Exploitation of naturally occurring genetic mutations could empower the discovery of novel aspects of established cancer genes. We report here that TRPS1, a gene linked to the tricho-rhino-phalangeal syndrome (TRPS) and recently identified as a potential breast cancer driver, promotes breast carcinogenesis through regulating replication. Epigenomic decomposition of TRPS1 landscape reveals nearly half of H3K9me3-marked heterochromatic origins are occupied by TRPS1, where it encourages the chromatin loading of APC/C, resulting in uncontrolled origin refiring. TRPS1 binds to the genome through its atypical H3K9me3 reading via GATA and IKAROS domains, while TRPS-related mutations affect its chromatin binding, replication boosting, and tumorigenicity. Concordantly, overexpression of wild-type but not TRPS-associated mutants of TRPS1 is sufficient to drive cancer genome amplifications, which experience an extrachromosomal route and dynamically evolve to confer therapeutic resistance. Together, these results uncover a critical function of TRPS1 in driving heterochromatin origin firing and breast cancer genome evolution.

利用自然发生的基因突变可以促进发现已建立的癌症基因的新方面。我们在这里报告说，TRPS1 是一种与毛发-鼻-指骨综合征 （TRPS） 相关的基因，最近被确定为潜在的乳腺癌驱动因素，它通过调节复制促进乳房癌变。TRPS1 景观的表观基因组分解显示，近一半的 H3K9me3 标记的异色性起点被 TRPS1 占据，它促进 APC/C 的染色质负载，导致不受控制的起点重新发射。TRPS1 通过其非典型 H3K9me3 读数通过 GATA 和 IKAROS 结构域与基因组结合，而 TRPS 相关突变会影响其染色质结合、复制促进和致瘤性。一致地，TRPS1 的野生型而非 TRPS 相关突变体的过表达足以驱动癌症基因组扩增，癌症基因组扩增经历染色体外途径并动态进化以赋予治疗耐药性。总之，这些结果揭示了 TRPS1 在驱动异染色质起源激发和乳腺癌基因组进化中的关键功能。