Radyasyon Maruziyetinin Onkogenler Üzerine Etkileri
Özet
DNA dizi analizi teknolojilerindeki gelişmeler, kalıtsal kanser yatkınlık genlerinin rutin klinik analizini yaygınlaştırmış ve germline onkogenik patojenik varyantların tanımlanmasını büyük ölçüde artırmıştır. Bu varyantlar, bireylerin kansere yatkınlığı ve genetik olarak tanımlanmış radyosensitivitesi gibi sağlıkla ilgili kritik bilgiler sunmaktadır. Ataksi Telenjiektazi (AT) ve Nijmegen Breakage Sendromu gibi DNA çift sarmal kopması onarım mekanizmalarındaki çift allellik mutasyonlar şiddetli radyasyon hipersensitivitesine yol açtığından bu hastalarda radyoterapi kontrendikedir. Ancak, tek allelinde varyant taşıyan heterozigot bireylerde radyasyon maruziyetinin klinik sonuçları farklılık göstermektedir. Yüksek penetranslı bir tümör baskılayıcı gen olan TP53 germline mutasyonuna sahip Li-Fraumeni sendromlu hastalarda radyasyon maruziyeti, yeni birincil ve ikincil tümör gelişim riskini çarpıcı biçimde artırdığı için radyasyon tedavisi kesinlikle kontrendikedir. Buna karşın, BRCA1 ve BRCA2 mutasyon taşıyıcılarında hücresel düzeyde radyosensitivite bildirilse de, radyasyonun klinik toksisiteyi veya karşı meme kanseri riskini önemli ölçüde artırdığına dair doğrudan bir kanıt bulunmamaktadır. Benzer şekilde, ATM heterozigotlarında normal doku toksisitesi değişkenlik gösterirken, genç hastalar haricinde radyoterapi dikkatle uygulanabilir. PALB2, CHEK2, BRIP1, RAD51C ve RAD51D gibi orta penetranslı onkogen varyantlarında ise radyasyona bağlı risk artışına dair kesin kanıt yoktur. Sonuç olarak, TP53, belirli zararlı ATM mutasyonları ve spesifik CHEK2 1100delC varyantı dışındaki durumlarda, germline varyant varlığı nedeniyle radyasyon tedavisinden kaçınılmamalıdır.
Advances in DNA sequencing have integrated the analysis of hereditary cancer predisposition genes into routine clinical settings, significantly increasing the detection of germline oncogenic pathogenic variants. These variants offer crucial insights into both cancer susceptibility and genetically defined radiosensitivity. While biallelic germline mutations in DNA damage response pathways, such as in Ataxia Telangiectasia and Nijmegen Breakage Syndrome, cause severe radiation hypersensitivity that contraindicates radiotherapy, the effects on heterozygous carriers with single-allele mutations remain nuanced. In Li-Fraumeni syndrome patients carrying germline mutations of the high-penetrance TP53 tumor suppressor gene, radiation exposure drastically elevates the risk of secondary malignancies, strictly contraindicating radiotherapy. Conversely, although heterozygous BRCA1 and BRCA2 mutation carriers exhibit increased cellular radiosensitivity, robust clinical data confirming significant increases in radiation toxicity or contralateral breast cancer risk are lacking. Similarly, for ATM heterozygotes, clinical outcomes remain variable, making radiotherapy acceptable except in young patients, provided secondary cancer screening is emphasized. Furthermore, moderate-penetrance genes like PALB2, CHEK2, BRIP1, RAD51C, and RAD51D show no definitive evidence of heightened radiation toxicity or secondary cancers, indicating that treatment decisions should not be altered solely based on mutation status. Consequently, except for TP53, specific deleterious ATM mutations, and the CHEK2 1100delC variant, radiation therapy should not be avoided.
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