Department of Molecular Structure and Function, The Hospital For Sick Children, 686 Bay Street, Toronto, Ontario, Canada M5G0A4.
Princess Margaret Cancer Centre, 101 College Street, Toronto, Ontario, Canada M5G 1L7.
Nat Commun. 2014 Nov 28;5:5469. doi: 10.1038/ncomms6469.
Cancer results from processes prone to selective pressure and dysregulation acting along the sequence-to-phenotype continuum DNA → RNA → protein → disease. However, the extent to which cancer is a manifestation of the proteome is unknown. Here we present an integrated omic map representing non-small cell lung carcinoma. Dysregulated proteins not previously implicated as cancer drivers are encoded throughout the genome including, but not limited to, regions of recurrent DNA amplification/deletion. Clustering reveals signatures composed of metabolism proteins particularly highly recapitulated between patient-matched primary and xenograft tumours. Interrogation of The Cancer Genome Atlas reveals cohorts of patients with lung and other cancers that have DNA alterations in genes encoding the signatures, and this was accompanied by differences in survival. The recognition of genome and proteome alterations as related products of selective pressure driving the disease phenotype may be a general approach to uncover and group together cryptic, polygenic disease drivers.
癌症源于易受选择压力和失调影响的过程，这些过程沿着从 DNA 到 RNA 到蛋白质再到疾病的序列到表型连续体发生作用。然而，癌症在多大程度上是蛋白质组的表现形式尚不清楚。在这里，我们呈现了一个代表非小细胞肺癌的综合组学图谱。失调的蛋白质以前没有被认为是癌症驱动因素，但它们在整个基因组中都有编码，包括但不限于重复 DNA 扩增/缺失的区域。聚类揭示了由代谢蛋白组成的特征，这些特征在患者匹配的原发和异种移植肿瘤之间特别高度重现。对癌症基因组图谱的分析揭示了一批肺癌和其他癌症患者的 DNA 改变，这些改变与基因编码的特征有关，这伴随着生存差异。将基因组和蛋白质组的改变视为驱动疾病表型的选择压力的相关产物的认识可能是一种发现和将隐匿性、多基因疾病驱动因素分组在一起的通用方法。
