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

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.

CRTC1–MAML2 fusion in mucoepidermoid carcinoma of the breast

“…Most prevalent in clear cell renal cell carcinoma, inactivating mutations have been described in multiple cancers . SETD2 mutations have been rarely reported in breast tumours (at most ~3% of cases), notably only in luminal A cancers and phyllodes tumours but not in triple‐negative breast carcinomas . No SETD2 alterations have been reported to date in MEC of the salivary gland, and the significance of this isolated finding in one breast MEC is uncertain.…”

Genetic analysis of uterine adenosarcomas and phyllodes tumors of the breast

“…Importantly, however, the prevalence of genetic alterations affecting TERT was higher in PTs than in adenosarcomas, and the mechanism by which TERT was altered differed in these lesions. While TERT was preferentially altered by hotspot gene promoter mutations in PTs (Cani et al ., ; Liu et al ., ; Piscuoglio et al ., ; Yoshida et al ., ), only TERT gene amplification events were detected in the adenosarcomas studied here (Fig. A).…”

“…In our cohort of adenosarcomas, we detected alterations in PI3K pathway in 26% (5/19) of cases ( PIK3CA , PIK3CG , PIK3R1 , PTEN mutations and/or amplification of AKT2 or ERBB3 ). In PTs of all grades, mutations in PI3K pathway‐related genes occur at a lower frequency (14% of 22 cases here described), whereas in malignant cases, they have been found to be more frequent (Liu et al ., ; Piscuoglio et al ., ; Tan et al ., ). Of 13 malignant PTs analyzed by Piscuoglio et al .…”

“…(), five (38%) displayed mutations in PI3K pathway‐related genes ( PIK3CA , PDGFRB , PTEN , AKT1 , MTOR , ERBB2 , and/or ERBB3 mutations). Additional previous studies described PIK3CA mutations in 5% of 79 PTs including all grades (Tan et al ., ), and in three of 10 (30%) malignant PTs (Liu et al ., ).…”

“…Notably, we found a potential association between rhabdomyoblastic differentiation in adenosarcomas and DICER1 mutations (Piscuoglio et al ., ), which occur in familial and sporadic forms of embryonal rhabdomyosarcomas (Doros et al ., ). By contrast, liposarcomatous differentiation in PTs is not underpinned by amplification of the MDM2/CDK4 locus (Liu et al ., ; Lyle et al ., ), which is a well‐characterized driver of well‐differentiated and dedifferentiated liposarcomas and frequently detected in uterine adenosarcomas (Howitt et al ., ; Piscuoglio et al ., ). Stromal overgrowth in uterine adenosarcomas has been reported by Howitt et al .…”