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作者：Jacquelyn K. Beals, PhD  
出處：WebMD醫學新聞

　　January 19, 2010 — 一個關於食物攝取之問卷以及抽菸者的痰液DNA分析發現，食用綠葉蔬菜、葉酸與綜合維他命可保護抽菸者對抗許多默默發生在肺癌中的基因的甲基化，甲基化就是在DNA的胞嘧啶加上一個甲基，使得基因無法被轉錄，而阻斷了基因的基本功能。
　　
　　這項發表於1月15日癌症研究(Cancer Research)期刊的研究，是根據飲食對病患呼吸道上皮細胞的表徵基因體（epigenome）的影響，為肺癌的預防帶來了新的概念。
　　
　　雖然肺癌大多數是香菸中的致癌物引起，但是造成癌症的變化歷時數十年，本研究中分析的八個基因，經常在肺癌中被促進子甲基化而「關閉」，在之前的研究中發現與發生疾病風險較大有關，因此，甲基化程度較高與風險增加有關。
　　
　　資深作者、新墨西哥州阿布奎基Lovelace呼吸道研究中心肺癌計畫主任Steven A. Belinsky博士在電子郵件中向Medscape Oncology表示，這八個基因中，七個是腫瘤抑制基因，另一個是與DNA修補有關的基因，最值得一提的是，這些基因之一是p16－調節細胞週期控制的一個重要基因。
　　
　　研究對象來自「Lovelace Smokers Cohort」這個世代，這些人是45-75歲曾抽菸者以及目前有抽菸者，菸齡與抽菸量至少是每年15包，這些人填寫哈佛大學食物頻率問卷飲食評估表(Harvard University Food Frequency Questionnaire Dietary Assessment)，指出他們對於大約150種食物選項的食用頻率，排除熱量攝取超過性別特定範圍者之後，剩下1,101名研究對象。
　　
　　已經確定或懷疑與甲基化或肺癌有關的食物被仔細地考量，評估包括動物脂肪；維他命C、E與B9 (葉酸)、與其他；酒；魚肝油；綜合維他命。食物分析包括有可能的六組：黃色蔬菜、綠葉蔬菜(葉酸的主要來源)、十字花科蔬菜、番茄、水果以及紅肉或加工肉類，研究假設是，動物脂肪與紅肉或加工肉類與較多甲基化有關，而水果、蔬菜及攝取維他命與較低的甲基化程度有關。
　　
　　這八個基因：p16、MGMT、DAPK、RASSF1A、PAX5α、PAX5β、GATA4以及GATA5 ，之前被確定與肺癌風險較高有關，從每個研究對象的痰液中分離出的細胞獲得DNA，使用聚合鏈反應來辨識這些基因的甲基化型式，以甲基化基因的數量為病患「評分」，並且分成少於兩個基因被甲基化(低)以及兩個以上基因被甲基化(高)等兩組。
　　
　　【甲基化狀態與飲食變項有顯著關聯】
　　統計分析發現，甲基化狀態與特定的飲食變項之間有顯著關聯，攝取綠葉蔬菜與高甲基化的風險降低有關(勝算比[OR]為 .84；95%信心區間[CI]為 .74 - .93；P < .001)，攝取葉酸有類似的結果(OR，.84；95% CI，.72 - .99；P = .04)。目前使用綜合維他命也與甲基化狀態有關(OR，.57；95% CI，.40 - .83；P = .01)。
　　
　　Belinsky博士觀察發現，與攝取蔬菜及持續使用維他命有劑量反應關係，使用期間增加則保護效果越好，綜合維他命與綠葉蔬菜有葉酸之外的其他東西，這有共通關聯，且綜合維他命與蔬菜的葉酸量有所不同，所以我不知道這對於劑量反應是否只是單純的有或無。
　　
　　該報告總結研究發現為，綠葉蔬菜是此次分析中，唯一可以對抗甲基化狀態的食物選項。此外，使用綜合維他命提供了許多和綠葉蔬菜一樣的成分，也有顯著的保護效果。
　　
　　應告訴所有的抽菸者多吃菠菜和甘藍嗎？Belinsky博士表示，我們的發現相當支持，多數癌症是由甲基化造成的不活化基因引起，所以我不認為吃綠葉蔬菜和綜合維他命有任何負面影響，它是有幫助的，不過，他也指出，需要後續研究來確認他們的發現。
　　
　　德州大學安德森癌症中心流行病學臨床教授Margaret R. Spitz醫師接受Medscape Oncology邀請發表獨立評論時，在電子郵件中表示，適當的攝取葉酸是重要的，因為葉酸是單碳代謝中的一個決定性輔助因子，在DNA合成與複製中扮演重要角色，而且，葉酸不足已經確定是與心血管疾病有關的風險因素。
　　
　　Spitz醫師表示，我還不認為我們可以做出任何的臨床建議，在美國，藉由葉酸強化食物，許多成人達到他們的葉酸建議量，不過，Spitz醫師結論指出，所有的抽菸者都應被建議戒菸，每個人都應遵守飲食原則常識。
　　
　　Belinsky博士是Oncomethylome Sciences公司的顧問且擁有智慧財產權， Spitz醫師宣告沒有相關財務關係。
　　
　　Cancer Res. 2010;70(2):568-574.


