Comprehensive
characterization of malignant phyllodes tumor by whole genomic and
proteomic analysis: biological implications for targeted therapy
opportunities.
Source
Department
of Investigational Cancer Therapeutics, The University of Texas MD
Anderson Cancer Center, 1515 Holcombe Blvd, FC8,3038, Box 0455, Houston,
TX 77030, USA. vsubbiah@mdanderson.org.
Abstract
BACKGROUND:
Phyllodes
tumors are uncommon breast tumors that account for less than 0.5% of
all breast malignancies. After metastases develop, the prognosis is
poor, with very few patients living more than 1 year. The biology of
this unusual cancer is not understood and, consequently, no potential
targets for treatments are currently available. There has been an
exponential increase in the number of commercially available tumor
profiling services. Herein, we report a case of metastatic malignant
phyllodes tumor for which a comprehensive molecular analysis was
performed by using Clinical Laboratory Improvement Amendments
(CLIA)-certified labs, providing new insights into the potential
opportunities for molecularly targeted therapies for this extremely rare
disease.
METHODS:
Next-generation sequencing was
performed by using the FoundationOne™ platform (Foundation Medicine,
Cambridge, MA). Whole-genome array-based comparative genomic
hybridization (array CGH) was performed by using the DNAarray™
(CombiMatrix Diagnostics, Irvine, CA). Immunohistochemical and
morphoproteomics analysis were performed at Consultative proteomics®,
The University of Texas, UT Health Medical School, Houston,TX (Robert E
Brown Lab); Clarient Diagnostics, Aliso Viejo, CA; and Caris Life
Sciences Target one, Irving, TX, USA.
RESULTS:
Next-generation
sequencing showed 3 aberrant genes: activating mutation Q61L on NRAS;
inactivating mutations Q504* and K740* on RB1; and TP53 loss.
Whole-genome array-based comparative genomic hybridization (array CGH)
revealed amplifications of chromosome (chr.) 1 (CKS1B gene), chr. 8 (MYC
gene), and chr. 9 (CDKN2A gene) Deletions of chr. 17 (TP53), chr. 10
(GATA3), chr. 11 (FGF4 and CCND1 genes), and chr.22 (PDGFβ).
Immunohistochemical analysis for relevant markers showed a positive
staining for transducing-like enhancer of split (TLE) 3; secreted
protein acidic and rich in cysteine (SPARC) was expressed at 2-3+ in the
cytoplasm of the tumors cells, whereas mammalian target of rapamycin
(mTOR) was expressed up to 2+ in the nuclei of the tumor cells.
CONCLUSIONS:
We
describe for the first time an NRAS mutation with concomitant
activation of PI3K/Akt/mTOR in phyllodes tumor. We also found markers
for sensitivity to taxane-based therapies, especially albumin-bound
paclitaxel. Exploring the biology of rare malignancies by CLIA certified
labs may be reasonable strategy for the development of targeted
treatments.
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