Son y\u0131llarda, a\u011f\u0131z ve bo\u011faz\u0131n arka k\u0131sm\u0131nda ortaya \u00e7\u0131kan HPV ili\u015fkili orofarengeal kanserlerin g\u00f6r\u00fclme s\u0131kl\u0131\u011f\u0131nda \u00f6nemli bir art\u0131\u015f ya\u015fanmaktad\u0131r. HPV-pozitif orofarengeal kanserlerin erken evrede te\u015fhisi, hastalara y\u00fcksek oranda sa\u011fkal\u0131m \u015fans\u0131 sunsa da, bu hastalar\u0131n yakla\u015f\u0131k y\u00fczde yirmisi agresif t\u00fcm\u00f6r biyolojisi ve geleneksel tedavilere diren\u00e7 nedeniyle k\u00f6t\u00fc prognozla kar\u015f\u0131 kar\u015f\u0131yad\u0131r. University of California San Diego\u2019da y\u00fcr\u00fct\u00fclen \u00f6nc\u00fc bir ara\u015ft\u0131rma, bu agresif HPV-pozitif kanser varyantlar\u0131n\u0131n molek\u00fcler temelini anlamaya y\u00f6nelik \u00f6nemli bulgular ortaya koymu\u015ftur. Bu \u00e7al\u0131\u015fman\u0131n merkezinde, insan genomu ile HPV DNA\u2019s\u0131n\u0131n par\u00e7alar\u0131n\u0131n f\u00fczyonu sonucu olu\u015fan hibrit ekstrakromozomal dairesel DNA (ecDNA) yap\u0131s\u0131 yer almaktad\u0131r.<\/p>\n
Ekstrakromozomal dairesel DNA, h\u00fccre \u00e7ekirde\u011finde standart kromozomal mimarinin d\u0131\u015f\u0131nda bulunan k\u00fc\u00e7\u00fck, dairesel DNA molek\u00fclleridir. Bu ecDNA’lar kromozomlara ba\u011fl\u0131 olmayan yap\u0131lar olmalar\u0131na ra\u011fmen, \u00f6zellikle kanserlerde h\u00fccresel i\u015flevlerin d\u00fczenlenmesinde a\u015f\u0131r\u0131 derecede rol oynarlar. \u00d6nceki ara\u015ft\u0131rmalar ecDNA\u2019n\u0131n t\u00fcm\u00f6rlerin ba\u011f\u0131\u015f\u0131kl\u0131k sisteminden ka\u00e7mas\u0131n\u0131 sa\u011flad\u0131\u011f\u0131n\u0131 ve onkogenlerin amplifikasyonuna katk\u0131da bulundu\u011funu g\u00f6stermi\u015ftir. Ancak bu yeni \u00e7al\u0131\u015fmada vurgulanan en dikkat \u00e7ekici geli\u015fme, viral HPV DNA par\u00e7alar\u0131n\u0131n insan kromozomal materyaliyle rastgele birle\u015ferek meydana getirdi\u011fi hibrit ecDNA\u2019lar\u0131n ke\u015ffedilmesidir. Bu yap\u0131lar, HPV-pozitif orofarengeal kanserlerin yakla\u015f\u0131k y\u00fczde 30\u2019unda saptanm\u0131\u015f ve kanserin malign potansiyelini art\u0131ran ortak bir mekanizma olarak g\u00f6r\u00fclmektedir.<\/p>\n
Orofarengeal t\u00fcm\u00f6r h\u00fccrelerinde saptanan hibrit ecDNA\u2019lar\u0131n ayr\u0131nt\u0131l\u0131 transkripsiyonel profillenmesi s\u0131ras\u0131nda, hem viral hem de insan DNA segmentlerinde daha \u00f6nce tan\u0131mlanmam\u0131\u015f g\u00fc\u00e7lendirici (enhancer) elementleri tespit edilmi\u015ftir. Bu enhancer\u2019lar, birbirleri ile sinerjik etkile\u015fim i\u00e7inde hareket ederek t\u00fcm\u00f6r \u00e7o\u011falmas\u0131n\u0131 destekleyen genlerin ifadesini art\u0131rmaktad\u0131r. Bu genomik etkile\u015fimler, viral HPV DNA\u2019n\u0131n replikasyonunu ve konak h\u00fccrelerde onkogenik sinyal yolaklar\u0131n\u0131 e\u015f zamanl\u0131 olarak kuvvetlendiren bir geri besleme d\u00f6ng\u00fcs\u00fc yaratmaktad\u0131r. \u00d6zetle, bu hibrit ecDNA molek\u00fcl\u00fc, hem viral hem de t\u00fcm\u00f6r h\u00fccrelerine ait genetik aktiviteleri g\u00fc\u00e7lendiren bir molek\u00fcler amplifikat\u00f6r g\u00f6revi g\u00f6rmektedir.<\/p>\n
