanayin ƙwayoyin cutar kansa. Kwayoyin da ke hana Tumor su ne kwayoyin halitta waɗanda ke hana rarraba tantanin halitta, rayuwa, ko wasu kaddarorin ƙwayoyin cutar kansa. Kwayoyin da ke hana Tumor sau da yawa suna naƙasa ta hanyar haɓaka canje-canjen kwayoyin halitta masu cutar kansa. A ƙarshe Oncovirinae, ƙwayoyin cuta waɗanda ke ɗauke da oncogene, an rarraba su azaman oncogenic saboda suna haifar da haɓakar kyallen ƙwayar cuta a cikin gidan . Ana kuma kiran wannan tsari azaman canji na hoto ko bidiyo mai zagaya yanar gizo da sauri.

Akwai nau'ikan rarrabuwa iri-iri don sauye-sauyen iri-iri na kwayoyin halitta waɗanda zasu iya ba da gudummawa ga haɓakar ƙwayoyin cutar kansa . ya kasan ce kuma yawancin waɗannan canje-canjen maye gurbi ne, ko canje-canje a cikin jerin nucleotide na DNA na genomic. Hakanan akwai canje-canje na epigenetic da yawa waɗanda ke canza ko an bayyana kwayoyin halitta ko ba a bayyana su ba. Aneuploidy, kasancewar adadin ƙananan ƙwayoyin chromosomes, shine canji na kwayoyin halitta wanda ba maye gurbi ba, kuma yana iya haɗawa da riba ko asarar ɗaya ko fiye da chromosomes ta hanyar kurakurai a cikin mitosis . Manyan maye gurbi sun ƙunshi ko dai shafewa ko kwafin wani yanki na chromosome. Ƙwararrun kwayoyin halitta yana faruwa ne lokacin da tantanin halitta ya sami kwafi da yawa (sau da yawa 20 ko fiye) na ƙaramin yanki na chromosomal, yawanci yana ɗauke da ɗaya ko fiye da oncogenes da kayan gado na kusa. Juyawa yana faruwa lokacin da yankuna biyu na chromosomal daban-daban suka zama masu haɗaka da juna, sau da yawa a wani yanayi na musamman. Wani sanannen misali na wannan shine chromosome Philadelphia, ko fassarar chromosomes 9 da 22, wanda ke faruwa a cikin ciwon sankarar jini na myelogenous na kullum, kuma yana haifar da samar da furotin BCR - abl fusion, wani oncogenic tyrosine kinase . Ƙananan maye gurbi sun haɗa da maye gurbi, gogewa, da shigarwa, wanda zai iya faruwa a cikin mai inganta kwayar halitta kuma ya shafi maganganunsa, ko kuma zai iya faruwa a cikin tsarin codeing na kwayar halitta kuma ya canza aiki ko kwanciyar hankali na samfurin furotin . Rushewar kwayar halitta guda ɗaya kuma na iya haifar da haɗuwa da kayan halitta daga kwayar cutar DNA ko retrovirus, kuma irin wannan lamarin na iya haifar da bayyanar cututtuka na ƙwayoyin cuta a cikin tantanin halitta da ya shafa da zuriyarsa.

Ana ɗaukar lalacewar DNA a matsayin tushen farko na cutar kansa.^[10] Fiye da 60,000 sababbin abubuwan da ke faruwa ta dabi'a na lalacewar DNA sun tashi, a matsakaici, kowane tantanin halitta, kowace rana, saboda tsarin tsarin salula na zamani (duba labarin lalacewar DNA (wanda ke faruwa a zahiri) ).

Ƙarin lalacewa na DNA na iya tasowa daga fallasa ga wasu abubuwan waje. A matsayin misali ɗaya na wakili na ƙwayar cuta na waje, hayaƙin taba yana haifar da ƙarin lalacewar DNA, kuma wannan lalacewar DNA na iya haifar da haɓakar cutar kansar huhu saboda shan taba.^[11] A cikin wasu misalan, hasken UV daga hasken rana yana haifar da lalacewar DNA wanda ke da mahimmanci a cikin melanoma,^[12] Helicobacter pylori kamuwa da cuta yana samar da nau'in oxygen mai yawa wanda ke lalata DNA kuma yana taimakawa ga ciwon daji na ciki, ^[13] da kuma Aspergillus flavus metabolite aflatoxin ne. wani wakili mai lalata DNA wanda ke haifar da ciwon hanta.^[14]

Hakanan ana iya haifar da lalacewar DNA ta abubuwan da aka samar a cikin jiki . Macrophages da neutrophils a cikin epithelium mai kumburi mai kumburi sune tushen nau'in oxygen mai amsawa wanda ke haifar da lalacewar DNA wanda ke haifar da tumorigenesis na colonic,^[15] da bile acid, a cikin manyan matakan da ke cikin mazaunin mutane suna cin abinci mai yawa, kuma suna haifar da lalacewar DNA. da kuma taimakawa ga ciwon daji na hanji. ^[16]

Irin waɗannan ɓangarorin ɓarna da ɓarna na lalacewa na DNA ana nuna su a cikin kwalayen da ke saman adadi a wannan sashe. Matsayin tsakiya na lalacewar DNA a ci gaba zuwa ciwon daji ana nuna shi a mataki na biyu na adadi. Abubuwan tsakiya na lalacewar DNA, sauye-sauye na epigenetic da ƙarancin gyaran DNA a ci gaba zuwa ciwon daji ana nunawa a cikin ja.

Rashin gyare-gyaren DNA zai haifar da ƙarin lalacewar DNA don tarawa, kuma yana ƙara haɗarin ciwon daji. Misali, mutanen da ke da nakasa da aka gada a cikin kowane nau'in halittar DNA guda 34 (duba labarin DNA gyara-rashi cuta ) suna cikin haɗarin cutar kansa, tare da wasu lahani suna haifar da damar kusan 100% na ciwon daji (misali p53 maye gurbi). ^[17] Ana nuna irin waɗannan maye gurbi na ƙwayoyin cuta a cikin akwati a gefen hagu na adadi, tare da nunin gudunmawar su ga ƙarancin gyara DNA. Duk da haka, irin wannan maye gurbi (wanda ke haifar da ciwon daji mai saurin shiga jiki) sune sanadin kusan kashi ɗaya cikin ɗari na cutar kansa. ^[18]

Yawancin ciwon daji ana kiran su marasa gado ko "ciwon daji". Kusan kashi 30 cikin 100 na cututtukan daji na lokaci-lokaci suna da wasu abubuwan gado waɗanda a halin yanzu ba a bayyana su ba, yayin da yawancin, ko kashi 70% na cututtukan daji na lokaci-lokaci, ba su da wani ɓangaren gado.^[19]

