Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Mod Pathol. 2021 Oct;34(10):1850-1859. doi: 10.1038/s41379-021-00837-3. Epub 2021 Jun 2.
The SWI/SNF family of proteins is a multisubunit ATPase complex frequently altered in human cancer. Inactivating mutations in SWI/SNF-related matrix-associated actin-dependent regulator of chromatin (SMARCs) underpin a subset of tumors such as the malignant rhabdoid tumor and small cell carcinoma of the ovary, hypercalcemic type. Here, we investigated the genotypic and phenotypic characteristics of breast cancers harboring somatic genetic alterations affecting genes of the SMARC family. We analyzed a series of 6026 primary and metastatic breast cancers subjected to targeted-capture sequencing. SMARC core subunit (SMARCA4, SMARCB1, and SMARCA2) alterations were identified in <1% of all breast cancers, consisting of 27 primary and 30 recurrent/metastatic tumors. The majority of SMARC alterations were monoallelic mutations (47/57, 82%) and thus categorized into two groups: Class 1 alterations consisting of potentially pathogenic mutations and rearrangements and Class 2 alterations consisting of missense mutations and small in-frame deletions of unknown significance. Biallelic events in a SMARC gene were present in a minority of cases (10/57, 18%). Histologic patterns in the form of rhabdoid, composite rhabdoid, sarcomatoid or anaplastic features were observed in a subset of Class 1 primary and metastatic tumors (7/57, 12%). SMARC protein was preserved in nearly all tumors analyzed with immunohistochemistry (26/30, 87%). Four Class 1 tumors demonstrated altered SMARC protein expression in the form of loss (1/30, 3%) or mosaic pattern (3/30, 10%). Complete loss of SMARCA2 (BRM) was observed in a sole tumor with composite rhabdoid morphology, and biallelic hits in the SMARCA2 gene. The genomic landscape of both primary Class 1 and 2 breast cancers did not reveal any characteristic findings. In summary, SMARC alterations likely contribute to the biology of a rare subset of breast cancers in the form of biallelic or pathogenic alterations in SMARC, as evidenced by SMARC-deficient phenotype or altered expression of SMARC protein.
SWI/SNF 家族蛋白是一种多亚基 ATP 酶复合物，经常在人类癌症中发生改变。SWI/SNF 相关基质相关肌动蛋白依赖性染色质调节剂（SMARCs）的失活突变是恶性横纹肌样瘤和小细胞卵巢癌、高钙血症型等一部分肿瘤的基础。在这里，我们研究了携带影响 SMARC 家族基因的体细胞遗传改变的乳腺癌的基因型和表型特征。我们分析了一系列接受靶向捕获测序的 6026 例原发性和转移性乳腺癌。在所有乳腺癌中，发现 SMARC 核心亚基（SMARCA4、SMARCB1 和 SMARCA2）改变不到 1%，包括 27 例原发性和 30 例复发性/转移性肿瘤。大多数 SMARC 改变是单等位基因突变（47/57，82%），因此分为两组：第 1 类改变包括潜在致病性突变和重排，第 2 类改变包括错义突变和小的无意义的框内缺失。少数情况下存在 SMARC 基因的双等位基因事件（10/57，18%）。在一组第 1 类原发性和转移性肿瘤中，观察到横纹肌样、复合横纹肌样、肉瘤样或间变特征的组织学模式（7/57，12%）。免疫组织化学分析几乎所有肿瘤均保留 SMARC 蛋白（26/30，87%）。4 例第 1 类肿瘤表现为 SMARC 蛋白表达缺失（1/30，3%）或镶嵌模式（3/30，10%）。在具有复合横纹肌样形态的单一肿瘤中观察到 SMARCA2（BRM）完全缺失，而 SMARCA2 基因存在双等位基因突变。原发性第 1 类和 2 类乳腺癌的基因组景观均未显示任何特征性发现。总之，SMARC 改变可能通过 SMARC 中的双等位基因或致病性改变以 SMARC 缺陷表型或 SMARC 蛋白表达改变的形式促进罕见乳腺癌亚群的生物学特性。