Ara\u015ft\u0131rmada tan\u0131mlanan bu g\u00fc\u00e7l\u00fc enhancer\u2019lar, hedefe y\u00f6nelik m\u00fcdahaleler i\u00e7in yeni kap\u0131lar aralam\u0131\u015ft\u0131r. CRISPR gen d\u00fczenleme teknolojisi kullan\u0131larak bu enhancer b\u00f6lgeleri ba\u015far\u0131yla devre d\u0131\u015f\u0131 b\u0131rak\u0131lm\u0131\u015f ve transkripsiyonel aktivite azalt\u0131lm\u0131\u015ft\u0131r. Benzer \u015fekilde, kromatin durumu ve gen ekspresyonunu d\u00fczenleyen proteinlerin fonksiyonlar\u0131 da bask\u0131lanarak t\u00fcm\u00f6r h\u00fccrelerinin \u00e7o\u011falma h\u0131z\u0131 \u00f6nemli \u00f6l\u00e7\u00fcde d\u00fc\u015f\u00fcr\u00fclm\u00fc\u015ft\u00fcr. Bu iki y\u00f6ntem, ekspre edilen gen ekspresyonuna dayanan HPV kaynakl\u0131 t\u00fcm\u00f6rlerde ecDNA\u2019ya ba\u011f\u0131ml\u0131l\u0131\u011f\u0131 vurgulayan \u00f6nemli bir k\u0131r\u0131lganl\u0131k noktas\u0131 ortaya koymu\u015ftur.<\/p>\n
Bu bilimsel \u00e7al\u0131\u015fma, viral ve insan DNA\u2019s\u0131n\u0131n hibrit ecDNA\u2019lar arac\u0131l\u0131\u011f\u0131yla genetik d\u00fczenleyici a\u011flar\u0131 nas\u0131l korsanla\u015ft\u0131rd\u0131\u011f\u0131n\u0131 ve t\u00fcm\u00f6r progresyonunu h\u0131zland\u0131rd\u0131\u011f\u0131n\u0131 ortaya koyarak HPV ili\u015fkili kanser biyolojisine \u00f6nemli bir katk\u0131 sa\u011flam\u0131\u015ft\u0131r. Yakla\u015f\u0131k y\u00fczde 20 oran\u0131nda k\u00f6t\u00fc prognozlu hastan\u0131n mevcut tedavi se\u00e7eneklerinin yetersiz oldu\u011fu d\u00fc\u015f\u00fcn\u00fcld\u00fc\u011f\u00fcnde, bu bulgular \u00f6ncelikli hastalar i\u00e7in tedavi geli\u015ftirmenin kritik bir temelini olu\u015fturacakt\u0131r. Hibrit ecDNA yap\u0131lar\u0131n\u0131n se\u00e7ici \u015fekilde hedeflenmesi, sa\u011fl\u0131kl\u0131 h\u00fccrelere zarar vermeden etkili terapi stratejilerinin tasarlanmas\u0131n\u0131 m\u00fcmk\u00fcn k\u0131lmaktad\u0131r.<\/p>\n
\u00c7al\u0131\u015fman\u0131n ilk yazar\u0131 ve alandaki y\u00fckselen isimlerden Takuya Nakagawa, Chiba \u00dcniversitesi Hastanesi\u2019nde y\u00fcr\u00fct\u00fclen \u00e7al\u0131\u015fmalar\u0131 \u0131\u015f\u0131\u011f\u0131nda, hibrit ecDNA \u00fczerindeki enhancer\u2019lar\u0131n hedeflenmesinin diren\u00e7li t\u00fcm\u00f6rlerde b\u00fcy\u00fcmenin durdurulmas\u0131 i\u00e7in olduk\u00e7a umut verici bir strateji oldu\u011funu vurgulam\u0131\u015ft\u0131r. Bu se\u00e7ici m\u00fcdahale \u015fekli, sa\u011fl\u0131kl\u0131 dokulara zarar veren geleneksel tedavilerin aksine daha etkin ve yan etkisiz bir yakla\u015f\u0131m sunmaktad\u0131r.<\/p>\n
UC San Diego Moores Kanser Merkezi Gleiberman Ba\u015f ve Boyun Kanser Merkezi direkt\u00f6r\u00fc Dr. Joseph Califano ise, ara\u015ft\u0131rman\u0131n daha geni\u015f etkilerine dikkat \u00e7ekmi\u015ftir. Kendi laboratuvar\u0131, ecDNA\u2019y\u0131 destabilize edebilecek farmakolojik ajanlar \u00fczerinde \u00e7al\u0131\u015fmakta olup, sadece orofarengeal kanserler de\u011fil, ecDNA\u2019n\u0131n malign fenotipleri destekledi\u011fi di\u011fer t\u00fcm\u00f6r t\u00fcrlerinde de potansiyel tedavi y\u00f6ntemleri geli\u015ftirilmesini ama\u00e7lamaktad\u0131r. Bu yakla\u015f\u0131m, kanserin genetik mimarisine m\u00fcdahale eden yeni nesil hassas ila\u00e7lar\u0131n geli\u015ftirilmesini h\u0131zland\u0131racakt\u0131r.<\/p>\n
