Newsletter No. 533

破解血漿DNA密碼 由無創產檢到癌症檢測 Deciphering the Codes in Plasma DNA From Non-invasive Prenatal Test to Cancer Screening 希 臘神話中，西西弗斯使計誘騙死神戴上手銬，最 終被諸神懲罰，要把大石推上斜坡，但大石到了山 頂卻會掉下來，西西弗斯又要再次推石上山。如此 日復日、年復年，永無止境。科研之路也是如此，科學家每 天在茫茫中探索，時而匍匐前進，時而推倒重來，也許窮一 生而徒勞。中大醫學院副院長（研究） 盧煜明 教授同樣堅持 自己的信念，縱然科研路上困難重重，數十年後，終把石頭 推上高峰。盧教授於2月15日主講第二場「智慧的探索」公 開講座系列，分享科研的挑戰和樂趣，吸引約二百名中大師 生、校友、中學生及公眾人士出席。 2011年以前，如果要在產前檢查胎兒有沒有唐氏綜合症， 只能透過入侵性的羊膜穿刺術（俗稱「抽羊水」），直接從 胎兒身上取得遺傳物質來檢測，但孕婦會有0.5%至1%的 流產風險。就在2011年，盧煜明教授研發的無創唐氏綜合 症產前診斷技術（T21）開始臨床應用，只需抽取孕婦的血 液檢驗便可，準媽媽不再有恐懼，可以安心接受檢查。至今 T21已獲全球超過九十個國家採用，數以百萬孕婦受惠。 盧教授早於牛津大學攻讀醫學博士學位時，已有意研究無 創產檢。然而，母親和胎兒各自有血液循環系統，雖然孕婦 的血液蘊藏胎兒的細胞，但數量極少，要抽取這些細胞檢 驗猶如大海撈針。盧教授深信，奧妙就在孕婦血液中，但茫 無頭緒。之後八年，盧教授也不得要領。 1997年，盧教授回流香港加入中大，他的研究有突破進展。 當時有研究指出癌細胞會在血漿釋放其DNA，盧教授得到 啟發：「既然小小腫瘤會釋放DNA，那麼幾磅的胎兒是否 會在血漿中釋出DNA？」這一次，他對了。盧教授發現母體 血漿內有胎兒的DNA，這次發現等同打開了醫學研究的寶 庫，各種突破隨之而來。 首先，盧教授發現，只要檢驗孕婦血漿內胎兒基因的21號 染色體，運用高頻基因排序技術，就可知道胎兒是否患有唐 氏綜合症，準確度達99.7%。 檢測血漿中的DNA，不但可應用於產前檢查，還可用來篩 查癌症。近年盧教授運用這種技術篩查鼻咽癌，已見成果。 鼻咽癌的癌細胞會在血漿中釋出EB病毒，因此盧教授想到 分析血漿中EB病毒DNA，便可確定有沒有患上鼻咽癌。研 究團隊於2013至2016年間，為二萬零一百七十四名沒有任 何鼻咽癌徵狀的香港40至60歲男子進行測試，三百零九人 在首次檢查及複檢時均呈陽性反應，當中三十四人最終被 確診罹患鼻咽癌，陽性預測值達11%，較一般癌症檢測約 3%的高。這項研究結果獲得國際權威醫學期刊《新英倫醫 學雜誌》選為「2017年度最受矚目研究文章」之一。 驀然回首，科研路艱，盧教授有八年停滯不前，但他反而為 這段空白期感恩：「如果在我做醫學生的時候，就已經在血 漿DNA研究中取得成果，我反而不能培養出續航能力。」石 頭，終於不再滾下來。 I n Greek mythology, Sisyphus was sentenced for cheating Death to the eternal task of pushing a boulder up a hill. The boulder would roll down the hill again just as it reaches the top. Such futile and thankless labour is not entirely unknown to the scientists whose pursuits are mostly motivated by their love and passions for scientific inquiries. Prof. Dennis Lo , Associate Dean (Research) of CUHK Faculty of Medicine, talked about his labour of love under ‘The Joys and Challenges of Scientific Research’ in the second part of ‘The Pursuit of Wisdom’ Public Lecture Series on 15 February, drawing around 200 CUHK staff members and students, alumni, secondary school students and members of the public. Before 2011, to detect whether their babies might have Down syndrome, pregnant women had no choice but to undergo amniocentesis, which directly draws fluids from inside the mother’s body for chromosomal study. Such invasive diagnostic method, however, is associated with a 0.5–1.0% risk of miscarriage. Since 2011, a non-invasive foetal DNA test for Down syndrome (T21) developed by Professor Lo has come into clinical use. The test simply takes blood samples from the pregnant women for analysis and thus rids them of the risk of miscarriage. Currently, T21 is applied in more than 90 countries and has benefitted millions of pregnant women. Professor Lo had the idea of developing non-invasive prenatal test when he was a doctoral medical student at Oxford University. However, since the mother and 透過檢驗孕婦血漿內胎兒基因的21號染色體，若發現多了一條染色體， 便可確診嬰兒患上唐氏綜合症 By detecting the presence of an additional copy of chromosome 21 in foetal DNA in maternal plasma, Down syndrome of baby can be diagnosed the foetus have separate blood circulation systems, the number of foetal cells that can be found in the mother’s blood was very few. Getting hold of these cells in the mother’s blood is like looking for a needle in a haystack. Although Professor Lo believed that the answer lies in the mother’s blood, he could not quite figure it out and had to wait. In 1997, Professor Lo returned to Hong Kong and joined CUHK. His research has since proceeded in leaps and bounds. He was inspired by some research that proved that cancer cells would release their DNAs into the patient’s plasma and he thought, ‘If a tiny tumour cell would release its DNAs into the patient’s plasma, then would it be possible that a foetus of much larger size releases its DNAs into the mother’s plasma?’ Professor Lo later proved his hypothesis and discovered cell-free foetal DNAs in maternal plasma. His discovery is the gateway to a number of breakthroughs later. First, Professor Lo found that checking chromosome 21 of the foetus’s DNAs in the mother’s plasma with massively parallel genomic sequencing technique could reveal whether the baby has Down syndrome. The accuracy rate can be as high as 99.7%. The plasma DNA analysis can not only be applied in prenatal tests but also cancer screening. From 2013 to 2016, Professor Lo and his team conducted a study of screening nasopharyngeal carcinoma (NPC) using plasma DNA analysis and the result is promising. By detecting the Epstein-Barr virus DNA, which is released by NPC tumour cells into the patient’s plasma, early diagnosis of NPC can be achieved. Professor Lo’s study involved 20,174 Chinese males aged between 40 and 60 without NPC symptoms. Among them, 309 participants had tested positive on the initial and follow-up blood tests and 34 were diagnosed with NPC. The predictive value is 11%, higher than the average of 3% of normal cancer screenings. The research was selected by The New England Journal of Medicine as one of the most ‘Notable Articles of 2017’. The road of scientific research is indeed intriguing and strange. Professor Lo did not make much headway for some years but he did not view it as a period entirely of no consequence. ‘If I had achieved a breakthrough in my plasma DNA research when I was still a medical student, I would not have developed tenacity.’ The boulder finally comes to rest on the top. M. Mak 06 # 5 3 3 | 0 4 . 0 3 . 2 0 1 9