Precancer Atlas to Drive Precision Prevention Trials.
Precancer Atlas to Drive Precision Prevention Trials.
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DOI：
10.1158/0008-5472.can-16-2346
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发表时间：
2017-04-01
期刊：
影响因子：
11.2
通讯作者：
Lippman SM
中科院分区：
文献类型：
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作者：
Spira A;Yurgelun MB;Alexandrov L;Rao A;Bejar R;Polyak K;Giannakis M;Shilatifard A;Finn OJ;Dhodapkar M;Kay NE;Braggio E;Vilar E;Mazzilli SA;Rebbeck TR;Garber JE;Velculescu VE;Disis ML;Wallace DC;Lippman SM
癌症的发展是一个复杂的过程，受遗传和获得性分子和细胞变化的影响。预防是根除癌症的圣杯，但要实现这一目标，需要基于对癌前生物学的深刻理解进行根本性的反思。虽然人类肿瘤发生的多步骤遗传模型早在三十年前就在结直肠腺瘤-癌序列中被定义，但通过下一代测序(NGS)分析的散发性腺瘤只有少数被报道，这与癌症中NGS数据的丰富形成了鲜明的对比。最近的癌前研究进展包括：胚系突变生物学驱动精确预防-在BRCA1携带者中对腔祖细胞的RANK-L效应导致在BRCA1携带者中进行国际试验，首个真正显示胰腺肿瘤早期检测研究潜在益处的信号，家族性腺瘤性息肉病联合化学预防的突破性试验，以及在肠道肿瘤发生中的种系/微生物群相互作用，包括在Lynch综合征小鼠模型中。其他进展包括：新的(例如，拷贝数改变)调节器和免疫抑制微环境成像；免疫预防(从HPV到癌症疫苗)；突变特征；在克隆造血中建立的癌前突变积累，最近的深层NGS表明一种更普遍的现象；以及对DCIS和Barrett食道的单细胞分析，确定了遗传异质性的重要性。挑战是巨大的，包括史无前例的全基因组、单细胞分辨率的高昂计算和数据成本，人口规模数据估计在艾字节范围(>；1018字节)，需要新的计算框架。为了加速癌症的预防，该领域需要大规模的、纵向的国家努力，利用不同的学科、技术和模型来开发综合的多组学和免疫癌前图谱(PCA)，以审问和靶向推动肿瘤发生的事件。
Cancer development is a complex process influenced by inherited and acquired molecular and cellular alterations. Prevention is the holy grail of cancer eradication, but making this a reality will take a fundamental rethinking based on deep understanding of premalignant biology. Although the seminal multi-step, genetic model of human tumorigenesis was defined in the colorectal adenoma-carcinoma sequence three decades ago, only a handful of sporadic adenomas analyzed by next-generation sequencing (NGS) have been reported, in striking contrast to the wealth of NGS data in cancers. Recent precancer advances include: germline mutation biology driving precision prevention – RANK-L effects on luminal progenitors leading to international trial in BRCA1 carriers, first real signal of potential benefit of early detection research in pancreatic neoplasia, breakthrough trial of combination chemoprevention in familial adenomatous polyposis, and germline/microbiota interactions in intestinal oncogenesis, including in mouse model of Lynch syndrome. Other developments include: novel (e.g., copy number alterations) regulators and imaging of immunosuppressive microenvironments; immune prevention (from HPV to cancer vaccines); mutational signatures; premalignant mutational accumulation in aging, established in clonal hematopoiesis, with recent deep NGS suggesting a more generalized phenomenon; and single-cell analyses of DCIS and Barrett’s esophagus identifying importance of genetic heterogeneity. The challenges are substantial, including hefty computational and data prices for unprecedented whole-genome, single-cell resolution, with population scale data estimates in the exabyte range (>1018 bytes), requiring new computational frameworks. To accelerate the prevention of cancer, this field needs a large-scale, longitudinal national effort, leveraging diverse disciplines, technologies, and models to develop an integrated multi-omics and immunity precancer atlas (PCA), to interrogate and target events that drive oncogenesis.