\u00d6zellikle Califano\u2019nun y\u00fcr\u00fctt\u00fc\u011f\u00fc \u00e7al\u0131\u015fmalar, HPV ili\u015fkili ecDNA ile konak kromozomal DNA aras\u0131ndaki karma\u015f\u0131k ileti\u015fimi detayland\u0131rmaktad\u0131r. \u0130lk bulgular, ecDNA etkilerinin bulunduklar\u0131 genlerle s\u0131n\u0131rl\u0131 kalmay\u0131p, genom genelinde kromozomal d\u00fczenleyici devreleri yeniden programlayarak t\u00fcm\u00f6r h\u00fccrelerinin dayan\u0131kl\u0131l\u0131\u011f\u0131n\u0131 ve adaptasyon yetene\u011fini art\u0131rd\u0131\u011f\u0131 y\u00f6n\u00fcndedir.<\/p>\n
Hibrit ecDNA\u2019n\u0131n ortaya \u00e7\u0131k\u0131\u015f\u0131, HPV\u2019nin kanserle\u015fme s\u00fcre\u00e7lerine dair geleneksel anlay\u0131\u015flar\u0131 sorgulatmaktad\u0131r. Vir\u00fcs\u00fcn konak genomuna pasif entegrasyonundan ziyade, viral DNA\u2019n\u0131n ekstrakromozomal yeni yap\u0131lar olu\u015fturarak gen reg\u00fclasyon mekanizmalar\u0131n\u0131 \u00e7arp\u0131tmas\u0131, HPV\u2019nin aktif bir \u015fekilde genetik yeniden yap\u0131land\u0131rmaya kat\u0131ld\u0131\u011f\u0131n\u0131 g\u00f6stermektedir. Bu paradigma de\u011fi\u015fikli\u011fi, HPV\u2019nin kanser patogenezindeki rol\u00fcn\u00fc yeniden de\u011ferlendirmeyi gerektirmektedir.<\/p>\n
ecDNA\u2019y\u0131 hedef alan terap\u00f6tik stratejiler, \u00f6zellikle mevcut tedavilere diren\u00e7li HPV pozitif orofarengeal kanserlerde devrim yaratma potansiyeline sahiptir. CRISPR tabanl\u0131 gen d\u00fczenleme ile epigenetik mod\u00fclat\u00f6rleri etkileyen ila\u00e7lar\u0131n kombinasyonu; kanserlerin genetik ve epigenetik destek sistemlerini \u00e7ok y\u00f6nl\u00fc olarak zay\u0131flatacak daha etkili tedavi rejimleri olu\u015fturabilir. Bu teknolojilerin y\u00fcksek do\u011fruluk oran\u0131, hedef d\u0131\u015f\u0131 etkilerin azalt\u0131lmas\u0131 ve hastalar\u0131n ya\u015fam kalitesinin art\u0131r\u0131lmas\u0131 a\u00e7\u0131s\u0131ndan \u00f6nem ta\u015f\u0131maktad\u0131r.<\/p>\n
Nature Communications dergisinde 26 Mart 2025\u2019te yay\u0131mlanan makale, y\u00fcksek kapasiteli dizileme teknikleri, kromatin imm\u00fcnprecipitasyon ve ileri d\u00fczey gen ekspresyon analizi gibi karma\u015f\u0131k molek\u00fcler y\u00f6ntemleri i\u00e7ermektedir. Bu kapsaml\u0131 y\u00f6ntemler sayesinde hibrit ecDNA\u2019lar\u0131n sakl\u0131 genomik etkile\u015fimleri a\u00e7\u0131\u011fa \u00e7\u0131kar\u0131lm\u0131\u015f ve viral geneti\u011fi entegre eden daha n\u00fcansl\u0131 kanser biyolojisi modellerine ge\u00e7i\u015f sa\u011flanm\u0131\u015ft\u0131r.<\/p>\n
HPV ili\u015fkili orofarengeal kanserlerin k\u00fcresel kanser y\u00fck\u00fcndeki y\u00fckseli\u015fi devam ederken, bu t\u00fcr bilimsel ilerlemeler hastalar ve klinisyenler i\u00e7in umut \u0131\u015f\u0131\u011f\u0131 olmaktad\u0131r. Hibrit ecDNA olu\u015fumu ve fonksiyonuna dair derinlemesine bilgi, g\u00fcn\u00fcm\u00fczde k\u00f6t\u00fc prognozla kar\u015f\u0131la\u015fan hastalar i\u00e7in hayati \u00f6nemde tedavi stratejilerinin geli\u015ftirilmesinin \u00f6n\u00fcn\u00fc a\u00e7acakt\u0131r.<\/p>\n
—<\/p>\n
