title: 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.
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Su-Yang
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Nancy M
authors.initials: NM
authors.lastname: Joseph
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Ajay
authors.initials: A
authors.lastname: Ravindranathan
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Stohr
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Greenland
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.|Department of Pathology, San Francisco General Hospital, San Francisco, CA, USA.
authors.forename: Poonam
authors.initials: P
authors.lastname: Vohra
authors.affiliation: Department of Pathology, Kaiser Permanente, Oakland, CA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hosfield
authors.affiliation: Department of Dermatology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Iwei
authors.initials: I
authors.lastname: Yeh
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Talevich
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Onodera
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Van Ziffle
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Grenert
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.|Department of Dermatology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Yunn-Yi
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: Gregor
authors.initials: G
authors.lastname: Krings
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D011905:Genes, ras; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D003557:Phyllodes Tumor / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics*; D012495:San Francisco; D015398:Signal Transduction / Q000235:genetics*; D059467:Transcriptome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1