台大楊泮池團隊 建議基因YAP1單點突變 (高危險肺癌) 應定期低劑量CT檢查

楊泮池團隊 找到肺腺癌基因 2015-08-06 14:15:04 聯合晚報 記者／彭宣雅台灣每年新增一萬多名肺癌病例，肺癌是國人癌症死亡第一位，台灣大學校長楊泮池所帶領的研究團隊，利用全基因體組「高速定序」技術，發現位於基因「YAP1」上的一個位點異常與肺腺癌相關，YAP1基因有異常比無異常罹患肺腺癌的風險高出5.9倍；未來高危險族群提早篩檢，就可早期發現治療，研究成果發表在國際重要醫學期刊臨床腫瘤學雜誌(Journal of Clinical Oncology)上。楊泮池表示，研究團隊先找出多個高度發生肺癌的家族，把所有家族成員全進行基因定序，找出和肺腺癌相關的基因異常；再用1000多名肺腺癌患者、1000多名健康者對照，發現YAP1基因上一個位點異常與肺腺癌相關。研究團隊追蹤離病患者後發現，「YAP1」基因若帶有位點異常，具有早發(小於60歲發病)、遺傳的特性，帶有這基因位點異常的民眾，也比較容易罹患肺腺癌。楊泮池說，研究個案中有一個家族有七人，結果父母、四個女兒都罹患肺腺癌，唯一有抽菸喝酒習慣的兒子，是家族中目前唯一沒有發現得肺腺癌的人，他推測，這基因位點異常，在罹患肺腺癌的遺傳與性別上，都扮演著關鍵性的角色。楊泮池表示，台灣罹患肺癌的患者，有一半有抽菸喝酒習慣，但另外一半沒有抽菸習慣，罹癌的原因不明確，且大多數初期都沒有症狀，等到腫瘤已經長至4至5公分，侵犯到其他器官、開始咳嗽、積水，大都已經是癌症末期，治療起來相對棘手。楊泮池說，找出肺腺癌「 YAP1」基因位點異常後，未來檢測非常簡單，只要患者抽血檢驗，大約五個工作天就可以完成檢測；目前這項發現僅在研究階段，還沒有應用在臨床篩檢 ；未來包括台大及其他各醫院，都可以發展肺腺癌基因檢測，費用大約2000元。台大表示，未來民眾家族中若有人罹患肺癌或肺腺癌，家族其他親屬就能提早進行基因檢測，若同樣帶有這個基因位點異常，可在健檢時進行低劑量電腦斷層檢查，有機會早期發現病兆，小於一公分的肺癌腫瘤，只要透過內視鏡手術治療，95%的患者都可以完全治癒。

R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability. J Clin Oncol. 2015 Jul PURPOSE: Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS: Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS: YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION: These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.