A cikin ciwon daji na lokaci-lokaci, rashi a gyaran DNA yana faruwa lokaci-lokaci saboda maye gurbi a cikin kwayar gyaran DNA; da yawa akai-akai, raguwa ko rashin bayyanar kwayoyin halittar DNA shine saboda sauye-sauyen epigenetic wanda ke rage ko yin shiru . Ana nuna wannan a cikin adadi a mataki na 3 daga sama. Alal misali, don ciwon daji na launi na 113 da aka yi nazari a cikin jerin, hudu kawai suna da maye gurbi a cikin DNA na gyaran MGMT, yayin da mafi yawan sun rage MGMT magana saboda methylation na yankin mai gabatarwa na MGMT (canjin epigenetic).^[20]

Lokacin da aka rage bayyanar kwayoyin halittar DNA, wannan yana haifar da ƙarancin gyaran DNA. Ana nuna wannan a cikin adadi a matakin na 4 daga sama. Tare da ƙarancin gyaran DNA, lalacewar DNA ta ci gaba a cikin sel a mafi girma fiye da matakin al'ada (matakin 5 daga sama a cikin adadi); wannan barnar da ta wuce gona da iri tana haifar da karuwar mitar maye gurbi da/ko epimutation (matakin 6 daga saman adadi). Gwaji, ƙimar maye gurbi yana ƙaruwa sosai a cikin sel marasa lahani a cikin gyara rashin daidaituwa na DNA^[21][22] ko a cikin gyaran haɗin gwiwa na Homologous (HRR).^[23] Sabuntawar chromosomal da aneuploidy suma suna ƙaruwa a cikin ƙwayoyin da ba su da lahani na HRR Yayin gyaran ɓangarorin DNA guda biyu, ko gyara wasu lalacewar DNA, wuraren da ba su cika cikakke ba na iya haifar da tsit na epigenetic.^[24][25]

Maye gurbin somatic da sauye-sauyen epigenetic da ke haifar da lalacewa ta DNA da rashi a cikin gyaran DNA sun taru a cikin lahani . Lalacewar filaye sune kyawu masu bayyana al'ada tare da sauye-sauye da yawa (an tattauna a cikin sashin da ke ƙasa), kuma su ne madogarar gama gari don haɓaka ɓarna da haɓakar ƙwayoyin nama a cikin ciwon daji. Irin wannan lahani na filin (mataki na biyu daga kasan adadi) na iya samun sauye-sauye da yawa da kuma sauye-sauye na epigenetic.

Ba shi yiwuwa a tantance dalilin farko na mafi yawan takamaiman cututtukan daji. A kuma wasu ƴan lokuta, dalili ɗaya kawai ya wanzu: alal misali, ƙwayar cuta HHV-8 tana haifar da duk sarcomas na Kaposi . Koyaya, tare da taimakon dabarun cututtukan cututtukan daji da bayanai, yana yiwuwa a samar da ƙididdigewa mai yuwuwar sanadi a cikin ƙarin yanayi. Misali,kuma ciwon huhu na huhu yana da dalilai da yawa, ciki har da shan taba da kuma radon gas . Maza masu shan taba a halin yanzu suna kamuwa da cutar kansar huhu a cikin adadin mazan da ba su taba shan taba ba sau 14: damar cutar kansar huhu a cikin mai shan taba na yanzu da shan taba ke haifar da shi kusan kashi 93% ne; akwai yuwuwar kashi 7% cewa cutar kansar huhu ta mai shan taba ta samo asali ne ta hanyar radon gas ko wani abin da ba na shan taba ba. ^[26] Waɗannan alaƙar ƙididdiga sun ba da damar masu bincike su fahimci cewa wasu abubuwa ko ɗabi'a na cutar kansa. Hayakin taba yana haifar da karuwar lalacewar DNA na waje, kuma wannan lalacewar DNA shine yuwuwar cutar kansar huhu saboda shan taba. Daga cikin fiye da 5,000 mahadi a cikin taba hayaki, da genotoxic DNA-damaging jamiái da ke faruwa duka biyu a mafi girma yawa, da kuma wanda ke da karfi mutagenic effects ne acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide da isoprerence . . ^[11]

Yin amfani da dabarun nazarin kwayoyin halitta, yana yiwuwa a siffata rikiɗewar, ƙayyadaddun ƙayyadaddun ƙwayoyin cuta ko ɓarna na chromosomal a cikin ƙari, kuma ana samun ci gaba cikin sauri a fagen hasashen hasashen wasu masu cutar kansar bisa ga nau'in maye gurbi. Misali, kusan rabin duk ciwace-ciwacen ciwace-ciwace suna da lahani na p53. Wannan maye gurbi yana da alaƙa da rashin hasashe, tun da waɗancan ƙwayoyin ƙwayar cuta ba su da yuwuwar shiga cikin apoptosis ko tsarin mutuwar tantanin halitta lokacin lalacewa ta hanyar jiyya. Maye gurbi na Telomerase yana cire ƙarin shinge, yana ƙara adadin lokutan da tantanin halitta zai iya raba. Sauran maye gurbi suna ba da damar ƙwayar cuta ta haɓaka sabbin hanyoyin jini don samar da ƙarin abubuwan gina jiki, ko kuma don daidaitawa, yaduwa zuwa wasu sassan jiki. Duk da haka, da zarar an kafa ciwon daji yana ci gaba da samuwa kuma yana samar da ƙananan clones. An ba da rahoto a cikin 2012 cewa samfurin ciwon daji na koda guda ɗaya, wanda aka yi samfurin a wurare daban-daban guda tara, yana da maye gurbi na "ko'ina" 40, wanda aka samu a duk yankuna tara, maye gurbi 59 da wasu suka raba, amma ba duka wurare tara ba, da kuma 29 "masu zaman kansu" kawai. samuwa a wani yanki. ^[27]

Layukan sel waɗanda duk waɗannan sauye-sauyen DNA suka taru suna da wahala a gano su, amma layukan shaidu biyu na baya-bayan nan sun nuna cewa ƙwayoyin sel na yau da kullun na iya zama sel na asali a cikin cututtukan daji.^[28][29] Na farko, akwai ingantacciyar alaƙa mai inganci (Spearman's rho = 0.81; P <3.5 × 10-8) tsakanin haɗarin haɓaka ciwon daji a cikin nama da adadin rarrabuwar sel ta al'ada da ke faruwa a cikin wannan nama. Haɗin gwiwar ya shafi nau'ikan ciwon daji guda 31 kuma ya wuce cikin umarni biyar na girma .^[30] Wannan alaƙar tana nufin cewa idan sel masu tushe na yau da kullun daga nama sun raba sau ɗaya, haɗarin kansa a cikin wannan nama yana kusan 1X. Idan sun raba sau 1,000, haɗarin ciwon daji shine 1,000X. Kuma idan sel masu tushe na al'ada daga nama sun raba sau 100,000, haɗarin ciwon daji a cikin wannan nama yana kusan 100,000X. Wannan yana ba da shawara mai ƙarfi cewa babban abin da ke haifar da cutar kansa shine gaskiyar cewa sel masu “al’ada” suna rarrabuwa, wanda ke nuna cewa ciwon daji ya samo asali ne daga al’ada, ƙwayoyin sel masu lafiya.^[29]

