Griffin Gabriel K, Sholl Lynette M, Lindeman Neal I, Fletcher Christopher D M, Hornick Jason L
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Mod Pathol. 2016 Jan;29(1):67-74. doi: 10.1038/modpathol.2015.130. Epub 2015 Nov 13.
Follicular dendritic cell sarcoma is a rare mesenchymal neoplasm with a variable and unpredictable clinical course. The genetic alterations that drive tumorigenesis in follicular dendritic cell sarcoma are largely unknown. One recent study performed BRAF sequencing and found V600E mutations in 5 of 27 (19%) cases. No other recurrent genetic alterations have been reported. The aim of the present study was to identify somatic alterations in follicular dendritic cell sarcoma by targeted sequencing of a panel of 309 known cancer-associated genes. DNA was isolated from formalin-fixed paraffin-embedded tissue from 13 cases of follicular dendritic cell sarcoma and submitted for hybrid capture-based enrichment and massively parallel sequencing with the Illumina HiSeq 2500 platform. Recurrent loss-of-function alterations were observed in tumor suppressor genes involved in the negative regulation of NF-κB activation (5 of 13 cases, 38%) and cell cycle progression (4 of 13 cases, 31%). Loss-of-function alterations in the NF-κB regulatory pathway included three cases with frameshift mutations in NFKBIA and two cases with bi-allelic loss of CYLD. Both cases with CYLD loss were metastases and carried concurrent alterations in at least one cell cycle regulatory gene. Alterations in cell cycle regulatory genes included two cases with bi-allelic loss of CDKN2A, one case with bi-allelic loss of RB1, and one case with a nonsense mutation in RB1. Last, focal copy-number gain of chromosome 9p24 including the genes CD274 (PD-L1) and PDCD1LG2 (PD-L2) was noted in three cases, which represents a well-described mechanism of immune evasion in cancer. These findings provide the first insight into the unique genomic landscape of follicular dendritic cell sarcoma and suggest shared mechanisms of tumorigenesis with a subset of other tumor types, notably B-cell lymphomas.
滤泡树突状细胞肉瘤是一种罕见的间叶性肿瘤，其临床病程多变且不可预测。驱动滤泡树突状细胞肉瘤肿瘤发生的基因改变在很大程度上尚不清楚。最近的一项研究进行了BRAF测序，在27例病例中的5例（19%）发现了V600E突变。尚未报道其他复发性基因改变。本研究的目的是通过对一组309个已知癌症相关基因进行靶向测序，来鉴定滤泡树突状细胞肉瘤中的体细胞改变。从13例滤泡树突状细胞肉瘤的福尔马林固定石蜡包埋组织中提取DNA，并提交用于基于杂交捕获的富集以及使用Illumina HiSeq 2500平台进行大规模平行测序。在参与NF-κB激活负调控（13例中的5例，38%）和细胞周期进程（13例中的4例，31%）的肿瘤抑制基因中观察到复发性功能丧失改变。NF-κB调节途径中的功能丧失改变包括3例NFKBIA发生移码突变和2例CYLD双等位基因缺失。2例CYLD缺失的病例均为转移灶，并且至少在一个细胞周期调节基因中存在并发改变。细胞周期调节基因中的改变包括2例CDKN2A双等位基因缺失、1例RB1双等位基因缺失以及1例RB1发生无义突变。最后，在3例病例中发现9号染色体p24区域包括CD274（PD-L1）和PDCD1LG2（PD-L2）基因的局灶性拷贝数增加，这是癌症中一种已充分描述的免疫逃逸机制。这些发现首次揭示了滤泡树突状细胞肉瘤独特的基因组格局，并提示其与其他一些肿瘤类型（尤其是B细胞淋巴瘤）存在共同的肿瘤发生机制。
