文章：

癌症的全基因组关联研究：当前的见解和未来的观点

Genome-wide association studies of cancer: current insights and future perspectives

原文发布日期：2017-10-13

DOI: 10.1038/nrc.2017.82

类型: Review Article

开放获取: 否

要点：

1. The architecture of inherited genetic susceptibility to cancer is defined by a spectrum of predisposition alleles that have differing frequencies and impact.
2. Genome-wide association studies (GWAS) provide an agnostic approach to the identification of genetic variation influencing cancer risk. For most cancers, GWAS have been performed, and hundreds of risk alleles have been identified, most of which are common and individually confer a modest increase in risk.
3. Most cancer risk loci identified through GWAS locate to non-coding regions of the genome and influence gene expression through diverse mechanisms.
4. As well as improving our understanding of cancer, information from GWAS has direct clinical relevance in identifying nongenetic aetiological risk factors, optimising population screening, identifying therapeutic targets, drug repositioning and prognostication.
5. Although challenging, deciphering the biological basis of identified associations is necessary to fully realise the potential of GWAS.

要点翻译：

1. 遗传性癌症易感性的结构由一系列具有不同频率和影响的易感等位基因所定义。
2. 全基因组关联研究（GWAS）为识别影响癌症风险的遗传变异提供了一种无偏倚的研究方法。针对大多数癌症类型开展的GWAS研究已成功识别出数百个风险等位基因，其中多数属于常见变异且单独仅能轻微提升患病风险。
3. 通过GWAS发现的多数癌症风险位点位于基因组的非编码区域，并通过多种机制调控基因表达。
4. GWAS获得的信息不仅深化了我们对癌症的认知，更在识别非遗传病因风险因素、优化人群筛查策略、发现治疗靶点、推动药物重定位及预后评估方面具有直接临床价值。
5. 尽管面临挑战，但充分解析已发现关联的生物学基础对于实现GWAS研究的全部潜力至关重要。

英文摘要：

The high metabolic demand of cancer cells leads to an accumulation of H+ ions in the tumour microenvironment. The disorganized tumour vasculature prevents an efficient wash-out of H+ ions released into the extracellular medium but also favours the development of tumour hypoxic regions associated with a shift towards glycolytic metabolism. Under hypoxia, the final balance of glycolysis, including breakdown of generated ATP, is the production of lactate and a stoichiometric amount of H+ ions. Another major source of H+ ions results from hydration of CO2 produced in the more oxidative tumour areas. All of these events occur at high rates in tumours to fulfil bioenergetic and biosynthetic needs. This Review summarizes the current understanding of how H+-generating metabolic processes segregate within tumours according to the distance from blood vessels and inversely how ambient acidosis influences tumour metabolism, reducing glycolysis while promoting mitochondrial activity. The Review also presents novel insights supporting the participation of acidosis in cancer progression via stimulation of autophagy and immunosuppression. Finally, recent advances in the different therapeutic modalities aiming to either block pH-regulatory systems or exploit acidosis will be discussed.

摘要翻译： 

发现一部分人类肿瘤依赖于突变失调的BRAF激酶，加速了RAF抑制剂作为潜在治疗药物的开发。美国食品药品监督管理局（FDA）批准的第二代RAF抑制剂维莫非尼（vemurafenib）和达拉非尼（dabrafenib）在治疗BRAF-V600E/K突变型黑色素瘤患者中取得了显著疗效并延长了生存期，但其疗效受到耐药性的限制。除黑色素瘤外，当前临床使用的RAF抑制剂在治疗结直肠癌和甲状腺BRAF-V600E肿瘤，或携带非V600突变的BRAF变异肿瘤时，疗效较为有限。越来越多的实验和临床证据表明，RAF激酶信号通路的复杂生化机制既决定了RAF抑制剂的有效性，也导致了肿瘤对其产生多种耐药机制。近年来，多种具有不同结构和生化特性的新一代RAF抑制剂已进入临床前和临床开发阶段。在本综述中，我们讨论了当前对RAF激酶调控、抑制剂作用机制及相关临床耐药性的理解。近期对RAF抑制剂作用的关键结构和生化机制的阐明，结合多种结构多样的RAF抑制剂在临床前和临床阶段的可用性，将有助于设计更有效的RAF抑制剂及基于RAF抑制剂的治疗策略，以适应不同的临床情境。

原文链接：

Genome-wide association studies of cancer: current insights and future perspectives