Na biyu, kididdiga ta nuna cewa yawancin cututtukan daji na ɗan adam ana gano su a cikin tsofaffi. Wani bayani mai yiwuwa shi ne cewa ciwon daji na faruwa ne saboda sel suna tara lalacewa ta hanyar lokaci. DNA shine kawai bangaren salula wanda zai iya tara lalacewa a tsawon rayuwar gaba daya, kuma sel mai tushe su ne kawai sel wadanda zasu iya watsa DNA daga zygote zuwa sel a ƙarshen rayuwa. Sauran sel, waɗanda aka samo daga sel mai tushe, ba sa kiyaye DNA daga farkon rayuwa har sai yiwuwar ciwon daji ya faru. Wannan yana nuna cewa yawancin ciwon daji suna tasowa ne daga sel masu tushe na yau da kullun.^[28][29]

An fara amfani da kalmar " ciwon daji na filin " a cikin 1953 don bayyana wani yanki ko "filin" na epithelium wanda aka tsara shi ta hanyar (a wancan lokacin) mafi yawan hanyoyin da ba a san su ba don ƙaddamar da shi zuwa ci gaban ciwon daji. ^[31] Tun daga wannan lokacin, an yi amfani da kalmomin "ciwon daji na filin" da "lalacewar filin" don kwatanta nama mai cutarwa wanda zai iya haifar da sababbin cututtuka.

An gano lahani na fili tare da ciwon daji kuma suna da mahimmanci wajen ci gaba zuwa ciwon daji.^[32][33] Duk da haka, Rubin ^[34] ya nuna cewa "mafi yawancin bincike a cikin binciken ciwon daji an yi su akan ciwace-ciwacen ciwace-ciwacen ƙwayar cuta a cikin vivo, ko kuma a kan tsararren neoplastic foci in vitro. Duk da haka akwai shaidar cewa fiye da kashi 80 cikin 100 na maye gurbi da aka samu a cikin mutator phenotype ɗan adam ciwace-ciwacen ciwace-ciwacen ciwace-ciwacen ciwace-ciwacen ciwace-ciwacen ciwace-ciwacen ciwace-ciwacen ciwace-ciwace na faruwa ne kafin farkon haɓakawar haɓakar clonal na ƙarshen…”^[35] Fiye da rabin maye gurbi da aka gano a cikin ciwace-ciwacen ciwace-ciwacen ciwace ya faru ne a cikin wani lokaci na pre-neoplastic ( a cikin lahani), yayin haɓakar sel na al'ada. Hakanan ana tsammanin cewa yawancin sauye-sauyen epigenetic da ke cikin ciwace-ciwacen ciwace-ciwace na iya faruwa a cikin lahani na filin pre-neoplastic. ^[36]

A cikin hanji kuma, mai yiwuwa lahani ya taso ta hanyar zaɓin yanayi na rikidar halitta ko tantanin halitta da aka canza a tsakanin sel mai tushe a gindin ɗaya daga cikin ɓoyayyen hanji a saman ciki na hanji. Mutant ko Epigenetically canza karan tantanin halitta na iya maye gurbin sauran sassan jikin da ke kusa da zabin yanayi. Wannan na iya haifar da facin nama mara kyau ya tashi. Hoton da ke cikin wannan sashe ya haɗa da hoton wani ɓangaren da aka sake gyarawa da tsayin tsayin sashe na hanjin yana nuna ciwon daji na hanji da polyps guda huɗu. A ƙasan hoton akwai zane mai ƙira na yadda babban facin sel ɗin mutant ko epigenetically canza sel, wanda babban yanki ke nunawa a cikin hoton. A cikin wannan babban faci na farko a cikin zane (babban clone na sel), na biyu irin wannan maye gurbi ko sauye-sauye na epigenetic na iya faruwa, ta yadda kwayar tantanin halitta da aka ba ta ta sami fa'ida idan aka kwatanta da maƙwabtanta, kuma wannan canjin tantanin halitta na iya faɗaɗa clonally, kafa. facin na biyu, ko ƙaramin clone, a cikin facin na asali. Ana nuna wannan a cikin zane ta ƙananan faci guda huɗu na launuka daban-daban a cikin babban yanki na asali na rawaya. A cikin waɗannan sabbin faci (sub-clones),ya kasan ce ana iya maimaita tsarin sau da yawa, waɗanda har yanzu ƙananan faci ke nunawa a cikin faci na biyu (tare da har yanzu launuka daban-daban a cikin zane) waɗanda ke faɗaɗa gabaɗaya, har sai sel masu tushe sun taso waɗanda ke haifar da ƙarami. polyps ko kuma m neoplasm (ciwon daji). A cikin hoton, wani lahani na fili a cikin wannan ɓangaren hanji ya haifar da polyps guda huɗu (wanda aka lakafta tare da girman polyps, 6mm, 5mm, da biyu na 3mm, da ciwon daji kimanin 3). cm tsayi a cikin mafi tsayinsa). Hakanan ana nuna waɗannan neoplasms (a cikin zanen da ke ƙasa hoto) ta 4 ƙananan tan da'irori (polyps) da yanki mai girma ja (ciwon daji). Ciwon daji a cikin hoton ya faru ne a cikin cecal area na hanji, inda hanji ya haɗu da ƙananan hanji (mai lakabi) da kuma inda abin da ke faruwa (labeled). Kitsen da ke cikin hoton yana waje zuwa bangon waje na hanjin. A cikin ɓangaren hanjin da aka nuna a nan, an yanke hanjin a buɗe tsawon tsayi don fallasa samansa da kuma nuna ciwon daji da polyps da ke faruwa a cikin rufin epithelial na ciki na hanjin.

Idan tsarin gaba ɗaya wanda ciwon daji na hanji ya taso shine samuwar pre-neoplastic clone wanda ke yaduwa ta zaɓin yanayi, sannan samuwar ƙananan ƙwayoyin cuta na ciki a cikin farkon clone, da ƙananan ƙananan ƙwayoyin cuta a cikin waɗannan, sannan ciwon daji na hanji. gabaɗaya ya kamata a haɗa su da, kuma a gabace su, fannonin haɓaka rashin daidaituwa, suna nuna gajeriyar abubuwan da suka faru. Mafi girman yanki na rashin daidaituwa (mafi girman yanki na rawaya mara daidaituwa a cikin zane) zai nuna farkon abin da ya faru na samuwar neoplasm mara kyau.

