Can transcriptomic alterations drive the evolution of tumors? We asked if changes in gene expression found in all patients arise earlier in tumor development and can be relevant to tumor progression. Our analyses of non-mutated genes from the non-amplified regions of the genome of 158 triple-negative breast cancer (TNBC) cases identified 219 exclusively expression-altered (EEA) genes that may play important role in TNBC. Phylogenetic analyses of these genes predict a “punctuated burst” of multiple gene upregulation events occurring at early stages of tumor development, followed by minimal subsequent changes later in tumor progression. Remarkably, this punctuated burst of expressional changes is instigated by hypoxia-related molecular events, predominantly in two groups of genes that control chromosomal instability (CIN) and those that remodel tumor microenvironment (TME). We conclude that alterations in the transcriptome are not stochastic and that early-stage hypoxia induces CIN and TME remodeling to permit further tumor evolution.

转录组改变可以驱动肿瘤的进化吗？我们询问所有患者中发现的基因表达变化是否出现在肿瘤发展的早期，并且可能与肿瘤进展相关。我们对 158 个三阴性乳腺癌 (TNBC) 病例基因组非扩增区域的非突变基因进行分析，确定了 219 个可能在 TNBC 中发挥重要作用的完全表达改变 (EEA) 基因。对这些基因的系统发育分析预测，在肿瘤发展的早期阶段会发生多个基因上调事件的“间断爆发”，随后在肿瘤进展的后期发生最小的后续变化。值得注意的是，这种间断的表达变化是由缺氧相关分子事件引发的，主要发生在控制染色体不稳定性（CIN）和重塑肿瘤微环境（TME）的两组基因中。我们得出的结论是，转录组的改变不是随机的，早期缺氧会诱导 CIN 和 TME 重塑，从而允许肿瘤进一步进化。