Foundation Medicine, Cambridge, Massachusetts, USA.
Department of Pathology, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, Rhode Island, USA.
Oncology. 2020;98(12):905-912. doi: 10.1159/000510241. Epub 2020 Sep 23.
Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal soft tissue neoplasm often linked to mTOR pathway activation via TSC2 mutation. We analyzed a series of 31 consecutive metastatic PEComa (mPEComa) cases using a combined DNA/RNA hybrid capture-based comprehensive genomic profiling (CGP) assay to assess the genomic landscape of mPEComa.
Formalin-fixed, paraffin-embedded (FFPE) blocks or slides were obtained from tumors from 31 unique patients with mPEC-oma. DNA and RNA were extracted and CGP was performed on 405 genes using a targeted next-generation sequencing (NGS) assay in a CLIA-certified lab.
All cases had locally advanced or metastatic disease, and 58% of patients were female with a median age of 50 years (range 8-76), and 17 and 14 specimens were from primary and metastatic sites, respectively. One hundred genomic alterations were identified in the cohort, with an average of 3.2 genomic alterations/case including alterations in TSC2 32.3% of cases (10), TSC1 9.6% (3), TFE3 16.1% (5, all fusions), and folliculin (FLCN) 6.4% (2), with all occurring in mutually exclusive fashion. Of TSC2 mutant cases, 70% had biallelic inactivation of this locus, as were 100% of TSC1 mutant cases. Two TSC1/2 wildtype cases harbored truncating mutations in FLCN, both of which were under LOH. Five TFE3 fusion cases were identified including the novel 5' fusion partner ZC3H4.
We describe for the first time mPEComa cases with FLCN mutations under LOH, further characterizing dysregulation of the mTOR pathway as a unifying theme in mPEC-oma. Cumulatively, we demonstrate the feasibility and potential utility of segregating mPEComa by TSC, TFE3, and FLCN status via CGP in clinical care.
血管周上皮样细胞瘤（PEComa）是一种罕见的间叶性软组织肿瘤，常与 TSC2 突变导致的 mTOR 通路激活有关。我们通过使用基于 DNA/RNA 杂交捕获的综合基因组分析（CGP）分析了 31 例连续的转移性 PEComa（mPEComa）病例，以评估 mPEComa 的基因组图谱。
从 31 例 mPEC-oma 患者的肿瘤中获得福尔马林固定、石蜡包埋（FFPE）块或切片。从 DNA 和 RNA 中提取，并在 CLIA 认证实验室中使用靶向下一代测序（NGS）分析对 405 个基因进行 CGP。
所有病例均为局部晚期或转移性疾病，58%的患者为女性，中位年龄为 50 岁（范围 8-76），17 例和 14 例标本分别来自原发和转移部位。该队列中确定了 100 个基因组改变，平均每个病例有 3.2 个基因组改变，包括 TSC2 改变 32.3%（10 例）、TSC1 改变 9.6%（3 例）、TFE3 改变 16.1%（5 例，均为融合）和滤泡素（FLCN）改变 6.4%（2 例），所有改变均为互斥式发生。在 TSC2 突变病例中，有 70%的病例存在该基因座的双等位基因失活，而 TSC1 突变病例则有 100%的病例存在该情况。2 例 TSC1/2 野生型病例存在 FLCN 截断突变，均存在 LOH。鉴定了 5 例 TFE3 融合病例，包括新的 5'融合伙伴 ZC3H4。
我们首次描述了 mPEComa 病例中存在 LOH 的 FLCN 突变，进一步将 mTOR 通路的失调描述为 mPEC-oma 的一个统一主题。总之，我们通过 CGP 分离 TSC、TFE3 和 FLCN 状态的 mPEComa，证明了其在临床护理中的可行性和潜在应用。
