Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Mod Pathol. 2022 Dec;35(12):1900-1909. doi: 10.1038/s41379-022-01148-x. Epub 2022 Sep 10.
SMARCB1 biallelic inactivation resulting in SMARCB1/INI1 deficiency drives a wide range of malignancies, including many mesenchymal tumors. However, the specific types of SMARCB1 alterations and spectrum of cooperating mutations among various types of sarcomas has not been well investigated. We profiled SMARCB1 genetic alterations by targeted DNA sequencing and fluorescence in situ hybridization (FISH) in a large cohort of 118 soft tissue and bone tumors, including SMARCB1-deficient sarcomas (78, 66%): epithelioid sarcomas, epithelioid peripheral nerve sheath tumors, poorly differentiated chordomas, malignant rhabdoid tumors, and soft tissue myoepithelial tumors, as well as non-SMARCB1-deficient sarcomas (40, 34%) with various SMARCB1 genetic alterations (mutations, copy number alterations). SMARCB1 loss by immunohistochemistry was present in 94% SMARCB1 pathogenic cases. By combined sequencing and FISH assays, 80% of SMARCB1-deficient tumors harbored homozygous (biallelic) SMARCB1 loss, while 14% demonstrated heterozygous SMARCB1 loss-of-function (LOF) alterations, and 6% showed no demonstrable SMARCB1 alterations. FISH and sequencing were concordant in the ability to detect SMARCB1 loss in 48% of cases. Epithelioid sarcomas most commonly (75%) harbored homozygous deletions, while a subset showed focal intragenic deletions or LOF mutations (nonsense, frameshift). In contrast, most soft tissue myoepithelial tumors (83%) harbored SMARCB1 nonsense point mutations without copy number losses. Additionally, clinically significant, recurrent co-occurring genetic events were rare regardless of histotype. By sequencing, extended 22q copy number loss in genes flanking the SMARCB1 locus (22q11.23) occurred in one-third of epithelioid sarcomas and the majority of poorly differentiated chordomas. Poorly differentiated chordomas and soft tissue myoepithelial tumors showed significantly worse overall and disease-free survival compared to epithelioid sarcomas. Overall, SMARCB1 LOF alterations predominate and account for SMARCB1 protein loss in most cases: majority being biallelic but a subset were heterozygous. In contrast, SMARCB1 alterations of uncertain significance can be seen in diverse sarcomas types and does not indicate a SMARCB1-deficient entity.
SMARCB1 双等位基因失活导致 SMARCB1/INI1 缺陷可驱动广泛的恶性肿瘤，包括许多间叶肿瘤。然而，各种肉瘤中 SMARCB1 改变的具体类型和合作突变谱尚未得到很好的研究。我们通过靶向 DNA 测序和荧光原位杂交（FISH）对 118 例软组织和骨肿瘤的大型队列进行了 SMARCB1 基因改变分析，包括 SMARCB1 缺陷性肉瘤（78 例，占 66%）：上皮样肉瘤、上皮样周围神经鞘肿瘤、分化差的脊索瘤、恶性横纹肌样肿瘤和软组织肌上皮肿瘤，以及具有各种 SMARCB1 基因改变（突变、拷贝数改变）的非 SMARCB1 缺陷性肉瘤（40 例，占 34%）。94%的 SMARCB1 致病性病例存在 SMARCB1 免疫组化缺失。通过联合测序和 FISH 检测，80%的 SMARCB1 缺陷性肿瘤存在纯合（双等位基因）SMARCB1 缺失，14%显示杂合性 SMARCB1 功能丧失（LOF）改变，6%显示无明显 SMARCB1 改变。FISH 和测序在检测 48%病例的 SMARCB1 缺失方面具有一致性。上皮样肉瘤最常见（75%）表现为纯合缺失，而部分病例表现为局灶性基因内缺失或 LOF 突变（无义、移码）。相比之下，大多数软组织肌上皮肿瘤（83%）存在无 SMARCB1 拷贝数缺失的点突变。此外，无论组织学类型如何，临床意义重大的复发性共发生遗传事件都很少见。通过测序，SMARCB1 基因座（22q11.23）侧翼基因的 22q 扩展拷贝数缺失发生在三分之一的上皮样肉瘤和大多数分化差的脊索瘤中。分化差的脊索瘤和软组织肌上皮肿瘤的总生存期和无病生存期明显差于上皮样肉瘤。总体而言，SMARCB1 LOF 改变占主导地位，并且在大多数情况下导致 SMARCB1 蛋白缺失：大多数是双等位基因缺失，但有一部分是杂合性缺失。相比之下，在不同的肉瘤类型中可以看到意义不明的 SMARCB1 改变，并不表明存在 SMARCB1 缺陷实体。
