PO.CL01.12 · 临床研究
FGFR2易位型鼻窦腺癌：一种具有独特且可靶向分子表型的双相性浆液黏液性腺癌
FGFR2 translocated sinonasal adenocarcinoma: A biphasic seromucinous adenocarcinoma with a distinctive and targetable molecular phenotype
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
鼻窦腺癌（SNAC）是鼻窦道内仅次于鳞状细胞癌的第二常见癌症类别，包括肠型腺癌、非肠型腺癌和涎腺型腺癌。手术联合术后放疗是SNAC的标准治疗。分子表征列出了若干暂定亚型（BRAF V600E突变的鼻窦导管样肿瘤、MAPK/PI3-K改变的SNAC、CTNNB1突变的鼻窦癌、融合激酶相关SNAC如ETV6::NTRK3、FGFR重排的双相性SNAC）。我们报告一例携带新型FGFR2::SORB3融合的双相性/基底样SNAC（以上颌窦为中心，延伸至鼻腔；pT4N0M0）。采用包含DNA测序和RNA测序的实体瘤综合检测进行靶向NGS。生成了与肿瘤-免疫相互作用相关的1392个基因的RNA表达谱。对代表性SNAC区域进行了10X Genomics Visium空间基因表达分析。NGS显示9个具有临床意义的变异：BMPR1A缺失；DICER1缺失、FGFR2扩增、GATA4缺失、p MITF、p NF2、PIK3R1、PTEN缺失、p PTEN；TMB低、MSI稳定；RNAseq上发现了新型FGFR2::SORBS3融合。FGFR2断裂分离FISH显示复杂重排，伴3'信号缺失及5'信号同时扩增。HTG panel显示上调最显著的IL类差异表达基因（IL12A、SPP1、IL12RAP），SOX2下调最显著。对注释点进行的空间转录组（ST）分析显示5个不同的簇，对应于组织学上不同的区室（双相性-2个簇；单相性/实性/透明-1个簇；间质-1个簇；肿瘤-间质界面-1个簇）。上调最显著的共有差异表达基因为OLFM4、LTF和KRT14，而下调最显著的差异表达基因为BPIFA1、ALOX15和C20orf85。跨多个MSigDB集合的GSEA显示肌细胞分化通路上调。在大多数簇中鉴定出磷酸化及细胞内信号级联通路PI3K-AKT、JAK、STAT3、IL6、IFNγ应答。间质/肿瘤-间质界面簇富集EMT通路，其次为炎症应答、血管生成、K-Ras信号上调。FGFR2易位型SNAC可能代表一种具有浆液黏液性表型的独特基底样双相性肿瘤。形态学及肌细胞分化富集提示其与涎腺上皮-肌上皮癌具有同源性，但其“更热”的免疫微环境使其在一定程度上区别于大多数涎腺型癌。FGFR2::SORBS3即使在其他肿瘤类型（如胆管癌）已鉴定的150多个融合伴侣中也属罕见，但其功能似乎相似，可上调磷酸化通路。识别该肿瘤亚型有助于筛选可能适合FDA批准的口服FGFR2抑制剂（pemigatinib、futibatinib）的患者。
查看英文原文 English abstract
Sinonasal adenocarcinomas (SNACs) are the second most common carcinoma category in the sinonasal tract after squamous cell carcinomas and include intestinal type adenocarcinoma, non-intestinal type adenocarcinomas and salivary-type adenocarcinomas. Surgery with postoperative radiation therapy is standard treatment for SNAC. Molecular characterization lists provisional subtypes ( BRAF V600E -mutated sinonasal ductal-like tumors, MAPK / PI3-K altered SNAC, CTNNB1 -mutated sinonasal carcinoma, fusion-kinase associated SNAC e.g. ETV6::NTRK3 , FGFR- rearranged biphasic SNAC).We report a biphasic/basaloid SNAC (maxillary sinus epicenter, extending into nasal cavity; pT4N0M0) with a novel FGFR2::SORB3 fusion. Targeted NGS was performed with a solid tumor comprehensive assay including DNA sequencing and RNA sequencing. RNA expression profiles of 1392 genes, related to tumor-immune interaction was generated. Representative SNAC region was subjected to 10X Genomics Visium Spatial Gene Expression analysis. NGS showed 9 clinically significant variants: BMPR1A loss; DICER1 loss, FGFR2 amplification, GATA4 loss, p MITF , p NF2 , PIK3R1 , PTEN loss, p PTEN ; TMB low, MSI stable; a novel FGFR2::SORBS3 fusion was noted on RNAseq. FGFR2 breakapart FISH showed a complex rearrangement with loss of the 3' signal and concurrent amplification of the 5' signal. The HTG panel showed the top upregulated IL DEGs( IL12A , SPP1 , IL12RAP ), with SOX2 most downregulated.ST analysis of the annotated spots demonstrated 5 distinct clusters corresponding to histologically distinct compartments (biphasic-2 clusters; monophasic/ solid/ clear-1 cluster; stroma-1 cluster; tumor-stroma interface-1 cluster). Top shared upregulated DEG were OLFM4 , LTF and KRT14 while the top downregulated DEG were BPIFA1 , ALOX15 , and C20orf85 . GSEA across several MSigDB collections showed muscle cell differentiation pathway upregulation. Phosphorylation and intracellular signaling cascade pathways PI3K-AKT, JAK, STAT3, IL6, IFNƔ response was identified in most clusters. Stromal/ tumor-stromal interface clusters were enriched for EMT pathways, followed by inflammatory response, angiogenesis, K-Ras signaling up. FGFR2 translocated SNAC may represent a distinct basaloid biphasic tumor with a seromucinous phenotype. Morphology and muscle cell differentiation enrichment suggests homology with salivary epithelial-myoepithelial carcinoma, but the ‘hotter' immune microenvironment sets it somewhat apart from most salivary type carcinomas. FGFR2::SORBS3 is rare even among the 150+ identified partners in other tumor types (i.e. cholangiocarcinoma) but appear to function similarly, upregulating phosphorylation pathways. Recognition of this tumor subtype could help select patients potentially amenable to FDA- approved oral FGFR2 inhibitors (pemigatinib, futibatinib).
利益披露 Disclosure
D. Bell, None..
R. S. Weber, None..
M. Zhang, None..
M. Afkhami, None..
R. R. Seethala, None.