Genetic analysis of uterine adenosarcomas and phyllodes tumors of the breast.
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ABSTRACT:
SUBMITTER: Geyer FC
PROVIDER: S-EPMC5537914 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PurposePhyllodes tumors (PTs) of the breast are rare, accounting for less than 1% of all breast tumors. Among PTs, malignant PTs (MPTs) have malignant characteristics and distant metastases occur in about 20% to 30% of MPTs. However, there is no effective treatment for MPTs with distant metastasis, resulting in an abject prognosis. We performed targeted deep sequencing on PTs to identify the associations between genetic alterations and clinical prognosis.MethodsWe performed targeted deep sequencing to evaluate the genetic characteristics of PTs and analyzed the relationships between clinical and genetic characteristics.ResultsA total of 17 PTs were collected between 2001 and 2012. Histologic review was performed by pathologists. The samples included three benign PTs, one borderline PT, and 13 MPTs. The most frequently detected genetic alteration occurred in the TERT promoter region (70.6%), followed by MED12 (64.7%). EGFR amplification and TP53 alteration were detected in four MPTs without genetic alterations in MED12 and TERT promoter regions. Genetic alterations of RARA and ZNF703 were repeatedly found in PTs with local recurrence, and genetic alterations of SETD2, BRCA2, and TSC1 were detected in PTs with distant metastasis. Especially, MPT harboring PTEN and RB1 copy number deletion showed rapid disease progression.ConclusionsIn this study, we provide genetic characterization and potential therapeutic target for this rare, potentially lethal disease. Further large-scale comprehensive genetic study and functional validation are warranted.
| S-EPMC5684533 | biostudies-literature
Project description:Fibroepithelial lesions (FL) of the breast, in particular, phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT and fibroadenomas. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including "The Cancer Genome Atlas" (TCGA) and "Gene Expression Omnibus" (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions, and EGFR amplifications may inform therapeutic decision-making.
| S-EPMC8833410 | biostudies-literature
Project description:PurposePhyllodes tumors (PTs) are biphasic tumors accounting for 0.3-1.5% of all breast tumors. Epithelial membrane proteins (EMPs) have been reported in various malignant tumors but their expression in PTs is unclear. In this study, we aimed to evaluate the expression of EMP1, EMP2, and EMP3 in breast phyllodes tumors (PTs), and to investigate their clinical implications.MethodsIn total, 185 PTs were used for constructing a tissue microarray. Immunohistochemical staining for EMP1, EMP2, and EMP3 was performed, and the results were analyzed along with the clinicopathologic parameters.ResultsIn total, 185 PTs were included in this study, and comprised 138 benign, 32 borderline, and 15 malignant PTs. In malignant PTs, the epithelial component showed decreased expression of EMP1 (P = 0.027), EMP2 (P = 0.004), and EMP3 (P = 0.032), compared to the benign and borderline PTs. Conversely, stromal component of borderline and malignant PTs showed higher expression of EMP1 (P = 0.027), EMP2 (P = 0.004), and EMP3 (P = 0.032) compared to benign PTs. Expression of EMP1 and EMP3 correlated positively with stromal cellularity and cellular atypia (P < 0.001). In the univariate analysis, stromal EMP3 was associated with shorter disease-free survival (P < 0.001), and shorter overall survival (P = 0.034).ConclusionThe expression of EMP1, EMP2, and EMP3 is decreased in the epithelial component and is increased in the stromal component of PT with higher histologic grade. Thus, stromal EMP3 expression may serve as an independent prognostic factor in PT.
| S-EPMC7454950 | biostudies-literature
Project description:Exon 2 of MED12, a subunit of the transcriptional mediator complex, has been frequently mutated in uterine leiomyomas and breast fibroadenomas; however, it has been rarely mutated in other tumors. Although the mutations were also found in uterine leiomyosarcomas, the frequency was significantly lower than in uterine leiomyomas. Here, we examined the MED12 mutation in phyllodes tumors, another biphasic tumor with epithelial and stromal components related to breast fibroadenomas. Mutations in MED12 exon 2 were analyzed in nine fibroadenomas and eleven phyllodes tumors via Sanger sequencing. A panel of cancer- and sarcoma-related genes was also analyzed using Ion Torrent next-generation sequencing. Six mutations in fibroadenomas, including those previously reported (6/9, 67%), and five mutations in phyllodes tumors (5/11, 45%) were observed. Three mutations in the phyllodes tumors were missense mutations at Gly44, which is common in uterine leiomyomas and breast fibroadenomas. In addition, two deletion mutations (in-frame c.133_144del12 and loss of splice acceptor c.100-68_137del106) were observed in the phyllodes tumors. No other recurrent mutation was observed with next-generation sequencing. Frequent mutations in MED12 exon 2 in the phyllodes tumors suggest that it may share genetic etiology with uterine leiomyoma, a subgroup of uterine leiomyosarcomas and breast fibroadenoma.
