Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity.

基因组分析揭示恶性叶状肿瘤中FGFR1和PI-3K/Ras信号转导通路的异常及肿瘤异质性

Liu SY,Joseph NM,Ravindranathan A,Stohr BA,Greenland NY,Vohra P,Hosfield E,Yeh I,Talevich E,Onodera C,Van Ziffle JA,Grenert JP,Bastian BC,Chen YY,Krings G

阅读：1703 Modern Pathology； Aug 2016; 29 (9): 1004 - 1113:1012-27

Abstract

Malignant phyllodes tumors of the breast are poorly understood rare neoplasms with potential for aggressive behavior. Few efficacious treatment options exist for progressed or metastatic disease. The molecular features of malignant phyllodes tumors are poorly defined, and a deeper understanding of the genetics of these tumors may shed light on pathogenesis and progression and potentially identify novel treatment approaches. We sequenced 510 cancer-related genes in 10 malignant phyllodes tumors, including 5 tumors with liposarcomatous differentiation and 1 with myxoid chondrosarcoma-like differentiation. Intratumoral heterogeneity was assessed by sequencing two separate areas in 7 tumors, including non-heterologous and heterologous components of tumors with heterologous differentiation. Activating hotspot mutations in FGFR1 were identified in 2 tumors. Additional recurrently mutated genes included TERT promoter (6/10), TP53 (4/10), PIK3CA (3/10), MED12 (3/10), SETD2 (2/10) and KMT2D (2/10). Together, genomic aberrations in FGFR/EGFR PI-3 kinase and RAS pathways were identified in 8 (80%) tumors and included mutually exclusive and potentially actionable activating FGFR1, PIK3CA and BRAF V600E mutations, inactivating TSC2 mutation, EGFR amplification and PTEN loss. Seven (70%) malignant phyllodes tumors harbored TERT aberrations (six promoter mutations, one amplification). For comparison, TERT promoter mutations were identified by Sanger sequencing in 33% borderline (n=12) and no (0%, n=8) benign phyllodes tumors (P=0.391 and P=0.013 vs malignant tumors, respectively). Genetic features specific to liposarcoma, including CDK4/MDM2 amplification, were not identified. Copy number analysis revealed intratumoral heterogeneity and evidence for divergent tumor evolution in malignant phyllodes tumors with and without heterologous differentiation. Tumors with liposarcomatous differentiation revealed more chromosomal aberrations in non-heterologous components compared with liposarcomatous components. EGFR amplification was heterogeneous and present only in the non-heterologous component of one tumor with liposarcomatous differentiation. The results identify novel pathways involved in the pathogenesis of malignant phyllodes tumors, which significantly increase our understanding of tumor biology and have potential clinical impact.

摘要

乳腺恶性叶状肿瘤是一种少见的具有潜在侵袭性的肿瘤，关于这一肿瘤的文献报道较少，针对其进展和转移缺乏有效的治疗方案。恶性叶状肿瘤的分子特征尚不明确，深入了解此肿瘤的遗传学可能有助于其发病机制和肿瘤进展的探索，并可能找到新的治疗方法。

我们测序了10例恶性叶状肿瘤的510个癌症相关基因，其中5例伴有脂肪肉瘤样分化，1例伴有粘液软骨肉瘤样分化。肿瘤异质性是通过测序7个肿瘤的两个不同区域来评估，包括异种分化肿瘤的非异源性和异源性成分。在2个肿瘤中检测到FGFR1基因突变热点的激活。其他的复发性突变基因包括TERT启动子（6/10），TP53（4/10），PIK3CA（3/10），MED12（3/10），SETD2（2/10）和KMT2D（2/10）。另外，在8个（80%）肿瘤中检测到FGFR/EGFR受体PI-3K和RAS通路发生染色体突变，包括互相抑制和潜在的促进激活FGFR1、PIK3CA和BRAF V600E突变，使TSC2突变失活，并使EGFR扩增和PTEN缺失。7个（70%）恶性叶状肿瘤发生TERT突变（6个启动子突变，1个扩增）。

通过Sanger测序法检测12例交界性叶状肿瘤和8例良性叶状肿瘤并与恶性叶状肿瘤对比确定TERT启动子发生突变（P = 0.391，P = 0.013）。恶性叶状肿瘤的遗传特征具体包括脂肪肉瘤样分化和CDK4/MDM2扩增，均未被确定。拷贝数分析显示肿瘤具有异质性，具有异源性分化的恶性叶状肿瘤有不同的肿瘤演化。具有脂肪肉瘤样分化肿瘤的非异源性成分更容易发生染色体突变。EGFR扩增具有异质性，而且只发生在有脂肪肉瘤样分化肿瘤的非异源性成分中。

本研究结果表明，新的通路参与恶性叶状肿瘤的发病机制，显著提高了我们对肿瘤生物学的认识，具有潜在的临床意义。