Pankreasın Ailesel, Herediter ve Genetik Hastalıkları
Özet
Pankreatik duktal adenokarsinoma (PDAK), erken teşhis edilememesi ve agresif doğası nedeniyle %5-10 gibi oldukça düşük bir beş yıllık sağ kalım oranına sahip, en ölümcül malign ekzokrin tümörlerden biridir. Hastalığın karsinogenez süreci; PanIN, MCN ve IPMN gibi prekürsör lezyonlarla karakterize olup, özellikle KRAS onkogeni ile TP53, CDKN2A ve SMAD4 tümör supresör genlerindeki mutasyonlar patogenezde merkezi rol oynamaktadır. KRAS mutasyonları vakaların %95'inde görülerek sinyal yolağını sürekli aktif tutarken, p16 (CDKN2A) kaybı hücre döngüsü kontrolünü bozmakta, p53 ve SMAD4 mutasyonları ise DNA onarımı ve büyüme inhibisyonu mekanizmalarını devre dışı bırakmaktadır. Olguların %4-10'u kalıtsal kökenli olup; Peutz-Jeghers sendromu (STK11), FAMMM sendromu (CDKN2A), Lynch sendromu (MLH1/MSH2), Herediter Meme ve Over Kanseri (BRCA1/2) ve Herediter Pankreatit (PRSS1) gibi tablolar pankreas kanseri riskini önemli ölçüde artırmaktadır. Yeni nesil dizileme teknolojileri, bu somatik ve germline mutasyonların hızlı tespitini sağlayarak, hem erken tanı potansiyelini artırmakta hem de sağ kalımı iyileştirebilecek hedefe yönelik moleküler tedavilerin geliştirilmesine olanak tanımaktadır.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant exocrine tumors, with a very low five-year survival rate of 5-10% due to the inability to achieve early diagnosis and its aggressive nature. The carcinogenesis process of the disease is characterized by precursor lesions such as PanIN, MCN, and IPMN, with mutations in the KRAS oncogene and TP53, CDKN2A, and SMAD4 tumor suppressor genes playing a central role in its pathogenesis. KRAS mutations are observed in 95% of cases, keeping the signaling pathway constantly active, while the loss of p16 (CDKN2A) disrupts cell cycle control, and mutations in p53 and SMAD4 disable DNA repair and growth inhibition mechanisms. Approximately 4-10% of cases are of hereditary origin, and conditions such as Peutz-Jeghers syndrome (STK11), FAMMM syndrome (CDKN2A), Lynch syndrome (MLH1/MSH2), Hereditary Breast and Ovarian Cancer (BRCA1/2), and Hereditary Pancreatitis (PRSS1) significantly increase the risk of pancreatic cancer. Next-generation sequencing technologies enable the rapid detection of these somatic and germline mutations, thereby increasing the potential for early diagnosis and allowing for the development of targeted molecular therapies that can improve survival.
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