癌症如何转移？“三”大特征揭示癌症进展过程
导语
耶鲁大学一项新的研究利用进化生物学工具回答了癌症如何转移的古老问题。据研究者称，获得的新的见解将帮助科学家更好地理解肿瘤转移的基因起源，发现更有效的治疗靶标。这项研究由公共卫生副教授Jeffrey Townsend领导，文章于2016年1月5日发表在the Proceedings of the National Academy of Sciences期刊。
医脉通编译整理，转载请务必注明出处。
科学家长久以来一直认为癌症是个进化的过程，涉及携带复制和保留下来的突变的细胞，这类细胞比正常细胞更有优势。但是关于肿瘤进展的时序和过程的问题一直困扰着科学家。
为了能够阐明这个过程，耶鲁大学的研究小组对多例不同癌症类型的患者的正常、原发性肿瘤和转移灶的肿瘤组织进行了测序。利用进化生物学的最新方法论，研究者在每例患者的癌症进化“树”上绘制了基因突变情况。与物种进化图谱很相似，研究者的分析揭示了遗传学关系和肿瘤年代变化表。
研究要点：
研究者证实了癌症的3个特性。
- 首先，研究者发现转移灶起源于原发性肿瘤中，沿着不同的通路或者谱系，以分支模式扩散，而不是线性模式。
“肿瘤内部存在很多基因差异，”Townsend医生说道，“不同的突变似乎会出现在不同的转移灶中。”
图1.四种最可能的癌症分子进化树
Four maximum likelihood cancer molecular evolutionary trees, with a horizontal scale proportional to the number of mutations. (A) Subject 424 had a colon primary tumor and metastases to the duodenum (M1) and liver (M2). The primary tumor was an ingroup to all metastases in 80.4% of the Bayesian posterior of trees for subject 424. (B) Subject 446 had a pancreatic adenocarcinoma primary tumor and metastases to the kidney (M2), bowel (M3), and liver (M4). The primary tumor was an outgroup to all metastases in 99.8% of the Bayesian posterior of trees for subject 446. (C) Subject 435 had a poorly differentiated lung adenocarcinoma primary tumor and metastases to the lung (M0), liver (M1), pancreas (M3), hilar lymph node (M4), paraprostatic soft tissue (M5), perirenal soft tissue (M6), and mediastinum (M7). The primary tumor was an outgroup to all metastases in 100% of the Bayesian posterior of trees for subject 435. (D) Subject 459 had a lung adenocarcinoma primary tumor and metastases to the lung (M1), liver (M2), spleen (M3), kidney (M4), adrenal (M5) and paratracheal lymph node (M6). The primary tumor was an outgroup to all metastases in 100% of the Bayesian posterior of trees for subject 459.
- 其次，研究者发现转移灶的基因与癌症发展早期的原发性肿瘤不同。“我们发现转移谱系在癌症发展的很早时期就分离出来了。”Townsend医生提示说道。这种分歧在原发性肿瘤诊断之前的很早时期就已经发生了。
图2. 基因分离发生时序
Timings of the first genetic divergence from normal tissue sequence (blue circle), of the first genetic divergence of metastases (blue dashes) and of diagnosis (red dashes) during tumor progression. (A) Subject 459 (lung adenocarcinoma, aged 54 y at death) provided an example of early diagnosis of the primary tumor without diagnosis of metastases, but also early divergence of the metastases. (B–D) Subjects 414 (lung, large cell, aged 25 y), 418 (ovarian, aged 47 y), and 439 (renal clear cell carcinoma, aged 58 y) provided examples of late metastasis in which diagnosis of the primary tumor and metastases occurred after the first genetic divergence of metastasis. (E) Probability density for the occurrence of the first genetic divergence of metastases and for the time of diagnosis. The x axis is scaled from 0 (the first genetic divergence of primary tumor tissue from normal tissue) to 1 (death). In our set of 40 lethal cancers, the first genetic divergences of metastatic lineages (blue triangles) are distributed so as to often occur earlier than diagnosis time (red triangles).
- 研究小组还发现在转移谱系分开之前常常已经发生主要的驱动基因突变，这种突变与新突变相比具有选择性优势。Townsend医生说道：“主要已知的癌症驱动基因常常在原发性肿瘤和所有的转移灶中发生突变，在治疗过程中成功靶向这些突变能带来广泛的治疗获益。”
研究意义
对癌症进化的理解对治疗具有关键的意义，Townsend医生提示说道：“除了指出我们需要靶向这些在癌症早期就发生突变的驱动基因外，这个进化生物学的手段也提供了准确描绘早期和晚期突变的基因的方法。这对于优先选择哪个突变作为治疗靶标，从而产生有效的治疗方法特别有用。”
这项研究为肿瘤学家提供了抗击癌症的新思路。“进化生物学的工具和理论对于理解癌症很实用。”Townsend医生补充说道。“因为我们现在知道癌症同时存在多种演化路径，未来的肿瘤学家为了能运用策略击败癌症，需要理解进化生物学。”
文献全文：Zhao ZM, Proc Natl Acad Sci U S A 2016 Feb 8;[Epub ahead of print] PMID: 26858460
医脉通编译自：Study Examines Evolution of Cancer, The ASCO Post, 2/12/2016
