肝吸蟲相關癌症進行基因定序


  【24drs.com】膽管癌佔全球原發性肝癌的10%-25%,一般預後相當不好;東南亞某些地方,感染肝吸蟲是嚴重的公衛問題,且與發生膽管癌有關。
  
  線上發表於5月6日Nature Genetics期刊的一篇信件中,研究者對於造成發生O viverrini相關膽管癌的「突變現象」提出一些看法。
  
  杜克-新加坡大學醫學研究院的Bin Tean The博士等人,對8種O viverrini相關腫瘤和對應的正常組織進行了全基因體定序,他們辨識了幾個已知和癌症有關的基因、以及和膽管癌突變現象有關的10個新基因的體細胞突變,他們的結果認為組蛋白修飾、G蛋白信號和基因組穩定性對於發生這種癌症有所影響。
  
  這篇研究針對特定基因,可以獲得更好的預後或診斷工具,改善治療。杜克-新加坡大學醫學研究院的Steve Rozen博士表示,我們在10個之前未認為和膽管癌有關的基因辨識出可能的因果突變。
  
  他表示,藉由這新資訊,研究者可以探討特定基因突變是否可預測哪種治療最有效;再者,我們發現的基因之一GNAS似乎是致癌因子,因此,它可能可以作為治療標靶。
  
  作者們指出,膽管癌在西方國家少見;它的年紀標準化發生率(ASR)小於1.5/100,000,不過,在東南亞某些區域,特別是O viverrini 蔓延率高的地方,此病相當盛行。例如,膽管癌是泰國東北部、寮國和柬埔寨的主要肝癌類型,ASRs高達94.8/100,000(男性)和39.4/100,000(女性)。
  
  手術切除依舊是治療首選,但是大部分案例無法開刀,對於這種癌症,目前尚無有效療法,不過,併用化療加上gemcitabine與cisplatin可以略為改善存活期。
  
  Teh博士等人進行全基因體定序之後,使用Sanger定序法辨識並確認1,187個基因的206種體突變,之後選擇15種基因在另外46名癌症患者進行體突變盛行率篩檢。
  
  除了已知的致癌基因—包括TP53 (在44.4%案例突變)、KRAS (16.7%)和SMAD4 (16.7%) —之外,在3.7% -14.8%的案例發現10種新的影響基因;這些基因中,不活化突變的有MLL3 (14.8%案例)、ROBO2 (9.3%)、RNF43 (9.3%)與PEG3 (5.6%)以及活化突變的GNAS致癌基因(9.3%)。
  
  作者們指出,這些基因的功能可廣泛地分成3個主要生物類別:組蛋白修飾去活化、G蛋白信號活化、以及失去基因組穩定性。GNAS、RNF43、ROBO2和PEG3的基因變化對於膽管癌是獨特的,表示它們在這個疾病有特定影響。
  
  作者們結論表示,這些突變強調了膽管癌的重要生物面向,需要後續研究探討它們在膽管癌的角色。
  
  資料來源:http://www.24drs.com/professional/list/content.asp?x_idno=6817&x_classno=0&x_chkdelpoint=Y
  

Cancer Associated With Liver Fluke Undergoes Genetic Sequencing

By Roxanne Nelson
Medscape Medical News

May 10, 2012 — Cholangiocarcinoma accounts for 10% to 25% of all primary liver cancers worldwide, and generally has a very poor prognosis. In certain parts of Southeast Asia, infection with the liver fluke Opisthorchis viverrini is a major public health problem and is associated with the development of cholangiocarcinoma.

In a letter published online May 6 in Nature Genetics, researchers provide some insight into the "mutational landscape" that contributes to the development of O viverrini–related cholangiocarcinoma.

Bin Tean Teh MD, PhD, from the Duke–National University of Singapore (NUS) Graduate Medical School, and colleagues conducted whole-exome sequencing of 8 O viverrini–related tumors and matched normal tissue. They identify somatic mutations in several genes known to be associated with cancer and in 10 genes newly implicated in the mutational landscape of cholangiocarcinoma. Their findings suggest a role for histone modifiers, G protein signaling, and genome stability in the development of this cancer.

This research could lead to better prognostic or diagnostic tools and improved therapies by targeting certain genes. "We identified likely causal mutations in 10 genes not previously linked to cholangiocarcinoma," coauthor Steve Rozen, PhD, also from the Duke–NUS Graduate Medical School, told Medscape Medical News.

"With this new information, researchers will be able to investigate whether mutations in specific genes can predict which treatments will be most beneficial," he said. "Furthermore, one of the genes that we uncovered, GNAS, seems to be acting as an oncogene. Therefore, it is a potential therapeutic target."

Cholangiocarcinoma is uncommon in Western countries; it has an age-standardized incidence rate (ASR) of less than 1.5 per 100,000, the authors note. However, in some areas of Southeast Asia, primarily in regions with high O viverrini infestation, it is highly prevalent. For example, cholangiocarcinoma is the predominant type of liver cancer found in northeastern Thailand, Laos, and Cambodia, with very high ASRs of 94.8 per 100,000 for men and 39.4 per 100,000 for women.

Surgical resection remains the treatment of choice, the authors note, but most cases are inoperable. There is currently no effective therapy for this malignancy, although the combination of chemotherapy plus gemcitabine and cisplatin does marginally improve the length of survival.

After conducting their whole-exome sequencing, Dr. Teh and colleagues identified and validated 206 somatic mutations in 1187 genes using Sanger sequencing. They then selected 15 genes to screen for the prevalence of mutations in another 46 people with cancer.

In addition to genes that are already known to be cancer causing — including TP53 (mutated in 44.4% of cases), KRAS (16.7%), and SMAD4 (16.7%) — somatic mutations were identified in 10 newly implicated genes in 3.7% to 14.8% of cases. Among these new genes are inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%), and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%).

These genes, the authors note, have functions that can be broadly categorized into 3 main biologic classes: deactivation of histone modifiers, activation of G protein signaling, and loss of genome stability. Genetic alterations to GNAS, RNF43, ROBO2, and PEG3 "are unique" to cholangiocarcinoma, indicating that they appear to have a specific role in this disease.

"The mutations identified highlight important biological aspects of cholangiocarcinoma, and further studies are needed to investigate their roles in cholangiocarcinoma," the authors conclude.

The study was supported in part by funding from the Singapore National Medical Research Council, The Singapore Millennium Foundation, The Lee Foundation, the Singapore National Cancer Centre Research Fund, the Duke–NUS Graduate Medical School, the Cancer Science Institute, Singapore, the Research Team Strengthening Grant, the National Genetic Engineering and Biotechnology Center, and the National Science and Technology Development Agency, Thailand. The authors have disclosed no relevant financial relationships.

Nat Genet. Published online May 6, 2012.

    
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