A cikin kimantawa na gwaji na ƙayyadaddun ƙarancin gyaran DNA a cikin cututtukan daji, yawancin ƙarancin gyaran DNA na musamman an kuma nuna suna faruwa a cikin lahani na filin da ke kewaye da waɗannan cututtukan. Teburin da ke ƙasa yana ba da misalan waɗanda aka nuna ƙarancin gyaran DNA a cikin ciwon daji da aka nuna ya haifar da sauye-sauyen epigenetic, da ɗan ƙaramin mitoci waɗanda aka sami ƙarancin gyaran DNA na epigenetically wanda ya haifar da lahani a kewayen filin.

Yawan sauye-sauye na epigenetic a cikin kwayoyin gyaran DNA a cikin ciwon daji na lokaci-lokaci da kuma cikin lahani na kusa.

Ciwon daji	Gene	Yawaita a Ciwon daji	Yawaita a Lalacewar Filin	Magana
Launi mai launi	MGMT	46%	34%
Launi mai launi	MGMT	47%	11%
Launi mai launi	MGMT	70%	60%
Launi mai launi	MSH2	13%	5%	[37]
Launi mai launi	Farashin ERCC1	100%	40%
Launi mai launi	PMS2	88%	50%	[38]
Launi mai launi	XPF	55%	40%	[38]
Kai da wuya	MGMT	54%	38%
Kai da wuya	MLH1	33%	25%
Kai da wuya	MLH1	31%	20%
Ciki	MGMT	88%	78%
Ciki	MLH1	73%	20%
Esophagus	MLH1	77% - 100%	23% -79%

Wasu ƙananan polyps a cikin lahani da aka nuna a cikin hoton ɓangaren hanji na iya zama ƙananan neoplasms. A cikin nazarin 1996 na polyps ya kasan ce kasa da 10mm a girman da aka samo a lokacin colonoscopy kuma an biyo baya tare da maimaita colonoscopies na shekaru 3, 25% ya kasance ba canzawa cikin girman, 35% ya koma baya ko raguwa a girman kuma 40% ya girma cikin girma. ^[39]

An san ciwon daji don nuna rashin zaman lafiyar kwayoyin halitta ko "mutator phenotype".^[40] DNA codeing sunadaran da ke cikin tsakiya shine kusan 1.5% na jimillar DNA na kwayoyin halitta. ^[41] A cikin wannan furotin-coding DNA (wanda ake kira exome ), matsakaicin ciwon daji na nono ko hanji zai iya samun kusan 60 zuwa 70 sunadaran maye gurbi, wanda game da 3 ko 4 na iya zama maye gurbin "direba", sauran kuma na iya zama " fasinja" maye gurbi. ^[36] Koyaya, matsakaicin adadin maye gurbi na jerin DNA a cikin dukkan kwayoyin halitta (ciki har da yankunan da ba su da sinadarai ) a cikin samfurin nama na nono kusan 20,000. ^[42] A cikin matsakaicin samfurin nama na melanoma (melanoma suna da mitar maye gurbi mafi girma), ^[36] ) jimlar adadin maye gurbi na DNA ya kai kusan 80,000. ^[43] Waɗannan manyan mitoci na maye gurbi a cikin jimillar jerin nucleotide a cikin cututtukan daji suna ba da shawarar cewa sau da yawa canjin wuri da wuri a lahani da ke haifar da ciwon daji (misali yankin rawaya a cikin zane a sashin da ya gabata) rashi ne a gyaran DNA. Babban lahani na fili da ke kewaye da kansar hanji (wanda ya kai kusan 10 cm a kowane gefe na ciwon daji) ana samun su^[38] akai-akai suna da lahani na epigenetic a cikin sunadaran gyaran DNA guda biyu ko uku ( ERCC1, ERCC4 (XPF) da / ko PMS2 ) a cikin dukan yanki na lahani. Lokacin da aka rage bayanin kwayoyin gyaran DNA, lalacewar DNA ta taru a cikin sel fiye da yadda aka saba, kuma wannan lalacewar da ta wuce gona da iri tana haifar da ƙara yawan maye gurbi da/ko epimutation. Adadin maye gurbi yana ƙaruwa sosai a cikin sel marasa lahani a cikin gyara rashin daidaituwa na DNA^[21][22] ko a cikin gyaran haɗin gwiwa ( HRR ).^[23] Rashin gyare-gyaren DNA, da kansa, na iya ba da damar lalacewa ta DNA ta taru, kuma kuskuren fassarar fassarar wasu wuraren da suka lalace na iya haifar da maye gurbi. Bugu da kari, kuskuren gyara wannan tararrakin lalacewar DNA na iya haifar da bayyanar cututtuka. Waɗannan sabbin maye gurbi da/ko ƙwanƙwasa na iya ba da fa'ida mai yaduwa, haifar da lahani na filin. Kodayake maye gurbi/emutation a cikin kwayoyin gyaran DNA ba su, da kansu, suna ba da fa'ida ta zaɓi, ana iya ɗaukar su tare da fasinjoji a cikin sel lokacin da tantanin halitta ya sami ƙarin maye gurbi / kwaikwaya wanda ke ba da fa'ida ta haɓaka.

Akwai adadin ra'ayoyin game da ciwon daji da kuma maganin ciwon daji da suka fadi a waje da babban ra'ayi na kimiyya, saboda rashin dalili na kimiyya, tunani, ko tushe shaida.ya kasan ce ana iya amfani da waɗannan ra'ayoyin don ba da hujjar madadin maganin cutar kansa. Ya kamata a bambanta su daga waɗancan ka'idodin carcinogenesis waɗanda ke da tushe mai ma'ana a cikin ilimin halittar kansa na yau da kullun, kuma daga cikinsu za a iya yin hasashe na al'ada.