Ara\u015ft\u0131rma Konusu<\/strong>: Hybrid extrachromosomal circular DNA formed by HPV-human DNA fusion in oropharyngeal cancer cells and its role in tumor progression<\/p>\n Makale Ba\u015fl\u0131\u011f\u0131<\/strong>: (Makale ba\u015fl\u0131\u011f\u0131 i\u00e7erikte belirtilmemi\u015ftir)<\/p>\n Haberin Yay\u0131n Tarihi<\/strong>: 26 Mart 2025<\/p>\n Web References<\/strong>: https:\/\/www.nature.com\/articles\/s41467-025-57447-9.epdf<\/p>\n Doi Referans<\/strong>: 10.1038\/s41467-025-57447-9<\/p>\n Anahtar Kelimeler<\/strong>: Kanser Ara\u015ft\u0131rmalar\u0131, DNA, Genler, T\u00fcm\u00f6r H\u00fccreleri, HPV, ekstrakromozomal dairesel DNA, orofarengeal kanser, CRISPR, gen enhancer\u2019lar\u0131, viral onkoloji<\/p>\n","protected":false},"excerpt":{"rendered":" Son y\u0131llarda, a\u011f\u0131z ve bo\u011faz\u0131n arka k\u0131sm\u0131nda ortaya \u00e7\u0131kan HPV ili\u015fkili orofarengeal kanserlerin g\u00f6r\u00fclme s\u0131kl\u0131\u011f\u0131nda \u00f6nemli bir art\u0131\u015f ya\u015fanmaktad\u0131r. HPV-pozitif orofarengeal kanserlerin erken evrede te\u015fhisi, hastalara y\u00fcksek oranda sa\u011fkal\u0131m \u015fans\u0131 sunsa da, bu hastalar\u0131n yakla\u015f\u0131k y\u00fczde yirmisi agresif t\u00fcm\u00f6r biyolojisi ve geleneksel tedavilere diren\u00e7 nedeniyle k\u00f6t\u00fc prognozla kar\u015f\u0131 kar\u015f\u0131yad\u0131r. University of California San Diego\u2019da y\u00fcr\u00fct\u00fclen…<\/p>\n","protected":false},"author":1,"featured_media":2967,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"_yoast_wpseo_title":"","_yoast_wpseo_metadesc":"","_yoast_wpseo_focuskw":"","rank_math_title":"","rank_math_description":"","rank_math_focus_keyword":"","_wpan_schema_json_ld":"","_wpan_ai_seo_metadata":"","_wpan_ai_seo_status":"","_wpan_ai_seo_policy":"","_wpan_ai_seo_faq_block":"","_jetpack_memberships_contains_paid_content":false,"footnotes":""},"categories":[28],"tags":[994,991,993,990,992],"tmauthors":[],"class_list":{"0":"post-2966","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-kanser","8":"tag-crispr-ile-hedefe-yonelik-kanser-tedavisi","9":"tag-hibrit-ekstrakromozomal-dairesel-dna-olusumu","10":"tag-hpv-dna-ve-insan-genomu-fuzyonu","11":"tag-hpv-iliskili-orofarengeal-kanser","12":"tag-hpv-pozitif-kanserlerde-enhancer-elementleri"},"jetpack_featured_media_url":"https:\/\/haber360.com\/wp-content\/uploads\/2025\/04\/Insanda-HPV-Genleriyle-Ekstrakromozomal-DNA-Olusumu-1744897465.jpg","jetpack_sharing_enabled":true,"_links":{"self":[{"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/posts\/2966","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/comments?post=2966"}],"version-history":[{"count":0,"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/posts\/2966\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/media\/2967"}],"wp:attachment":[{"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/media?parent=2966"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/categories?post=2966"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/tags?post=2966"},{"taxonomy":"tmauthors","embeddable":true,"href":"https:\/\/haber360.com\/index.php\/wp-json\/wp\/v2\/tmauthors?post=2966"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}