低级别腺鳞癌（LGASC）是一种罕见的乳腺间质性癌（MBC），其临床过程温和。已报道有一些LGASC病例发生高级别转化，但是LGASC恶性进展的遗传学仍不清楚。我们对4名患者的5例MBC进行了全基因组测序分析，包括一例具有一致的原发性LGASC和一个由LGASC进展而来的淋巴结转移肿瘤，该肿瘤主要由高级别MBC和优势的间质性鳞状细胞癌组分（MSC）组成，以及3例独立的新发MSC。与新发MSC不同，LGASC及其相关的MSC没有TP53基因突变，并且结构变异较新发MSC少。LGASC及其相关的MSC均携带常见的GNAS c.C2530T：p.Arg844Cys突变，该突变在MSC的癌细胞部分中的检测频率更高。与LGASC相关的MSC显示了多个肿瘤抑制基因的致病性缺失，例如KMT2D和BTG1。拷贝数分析显示，LGASC和相关的MSC均可能存在18q等位基因丧失。由于缺失而导致的SMAD4 :: DCC融合的频率随着进展到MSC而增加，然而未检测到嵌合蛋白。SMAD4蛋白的表达在LGASC阶段已经由于未知机制而降低。不仅LGASC，而且其相关的高级别MBC与新发的高级别MBC可能在基因上有所不同。从LGASC到高级别MBC的进展可能涉及由克隆选择引起的驱动突变的积聚以及肿瘤抑制基因的失活。©2023. 作者。

Low-grade adenosquamous carcinoma (LGASC) is a rare type of metaplastic carcinoma of the breast (MBC) with an indolent clinical course. A few LGASC cases with high-grade transformation have been reported; however, the genetics underlying malignant progression of LGASC remain unclear.We performed whole-genome sequencing analysis on five MBCs from four patients, including one case with matching primary LGASC and a lymph node metastatic tumor consisting of high-grade MBC with a predominant metaplastic squamous cell carcinoma component (MSC) that progressed from LGASC and three cases of independent de novo MSC.Unlike de novo MSC, LGASC and its associated MSC showed no TP53 mutation and tended to contain fewer structural variants than de novo MSC. Both LGASC and its associated MSC harbored the common GNAS c.C2530T:p.Arg844Cys mutation, which was more frequently detected in the cancer cell fraction of MSC. MSC associated with LGASC showed additional pathogenic deletions of multiple tumor-suppressor genes, such as KMT2D and BTG1. Copy number analysis revealed potential 18q loss of heterozygosity in both LGASC and associated MSC. The frequency of SMAD4::DCC fusion due to deletions increased with progression to MSC; however, chimeric proteins were not detected. SMAD4 protein expression was already decreased at the LGASC stage due to unknown mechanisms.Not only LGASC but also its associated high-grade MBC may be genetically different from de novo high-grade MBC. Progression from LGASC to high-grade MBC may involve the concentration of driver mutations caused by clonal selection and inactivation of tumor-suppressor genes.© 2023. The Author(s).