Da yawa madadin ka'idojin carcinogenesis, duk da haka kuma, sun dogara ne akan shaidar kimiyya kuma ana ƙara yarda da su. Wasu masu bincike sun yi imanin cewa ciwon daji na iya kasancewa ta hanyar aneuploidy (nakasar ƙididdiga da tsari a cikin chromosomes) ^[44] maimakon maye gurbi ko epimutation. Har ila yau, an yi la'akari da ciwon daji a matsayin cututtuka na rayuwa, wanda tsarin salula na oxygen ya juya daga hanyar da ke haifar da makamashi ( phosphorylation oxidative ) zuwa hanyar da ke haifar da nau'in oxygen mai amsawa . ^[45] Wannan yana haifar da sauyawar makamashi daga oxidative phosphorylation zuwa aerobic glycolysis ( Warburg's hypothesis ), da kuma tarin nau'in oxygen mai amsawa wanda ke haifar da damuwa na oxidative ("ka'idar danniya na ciwon daji"). ^[45] Wani ra'ayi na ci gaban ciwon daji ya dogara ne akan fallasa zuwa filayen maganadisu mai rauni da na lantarki da kuma tasirin su akan damuwa na oxidative, wanda aka sani da magnetocarcinogenesis. ^[46]

Yawancin marubuta sun yi tambaya game da zato cewa ciwon daji ke haifarwa daga sauye-sauye na bazuwar a matsayin wuce gona da iri, suna ba da shawarar cewa ciwon daji yana haifar da gazawar jiki don hana haɓakar dabi'un da aka tsara. ^[47] Ka'idar da ke da alaƙa ta nuna cewa kansar cuta ce ta atavism, juyin juyin juya hali zuwa wani nau'i na rayuwa mai yawa a baya . ^[48] Kwayoyin halittar da ke da alhakin haɓakar ƙwayoyin sel marasa sarrafawa da haɗin kai tsakanin ƙwayoyin cutar kansa suna kama da waɗanda suka ba da damar sifofin rayuwa masu yawa na farko don haɗawa tare da bunƙasa. Wadannan kwayoyin halitta har yanzu suna wanzu a cikin kwayoyin halittar metazoans da suka fi hadaddun, kamar mutane, ko da yake kwanan nan kwayoyin halittar da suka samo asali suna kiyaye su. Lokacin da sabbin kwayoyin halittar da ke sarrafa su suka kasa ga kowane dalili, tantanin halitta zai iya komawa ga mafi girman shirye-shiryensa kuma ya sake haifuwa ba tare da kulawa ba. Ka'idar ita ce madadin ra'ayin cewa ciwon daji yana farawa da ƙwayoyin da ba a so ba waɗanda ke jurewa juyin halitta a cikin jiki. Madadin haka, suna da ƙayyadaddun adadin ƙwayoyin halitta na farko waɗanda ake kunna su gabaɗaya, suna ba su iyakataccen canji. ^[49] Wani ka'idar juyin halitta ta sanya tushen ciwon daji zuwa asalin kwayar halitta ta eukaryote (nucleated) ta hanyar jigilar kwayar halitta mai girma, lokacin da kwayoyin halittar kwayoyin cuta suka katse (kuma ta haka ne attenuated) ta wurin mai watsa shiri, amma guntuwar su sun hade cikin kwayar halittar kwayoyin halitta. a matsayin kariya ta rigakafi. Ciwon daji ya samo asali ne lokacin da ba kasafai maye gurbi ya sake hada irin wannan gutsuttsura zuwa aikin yaduwan tantanin halitta. ^[50]

Sau da yawa, yawancin canje-canjen kwayoyin halitta waɗanda ke haifar da ciwon daji na iya ɗaukar shekaru masu yawa don tarawa. A wannan lokacin, dabi'ar ilimin halitta na sel pre-malignant sannu a hankali yana canzawa daga kaddarorin sel na al'ada zuwa kaddarorin masu kama da kansa. Naman da ya rigaya ya yi muni na iya samun siffa ta musamman a ƙarƙashin na'urar hangen nesa. Daga cikin halayyar rarrabuwa na masarar pre-mawuyacin hali sune karu adadin sel sel, bambancin nukiliya da sifa, da asarar kwayar halitta, da kuma asarar tsari na al'ada. Dysplasia wani nau'in nau'in cuta ne na ƙwayar cuta. Wadannan canje-canje na farko na neoplastic dole ne a bambanta su daga hyperplasia, karuwa mai canzawa a cikin rarraba tantanin halitta wanda ya haifar da wani abu na waje, irin su rashin daidaituwa na hormonal ko fushi na yau da kullum.

Mafi tsanani lokuta na dysplasia ana kiransa carcinoma a wurin. A Latin, kalmar a wurin tana nufin "a wurin"; carcinoma a wurin yana nufin haɓakar sel dysplastic wanda ba a sarrafa shi ba wanda ya rage a wurinsa na asali kuma bai nuna mamayewa cikin wasu kyallen takarda ba. Carcinoma a wurin na iya haɓaka zuwa mummunan cutarwa kuma yawanci ana cire shi ta hanyar tiyata idan an gano shi.

Kamar dai yadda yawan dabbobi ke fuskantar juyin halitta, yawan sel wanda ba a tantance shi ba zai iya samun "juyin halitta". Wannan tsarin da ba a so ana kiransa juyin halitta somatic, kuma shine yadda ciwon daji ke tasowa kuma ya zama mafi muni a cikin lokaci.^[51]

Yawancin canje-canje a cikin salon salula wanda ke ba da damar sel suyi girma cikin yanayin rashin lafiya suna haifar da mutuwar tantanin halitta. Koyaya, da zarar ciwon daji ya fara, ƙwayoyin kansa suna jurewa tsarin zaɓin yanayi : ƴan sel waɗanda ke da sabbin sauye-sauyen kwayoyin halitta waɗanda ke haɓaka rayuwarsu ko haifuwa suna haɓaka da sauri, kuma nan da nan suka mamaye ƙari mai girma yayin da sel waɗanda ke da ƙarancin canji na kwayoyin halitta sun fita gasa. . ^[52] Wannan ita ce hanyar da nau'ikan cututtuka irin su MRSA za su iya zama masu juriya na ƙwayoyin cuta kuma ta hanyar da kwayar cutar HIV za ta iya zama mai juriya da kwayoyi ), kuma ta yadda cututtuka da kwari za su iya zama masu jurewa maganin kwari . Wannan juyin halitta ya bayyana dalilin da ya sa komawar ciwon daji yakan ƙunshi sel waɗanda suka sami juriya-maganin ciwon daji ko juriya ga aikin rediyo ).

A cikin labarin 2000 na Hanahan da Weinberg, an taƙaita kaddarorin halittu na ƙwayoyin cuta masu cutarwa kamar haka:^[53]

• Samun wadatar kai a cikin siginar girma, yana haifar da ci gaban da ba a kula da shi ba.
• Rashin hankali ga sigina na hana haɓaka girma, kuma yana haifar da haɓakar da ba a kula ba.
• Asarar iya aiki don apoptosis, ƙyale girma duk da kurakuran kwayoyin halitta da siginonin rigakafin ci gaba na waje.
• Asarar iyawa don tsufa, yana haifar da yuwuwar kwafi mara iyaka (dawwama)
• Samun ci gaba da angiogenesis, ƙyale ƙwayar cuta ta girma fiye da iyakancewar yaduwar abinci mai gina jiki.
• Samun ikon mamaye kyallen maƙwabta, ƙayyadaddun ƙayyadaddun ƙayyadaddun ƙwayar cutar sankara.
• Samun ikon zuriyar metastases a wurare masu nisa, kayan da ke bayyana a ƙarshen lokaci na wasu ciwace-ciwacen ƙwayar cuta (carcinomas ko wasu).

