有多少文献支持DNA甲基化异常是肿瘤发生的早期事件?

Tlexander

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我一直认为dna methylation alternation是肿瘤发生的早期事件，但是真认真地去找支持这个证据的问题，怎么找不到呢？ 所有的文献都指向Esteller的文章（并且是乱七八糟的文章）。就没找到一个靠谱的. 感兴趣的同志可以一起跟帖列举一下,你感觉证明了: DNA甲基化异常是肿瘤发生的早期事件
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Br J Cancer. 1997;75(3):396-402.
& E4 o, z! \- m- n9 @; U, }9 JAlterations in DNA methylation are early, but not initial, events in ovarian tumorigenesis.
' Z% H6 V' w# o/ u: J: j, \Cheng P, Schmutte C, Cofer KF, Felix JC, Yu MC, Dubeau L./ f% P8 G3 S6 u7 ~/ ^% J5 ^7 Y0 {6 `
Source
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$ ]( [- r' F$ G, dDepartment of Gynecologic Oncology, USC/Norris Comprehensive Cancer Center, University of Southern California School of Medicine, Los Angeles 90033-0800, USA.
  z4 F: N1 N* S' w9 |) T& o5 ]Abstract
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We compared global levels of DNA methylation as well as methylation of a specific locus (MyoD1) in ovarian cystadenomas, ovarian tumours of low malignant potential (LMP) and ovarian carcinomas to investigate the association between changes in DNA methylation and ovarian tumour development. As we realized that cystadenomas showed different methylation patterns from both LMP tumours and carcinomas, we verified their monoclonal origin as a means of confirming their true neoplastic nature. High-pressure liquid chromatographic (HPLC) analyses showed that global methylation levels in LMP tumours and carcinomas were 21% and 25% lower than in cystadenomas respectively (P = 0.0001 by one-way variance analysis). Changes in the methylation status of the MyoD1 locus were not seen in any of ten cystadenomas analysed but were present in five of ten LMP tumours and in five of ten carcinomas (P = 0.03). These findings suggest that alterations in DNA methylation are absent (or at least not as extensive) in ovarian cystadenomas, but are present in LMP tumours, the phenotypic features of which are intermediate between those of benign and malignant ovarian tumours. The results also emphasize the merit of distinguishing ovarian LMP tumours from cystadenomas, in spite of their similar clinical characteristics.
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waitaddress

那不是很好么？自己可以提出这个假说，然后再证明。很好的一个课题呀。。。。

ambassador

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4 B* M. y# R, S0 c6 Q4 a这篇文章提示，乳腺癌的发生早在前几年检测ATM甲基化的程度来预测其发生概率。

Tlexander

回复 ambassador 的帖子
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但是这种文章,不能从根本上证明咱们的hypothesis, 要说预测,什么东西都能用来预测, 可能压根没有因果关系的东西,也能用来预测的很准.

Tlexander

回复 waitaddress 的帖子, p2 c3 h4 w/ y  m8 G

1 H4 p3 S3 r1 [% w/ C! }1, 很难找到同一个东西的stage;
) E8 n& x, w% S+ r2, 很难从全基因组水平进行评估! E: r4 [* {/ M! Z4 x% a: L
3, 很难保证所有的肿瘤都能看到这个现象
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确实是个好课题,可以打破传统观点的,如果能做好的话,Nature应该没问题

zhouleiwang2

回复 Tlexander 的帖子# d: T; X0 H2 ^2 J; S9 M, M

' l5 j( X! K% B: ^  S* SDNA methylation甲基化异常确实可能是某些肿瘤发生的早起事件，5mC可以分别通过脱氨基作用和氧化脱甲基转变成U和T从而引入点突变，如果甲基化异常，很可能会增大这些异常事件导致细胞突变积累而成瘤的概率。
( `, h' o0 _7 |9 s, F: N8 @4 c但是甲基化毕竟只是一种基因活性的调控方式，甲基化异常对肿瘤发生的作用肯定存在，但是我相信并不是所有肿瘤的发生都必须先有甲基化异常的。" t5 ]# I& V# c; Y4 T, j
还有，要研究甲基化异常与肿瘤发生之间的直接联系，感觉技术上会很难……

zzzhouzhong

Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host  好像有点关系，没细看~lz感兴趣可以去看看http://www.nature.com/nrc/journal/v13/n7/full/nrc3486.html

waitaddress

回复 Tlexander 的帖子
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1.个人感觉哈，最关键问题是看你如何定义好“早期事件”，这个问题搞好了就可以了。（原位癌？还是癌前病变？）) z8 C- r/ l0 d. x) j  A6 o
2.为什么要一开始就考虑“所有肿瘤”？只要有一种肿瘤上有突破就够满足了吧。
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Tlexander

回复 zhouleiwang2 的帖子
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% Z; D  d4 I6 ?3 t3 Y有道理,这是否就意味着"脱氨基作用和氧化脱甲基"是非常关键的肿瘤事件.

Tlexander

回复 waitaddress 的帖子. P" k# {' _( X* N/ B2 {) C

" c8 V0 d  V" a8 C早期事件是个相对概念, 原位癌,癌前病变都是早期事件. 目前在lung cancer中把stage I, II作为早期阶段.