Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity
Genomic profiling of malignant phyllodes tumors reveals aberrations in FGFR1 and PI-3 kinase/RAS signaling pathways and provides insights into intratumoral heterogeneity
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DOI：
10.1038/modpathol.2016.97
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发表时间：
2016-09-01
期刊：
影响因子：
7.5
通讯作者：
Krings, Gregor
中科院分区：
文献类型：
--
作者：
Liu, Su-Yang;Joseph, Nancy M.;Krings, Gregor
乳腺恶性叶状瘤是一种罕见的肿瘤，具有潜在的侵袭性行为。对于进展或转移性疾病，几乎没有有效的治疗选择。恶性叶状肿瘤的分子特征尚不明确，对这些肿瘤的遗传学更深入的了解可能会揭示其发病机制和进展，并有可能确定新的治疗方法。我们对10个恶性叶状瘤的510个癌症相关基因进行了测序，其中5个为脂肪肉瘤分化瘤，1个为粘液样软骨肉瘤样分化瘤。通过对7个肿瘤的两个不同区域进行测序来评估肿瘤内的异质性，包括异源分化肿瘤的非异源成分和异源成分。在2个肿瘤中发现了激活FGFR1的热点突变。其他反复突变的基因包括TERT启动子（6/10）、TP53（4/10）、PIK3CA（3/10）、MED12（3/10）、SETD2（2/10）和KMT2D（2/10）。总之，在8个（80%）肿瘤中鉴定出FGFR/EGFR PI-3激酶和RAS通路的基因组畸变，包括相互排斥和潜在可操作的激活FGFR1， PIK3CA和BRAF V600E突变，灭活TSC2突变，EGFR扩增和PTEN丢失。7例（70%）恶性叶状瘤存在TERT畸变（6个启动子突变，1个扩增）。相比之下，Sanger测序在33%的交界性（n = 12）和0% （n = 8）良性分叶肿瘤中检测到TERT启动子突变（与恶性肿瘤相比，P = 0.391和P = 0.013）。脂肪肉瘤特有的遗传特征，包括CDK4/MDM2扩增，尚未确定。拷贝数分析揭示了瘤内异质性和肿瘤分化分化的证据。与脂肪肉瘤分化的肿瘤相比，非异种成分的染色体畸变更多。EGFR扩增是异质的，仅存在于一个脂肪肉瘤分化肿瘤的非异源成分中。这些结果发现了参与恶性叶状瘤发病机制的新途径，显著增加了我们对肿瘤生物学的认识，并具有潜在的临床影响。
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.