Kammala waɗannan matakai da yawa zai zama wani abu mai wuyar gaske ba tare da:

• Rashin ƙarfin gyara kurakuran kwayoyin halitta, yana haifar da haɓakar haɓakar maye gurbi (rashin lafiyar kwayoyin halitta), don haka yana hanzarta duk sauran canje-canje.

Wadannan canje-canjen halittu sune na gargajiya a cikin carcinomas ; sauran mugayen ciwace-ciwace na iya buƙatar cimma su duka. Misali, da aka ba cewa mamayewar nama da ƙaura zuwa wurare masu nisa sune abubuwan al'ada na leukocytes, waɗannan matakan ba a buƙatar su don haɓakar cutar sankarar bargo . Haka kuma matakan daban-daban ba lallai ba ne suna wakiltar maye gurbin mutum ɗaya. Alal misali, rashin kunna kwayar halitta guda ɗaya, codeing don furotin p53, zai haifar da rashin zaman lafiyar kwayoyin halitta, kaucewa apoptosis da karuwar angiogenesis. Bugu da ari, ba duka kwayoyin cutar kansa ke rarraba ba. Maimakon haka, wani yanki na sel a cikin wani ƙari, wanda ake kira ciwon daji mai tushe, suna maimaita kansu yayin da suke haifar da sel daban-daban.^[54]

A al'ada, da zarar nama ya ji rauni ko ya kamu da cutar, ƙwayoyin da suka lalace suna haifar da kumburi ta hanyar haɓaka takamaiman tsarin aikin enzyme da kuma bayyanar kwayar halittar cytokine a cikin sel kewaye. ^[55][56] An ɓoye gungu masu hankali ("gungu na cytokine") na ƙwayoyin cuta, waɗanda ke aiki azaman matsakanci, suna haifar da ayyukan sauye-sauye na biochemical na gaba. ^[57] Kowane cytokine yana ɗaure ga takamaiman masu karɓa akan nau'ikan tantanin halitta daban-daban, kuma kowane nau'in tantanin halitta yana amsawa bi da bi ta hanyar canza ayyukan hanyoyin jigilar siginar ciki, dangane da masu karɓan da tantanin halitta ke bayyanawa da ƙwayoyin siginar da ke cikin tantanin halitta. ^[58][59] Gabaɗaya, wannan tsarin sake tsarawa yana haifar da canji na mataki-mataki a cikin nau'ikan halittun tantanin halitta, wanda a ƙarshe zai haifar da maido da aikin nama kuma zuwa ga maido da ingantaccen tsarin tsari.^[60][61] Nama zai iya warke ta haka, ya danganta da ingantaccen sadarwa tsakanin sel da ke wurin lalacewa da tsarin rigakafi. ^[62] Ɗaya daga cikin mahimmin abu a cikin warkaswa shine ka'idodin maganganun kwayoyin halitta na cytokine, wanda ke ba da damar ƙungiyoyin haɗin gwiwa na sel don amsawa ga masu shiga tsakani ta hanyar da a hankali ke haifar da canje-canje masu mahimmanci a cikin ilimin halittar jiki.^[63][64][65] Kwayoyin ciwon daji suna da ko dai na dindindin (kwayoyin halitta) ko masu canzawa (epigenetic) canje-canje zuwa kwayoyin halittarsu, wanda wani bangare ya hana sadarwar su tare da ƙwayoyin da ke kewaye da kuma tare da tsarin rigakafi.^[66][67] Kwayoyin ciwon daji ba sa sadarwa tare da microenvironment na nama ta hanyar da ke kare mutuncin nama; a maimakon haka, motsi da tsirar ƙwayoyin cutar kansa ya zama mai yiwuwa a wuraren da za su iya lalata aikin nama.^[68][69] Kwayoyin ciwon daji suna rayuwa ta hanyar "sakewa" hanyoyin sigina waɗanda yawanci ke kare nama daga tsarin rigakafi. Wannan canji na martanin rigakafi yana bayyana a farkon matakan cutar ma.^[70][71]

Ɗaya daga cikin misalan aikin gyaran nama a cikin ciwon daji shine aikin factor factor NF-κB . ^[72] NF-κB yana kunna bayyanar da yawancin kwayoyin halitta da ke cikin canji tsakanin kumburi da sabuntawa, wanda ke ɓoye cytokines, abubuwan mannewa, da sauran kwayoyin da zasu iya canza yanayin tantanin halitta.^[73] Wannan sake fasalin fasalin salon salula yana ba da damar haɓaka nama maras aiki cikakke. ^[74] Ayyukan NF-κB ana sarrafa su ta hanyar sunadaran sunadaran da yawa, waɗanda ke tare da tabbatar da cewa NF-κB ne kawai ke haifar da tantanin halitta kuma a lokacin da aka ba da shi.^[75] Wannan ƙaƙƙarfan ƙa'idar musayar sigina tsakanin sel yana kare nama daga kumburi da yawa, kuma yana tabbatar da cewa nau'ikan tantanin halitta daban-daban a hankali suna samun ƙarin ayyuka da takamaiman matsayi. Rashin wannan ƙa'ida ta juna tsakanin tsarin tsarin kwayoyin halitta da hulɗar tantanin halitta yana ba da damar ƙwayoyin kansa su haifar da metastasis. Kwayoyin ciwon daji suna amsawa ga cytokines, kuma suna kunna siginar sigina wanda zai iya kare su daga tsarin rigakafi.^[76][77]

Ba a fahimta gaba ɗaya rawar da iodine ke takawa a cikin kifin ruwa (mai arzikin iodine) da kuma kifin ruwa mai tsabta (rashin iodine) ba, amma an ruwaito cewa kifin ruwa ya fi kamuwa da cututtuka kuma, musamman, cututtukan neoplastic da atherosclerotic, fiye da na ruwa. kifi.^[77][78] Kifayen elasmobranch na ruwa kamar su sharks, stingrays da dai sauransu ba su da cutar kansa da yawa fiye da kifin ruwa mai daɗi, don haka sun ƙarfafa binciken likita don ƙarin fahimtar cutar sankara. ^[79]