Green Vegetables Protect Smokers From Genetic Changes Associated With Lung Cancer Risk

By Jacquelyn K. Beals, PhD
Medscape Medical News

January 19, 2010 — A questionnaire on food intake combined with an analysis of DNA from the sputum of smokers shows that intake of leafy green vegetables, folate, and multivitamins protects smokers against the methylation of several genes often silenced in lung cancer. Methylation, the addition of methyl groups to cytosine bases of DNA, prevents a gene from being transcribed, essentially blocking its function.

Published in the January 15 issue of Cancer Research, this study leads to new conceptions of lung cancer prevention based on the influence of diet on the epigenome of patients' respiratory epithelium.

Although lung cancer most frequently results from the carcinogenic effects of tobacco, changes leading to cancer occur over the course of several decades. The 8 genes analyzed in this study are frequently "turned off" in lung cancer by promoter methylation, associated in previous studies with greater risk of developing the disease. Thus, higher methylation levels are associated with increased risk.

Of these 8 genes, 7 "are tumor suppressor genes, and the eighth is a gene involved in DNA repair," said senior author Steven A. Belinsky, PhD, director of the Lung Cancer Program, Lovelace Respiratory Research Institute, Albuquerque, New Mexico, in his email to Medscape Oncology. "Most notably, one of the genes is p16, a critical gene for regulating cell cycle control."

Participants were drawn from the Lovelace Smokers Cohort. Cohort members are former and current smokers between 40 and 75 years old with at least 15 pack-years of smoking history. Individuals from the cohort filled out the Harvard University Food Frequency Questionnaire Dietary Assessment form to indicate their intake frequency of approximately 150 food items. After excluding individuals with caloric intakes exceeding sex-specific ranges, 1101 participants remained.

Foods with established or suspected connections with methylation or lung cancer were considered most carefully. The assessments included animal fat; vitamins C, E, and B9 (folate), among others; alcohol; cod liver oil; and multivitamins. Foods analyzed included 6 groups of potential relevance: yellow vegetables, leafy green vegetables (a major source of folate), cruciferous vegetables, tomatoes, fruit, and red or processed meats. The hypothesis was that animal fat and red and processed meats would be associated with greater methylation, whereas fruit, vegetable, and vitamin intake would be associated with lower methylation status.

The 8 genes — p16, MGMT, DAPK, RASSF1A, PAX5α, PAX5β, GATA4, and GATA5 — had previously established associations with the risk for lung cancer. DNA was obtained from cells isolated from each participant's sputum samples, and polymerase chain reaction was used to identify methylated forms of the genes of interest. Patients were "scored" by the number of methylated genes and were grouped into those having fewer than 2 genes methylated (low) and those with 2 or more genes methylated (high).

Significant Links Between Methylation Status and Dietary Variables

Statistical analysis found significant associations between methylation status and specific dietary variables. Intake of leafy green vegetables was associated with decreased risk for high methylation (odds ratio [OR], .84; 95% confidence interval [CI], .74 - .93; P < .001). Folate intake yielded similar results (OR, .84; 95% CI, .72 - .99; P = .04). Even current multivitamin use was significantly associated with methylation status: current use (OR, .57; 95% CI, .40 - .83; P = .01).

"There was a dose response with consumption of vegetables and sustained vitamin use, and increased duration was associated with better protection," observed Dr. Belinsky. "Multivitamins and leafy green vegetables have things other than folate, although that is the common link, and...the amount of folate varies by multivitamin and vegetable, so I don't know that there is a simple yes or no answer [regarding dose dependence]," he said.

The report summarizes their findings: "Green leafy vegetables were the only food item in this analysis to exhibit protection against methylation status." In addition, the use of multivitamins, which supply many of the same substances as leafy green vegetables, had a significant protective effect.

Should all smokers be told to increase their intake of spinach and kale? "Our findings certainly support yes for smokers," said Dr. Belinsky. "Most cancers arise through inactivating genes by methylation, so I don't think consumption of leafy green vegetables and a multivitamin would do anything negative, and it could help." He noted, however, that further studies are needed to validate their findings.

"Adequate folate intake is essential, because folate is a crucial cofactor in one-carbon metabolism and has an important role in DNA synthesis and replication," said Margaret R. Spitz, MD, MPH, clinical professor of epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, in her email replying to Medscape Oncology's request for independent commentary. "Also remember that folate deficiency is associated with...an established risk factor for cardiovascular disease.

"I do not think we can make any clinical recommendations yet," said Dr. Spitz. With folate-fortified foods in the United States, many adults achieve their recommended allowance of folate from those sources alone. Nevertheless, "All smokers should be advised to quit, and everyone should follow common-sense dietary principles," Dr. Spitz concluded.

Dr. Belinsky is a consultant and has licensed intellectual property with Oncomethylome Sciences. Dr. Spitz has disclosed no relevant financial relationships.

Cancer Res. 2010;70(2):568-574.