Domin sel su fara rarrabuwa ba tare da kamewa ba, dole ne a lalatar da kwayoyin halittar da ke daidaita girman tantanin halitta. ^[80] Proto-oncogenes su ne kwayoyin halitta waɗanda ke haɓaka haɓakar tantanin halitta da mitosis, yayin da ƙwayoyin cuta masu hana ƙari ke hana haɓakar tantanin halitta, ko dakatar da rarraba tantanin halitta na ɗan lokaci don aiwatar da gyaran DNA . Yawanci, ana buƙatar jerin maye gurbi da yawa zuwa waɗannan kwayoyin halitta kafin tantanin halitta ta al'ada ya rikide zuwa kwayar cutar kansa . ^[5] Wannan ra'ayi wani lokaci ana kiransa "oncoevolution." Maye gurbi ga waɗannan kwayoyin halitta suna ba da sigina don ƙwayoyin ƙari don fara rarrabawa ba tare da kulawa ba. Amma sashin sel wanda ba a sarrafa shi wanda ke siffanta kansar kuma yana buƙatar cewa mai rarraba tantanin halitta ya kwafi duk abubuwan da ke cikin salula don ƙirƙirar ƴan mata biyu. Kunna glycolysis anaerobic ( sakamako na Warburg ), wanda ba lallai ba ne ya haifar da maye gurbi a cikin proto-oncogenes da ƙwayoyin cuta masu hana ƙari, ^[81] yana ba da mafi yawan ginshiƙan ginin da ake buƙata don kwafi sassan salula na tantanin halitta mai rarraba kuma, saboda haka, Hakanan yana da mahimmanci ga carcinogenesis. ^[45]

Oncogenes suna haɓaka haɓakar sel ta hanyoyi daban-daban. Mutane da yawa za su iya samar da hormones, "manzon sunadarai" tsakanin sel da ke ƙarfafa mitosis, sakamakon abin da ya dogara da siginar siginar nama mai karɓa ko sel. A wasu kalmomi, lokacin da aka kunna mai karɓar hormone a kan tantanin halitta mai karɓa, ana gudanar da siginar daga saman tantanin halitta zuwa kwayar halitta don rinjayar wasu canje-canje a tsarin rubutun kwayoyin halitta a matakin nukiliya. Wasu oncogenes wani ɓangare ne na tsarin watsa siginar kanta, ko kuma masu karɓar siginar a cikin sel da kyallen jikinsu da kansu, don haka suna sarrafa hankalin irin wannan hormones. Oncogenes sau da yawa suna samar da mitogens, ko kuma suna shiga cikin rubutun DNA a cikin haɗin furotin, wanda ke haifar da sunadaran da enzymes da ke da alhakin samar da samfurori da kwayoyin halitta suna amfani da su kuma suna hulɗa da su.

Maye gurbi a cikin proto-oncogenes, waɗanda su ne takwarorinsu na yau da kullun na oncogenes, na iya canza magana da aikin su, ƙara adadin ko ayyukan furotin samfurin. Lokacin da wannan ya faru, proto-oncogenes sun zama oncogenes, kuma wannan canji yana tayar da ma'auni na al'ada na tsarin sake zagayowar tantanin halitta a cikin tantanin halitta, yana sa haɓakar rashin kulawa zai yiwu. Ba za a iya rage damar ciwon daji ta hanyar cire proto-oncogenes daga kwayoyin halitta, koda kuwa hakan zai yiwu, saboda suna da mahimmanci ga girma, gyarawa da homeostasis na kwayoyin halitta. Sai kawai lokacin da suka zama rikida ne alamun girma ya wuce kima.

Ɗaya daga cikin na farko oncogenes da za a bayyana a cikin binciken ciwon daji shine ras oncogene . Maye gurbi a cikin dangin Ras na proto-oncogenes (wanda ya ƙunshi H-Ras, N-Ras da K-Ras) suna da yawa, ana samun su a cikin 20% zuwa 30% na duk ciwace-ciwacen ɗan adam. ^[82] An gano asalin Ras a cikin kwayar cutar kwayar cutar Harvey sarcoma, kuma masu bincike sun yi mamakin cewa ba wai kawai wannan kwayar halitta ta kasance a cikin kwayoyin halittar dan adam ba amma kuma, idan aka danganta shi da wani nau'in sarrafawa mai motsa rai, yana iya haifar da cutar kansa a cikin al'adun layin salula.^[83]

Proto-oncogenes ya kasan ce suna haɓaka tantanin halitta ta hanyoyi daban-daban. Mutane da yawa na iya samar da hormones, "manzannin sunadarai" tsakanin sel waɗanda ke ƙarfafa mitosis, sakamakon abin da ya dogara da siginar siginar nama mai karɓa ko sel. Wasu suna da alhakin tsarin siginar sigina da masu karɓar sigina a cikin sel da kyallen jikin su da kansu, don haka suna sarrafa hankalin irin wannan hormones. Sau da yawa suna samar da mitogens, ko kuma suna shiga cikin rubutun DNA a cikin haɗin furotin, wanda ke haifar da sunadaran da enzymes da ke da alhakin samar da samfurori da kwayoyin halitta suna amfani da su kuma suna hulɗa da su.

Maye gurbi a cikin proto-oncogenes na iya canza magana da aikin su, ƙara adadi ko ayyukan furotin samfurin. Lokacin da wannan ya faru, sun zama oncogenes, kuma, don haka, sel suna da damar da za su rarraba fiye da kima kuma ba tare da kulawa ba. Ba za a iya rage damar ciwon daji ta hanyar cire proto-oncogenes daga kwayoyin halitta, kamar yadda suke da mahimmanci ga girma, gyarawa da homeostasis na jiki. Sai kawai lokacin da suka zama rikida ne alamun girma ya wuce kima. Yana da mahimmanci a lura cewa kwayar halittar da ke da rawar haɓaka haɓaka na iya ƙara yuwuwar cutar sankara ta tantanin halitta, ƙarƙashin yanayin cewa ana kunna duk mahimman hanyoyin salula waɗanda ke ba da izinin haɓakawa. ^[84] Wannan yanayin kuma ya haɗa da rashin kunna takamaiman ƙwayoyin cuta masu hana ƙari (duba ƙasa). Idan yanayin bai cika ba, tantanin halitta na iya daina girma kuma zai iya ci gaba da mutuwa. Wannan ya sa gano mataki da nau'in kwayar cutar kansa da ke girma a ƙarƙashin kulawar da aka ba wa oncogene mai mahimmanci don haɓaka dabarun jiyya.

Tumor suppressor genes code for anti-proliferation signals and proteins da ke hana mitosis da ci gaban cell. Gabaɗaya, masu hana ƙari abubuwan rubutu ne waɗanda ke kunna su ta hanyar damuwa ta salula ko lalata DNA. Sau da yawa lalacewar DNA zai haifar da kasancewar kayan kwayoyin halitta masu kyauta da sauran alamu, kuma zai haifar da enzymes da hanyoyin da ke haifar da kunna kwayoyin cutar ciwon tumo . Ayyukan irin waɗannan kwayoyin halitta shine kama ci gaban tsarin tantanin halitta don gudanar da gyaran DNA, ya kasan ce yana hana maye gurbi daga shiga cikin sel diya mace. Sunan furotin p53, ɗayan mahimman binciken ƙwayoyin cuta masu hana ƙari, wani abu ne na rubutu wanda yawancin matsalolin salon salula ke kunna ciki har da hypoxia da lalacewar radiation ultraviolet .

Duk da kusan rabin duk cututtukan daji mai yuwuwa sun haɗa da gyare-gyare a cikin p53, aikin hana ƙwayar cuta ba a fahimta sosai ba. p53 a fili yana da ayyuka guda biyu: ɗaya rawar nukiliya a matsayin nau'in rubutu, ɗayan kuma rawar cytoplasmic wajen daidaita tsarin tantanin halitta, rabon tantanin halitta, da apoptosis.

Hasashen Warburg shine fifikon amfani da glycolysis don kuzari don ci gaban cutar kansa. An nuna p53 don daidaita motsi daga numfashi zuwa hanyar glycolytic. ^[85]

Duk da haka, maye gurbi na iya lalata kwayar cutar ƙwayar cuta da kanta, ko kuma hanyar siginar da ke kunna ta, "canza shi". Sakamakon da ba za a iya canzawa ba shine cewa gyaran DNA yana hanawa ko hanawa: lalacewar DNA ta taru ba tare da gyara ba, babu makawa yana haifar da ciwon daji.

Maye gurbi na ƙwayoyin cuta masu hana ƙari waɗanda ke faruwa a cikin ƙwayoyin cuta suna wucewa zuwa zuriya, kuma suna ƙara yuwuwar gano cutar kansa a cikin tsararraki masu zuwa. Membobin waɗannan iyalai sun ƙaru kuma sun rage jinkirin ciwace-ciwace da yawa. Nau'in ciwon daji sun kasance na yau da kullun ga kowane nau'in ƙwayar cuta mai hana ƙwayar ƙwayar cuta, tare da wasu maye gurbi suna haifar da cututtukan daji na musamman, da sauran maye gurbi suna haifar da wasu. Yanayin gado na mutant tumor suppressors shi ne cewa memba da abin ya shafa ya gaji nakasar kwafi daga iyaye ɗaya, da kwafi na yau da kullun daga ɗayan. Misali, mutanen da suka gaji mutant p53 allele (saboda haka heterozygous don maye gurbin p53 ) na iya haifar da melanoma da ciwon daji na pancreatic, wanda aka sani da cutar Li-Fraumeni . Sauran cututtukan cututtukan cututtukan cututtukan ƙwayar cuta da aka gada sun haɗa da maye gurbi na Rb, wanda ke da alaƙa da retinoblastoma, da maye gurbi na APC, wanda ke da alaƙa da ciwon daji na adenopolyposis . Adenopolyposis ciwon daji na hanji yana da alaƙa da dubban polyps a cikin hanji yayin ƙanana, wanda ke haifar da ciwon daji a hanji tun yana ƙanana. A ƙarshe, maye gurbi da aka gada a cikin BRCA1 da BRCA2 suna haifar da farkon farkon ciwon nono .

An kuma ba da shawarar haɓaka ciwon daji a cikin 1971 don dogara da aƙalla abubuwan maye gurbi guda biyu. A cikin abin da aka fi sani da Knudson na biyu-buga hasashe, gadon, maye gurbi a cikin kwayar cutar da ke kawar da ƙari zai haifar da ciwon daji kawai idan wani yanayin maye gurbi ya faru daga baya a cikin rayuwar kwayoyin halitta, wanda ba ya kunna sauran allele na wannan kwayar cutar ciwon daji .^[86]

Yawancin lokaci, oncogenes ya kasan ce suna da rinjaye, kamar yadda suke dauke da maye gurbi, yayin da rikitattun ƙwayoyin cuta suna raguwa, ya kasan ce kuma kamar yadda suka ƙunshi maye gurbi na asarar aiki . Kowane tantanin halitta yana da kwafi guda biyu na kwayar halitta iri ɗaya, ɗaya daga kowane iyaye, kuma a mafi yawan lokuta samun sauye-sauyen aiki a cikin kwafin guda ɗaya na takamaiman proto-oncogene ya kuma isa ya sanya wannan kwayar halitta ta zama oncogene na gaske. A gefe guda, asarar maye gurbi na aiki yana buƙatar faruwa a cikin kwafi biyu na kwayar cutar da ke hana ƙari don mayar da wannan ƙwayar gaba ɗaya baya aiki. Koyaya, akwai lokuta waɗanda ɗayan mutatattun kwafin ƙwayar ƙwayar cuta mai hana ƙari zai iya sanya ɗayan, kwafin nau'in daji mara aiki. Ana kuma kiran wannan al'amari babban tasiri mara kyau kuma ana lura dashi a yawancin maye gurbi na p53.

Ya kasan ce kwanan nan masu bincike damara kyau kuma ana lura dashi a yawancin maye gurbi na p53. yawa sun ƙalubalanci samfurin Knudson guda biyu. ya kasan ce Rashin kunna allele guda ɗaya na wasu ƙwayoyin cuta masu hana ƙari ya wadatar don haifar da ciwace-ciwace. Ana kiran wannan al'amari haploinsufficiency kuma an nuna shi ta hanyoyi da yawa na gwaji. Ciwon daji da ke haifar da haploinsufficiency yawanci suna da shekaru masu zuwa na farawa idan aka kwatanta da waɗanda ta hanyar bugu biyu. ^[87]

Gabaɗaya, maye gurbi a cikin nau'ikan kwayoyin halitta guda biyu ana buƙatar don cutar kansa. Misali, maye gurbi da aka iyakance ga oncogene guda ɗaya za a kashe shi ta hanyar sarrafa mitosis na al'ada da ƙwayoyin cuta masu hana ƙari, wanda aka fara hasashe ta hasashen Knudson^[3] Canje-canje ga ƙwayar ƙwayar cuta guda ɗaya kawai ba zai haifar da ciwon daji ba, saboda kasancewar “kwayoyin halitta” da yawa waɗanda ke yin kwafin ayyukansa. Sai kawai lokacin da isassun proto-oncogenes suka rikide zuwa cikin oncogenes, kuma isassun ƙwayoyin ƙwayoyin cuta masu hana ƙari suka lalace ko suka lalace, siginonin haɓakar tantanin halitta ya mamaye sigina don daidaita shi, haɓakar tantanin halitta da sauri ya karkace daga sarrafawa. ^[5] Sau da yawa, saboda waɗannan kwayoyin halitta suna tsara hanyoyin da ke hana yawancin lalacewa ga kwayoyin halitta da kansu, adadin maye gurbi yana ƙaruwa yayin da mutum ya tsufa, saboda lalacewar DNA ta haifar da madauki na amsawa .

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