| S-EPMC4529349 | biostudies-literature
Project description:BackgroundMalignant phyllodes (MP) and primary breast sarcomas (PBS) are rare neoplasms with overlapping histopathologic features. We compared overall survival (OS) and estimated the association of surgery and therapies with OS.MethodsWe utilized the National Cancer Database (2004-2016). Patients without surgery, unknown surgery, or margins, or Stage IV disease were excluded. Kaplan-Meier curves and Cox proportional hazards models were used to estimate unadjusted and adjusted OS, respectively.ResultsA total of 3209 (59.5%) MP, and 2185 (40.5%) PBS were identified. Despite a larger median tumor size in MP (46 vs. 40 mm PBS, p < 0.001), lumpectomy rate was higher for MP (52.9% vs. 27.0% PBS, p < 0.001). Compared to MP, PBS patients more frequently received radiation (28.9% vs. 24%), and chemotherapy (28.1% vs. 4%), both p < 0.001. Unadjusted OS was lower for PBS (57% vs. 85% MP, log-rank p < 0.001). PBS (vs. MP) had persistently worse survival (hazard ratio [HR]: 1.98, 95% confidence interval [CI]: 1.69-2.31) after adjustment. Receipt of adjuvant therapies was not associated with OS (either neoplasm); however, lumpectomy was associated with improved OS (vs. mastectomy) for both PBS (HR: 0.59, 95% CI: 0.50-0.75) and MP (HR: 0.65, 95% CI: 0.53-0.81). Positive margins had no association with OS for MP (HR: 1.09, 95% CI: 0.75-1.60), but was associated with worse survival for PBS (HR: 2.35, 95% CI: 1.82-3.02).DiscussionWe found significant survival differences between MP and PBS, with PBS having a consistently worse OS. Our findings support surgery as the mainstay of treatment for both tumor types and suggest that lumpectomy may be a reasonable option for select patients without compromising outcomes.
| S-EPMC8995353 | biostudies-literature
Project description:Phyllodes tumor of the breast (human) as well as a set of related tumors Phyllodes tumor, Fibroadenoma, Breast Cancer
2021-07-07 | GSE179458 | GEO
Project description:BackgroundAs the efficacy of radiotherapy and chemotherapy for treatment of phyllodes tumors (PTs) remains unclear, this study aimed to review all available data and evaluate the roles of radiotherapy and chemotherapy in PT treatment.MethodsWe performed a comprehensive search of databases, including PubMed, Web of Science and the Cochrane Library. The outcomes of interest included the local recurrence (LR) rate, metastasis rate, disease-free survival rate and overall survival rate.ResultsSeventeen studies enrolling 696 patients were included in this random effect meta-analysis. Subgroup analysis and meta-regression were also conducted to determine study heterogeneity. A pooled local recurrence rate of 8% (95% CI: 1-22%) was observed with a statistical heterogeneity of I2 = 86.6% (p < 0.01) for radiotherapy. This was lower than the recurrence rate of 12% for simple surgical treatment (95% CI: 7-18%). Meta-regression analysis found that surgical margin status was the main source of heterogeneity (p = 0.04). The metastasis rate of 4% (95% CI: 0-11%) for patients receiving radiotherapy without significant heterogeneity was also lower than the rate for the simple surgery group (8, 95% CI: 3-15%). The available data for chemotherapy were too limited to support meta-analysis. Accordingly, we offer a pure review of these data.ConclusionOur findings suggest that radiotherapy is effective in achieving local disease control and preventing metastasis.
| S-EPMC6480723 | biostudies-literature
Project description:Background: The preoperative diagnosis of phyllodes tumors (PTs) of the breast is critical to appropriate surgical treatment. However, reliable differentiation between PT and fibroadenoma (FA) remains difficult in daily clinical practice. The purpose of this study was to investigate the utility of breast MRI texture analysis for differentiating PTs from FAs. Materials and Methods: Forty-two PTs and 42 FAs were enrolled in this retrospective study. Clinical and conventional MRI features (CCMF) and MRI texture analysis were used to distinguish between PT and FA. Texture features were extracted from the axial short TI inversion recovery T2-weighted (T2W-STIR), T1-weighted pre-contrast, and two contrast-enhanced series (first contrast and third contrast). The Mann-Whitney U test was used to select statistically significant features of texture analysis and CCMF. Using a linear discriminant analysis, the most discriminative features were determined from statistically significant features. The K-nearest neighbor classifier and ROC curve were applied to evaluate the diagnostic performance. Results: With a higher classification accuracy (89.3%) and an AUC of 0.89, the texture features on T2W-STIR outperformed the texture features on other MRI sequences and CCMF. The AUC of the combination of CCMF with texture features on T2W-STIR was significantly higher than that of CCMF or texture features on T2W-STIR alone (p < 0.05). Based on the result of the classification accuracy (95.2%) and AUC (0.95), the diagnostic performance of the combination strategy performed better than texture features on T2W-STIR or CCMF separately. Conclusions: Texture features on T2W-STIR showed better diagnostic performance compared to CCMF for the distinction between PTs and FAs. After further validation of multi-institutional large datasets, MRI-based texture features may become a potential biomarker and be a useful medical decision tool in clinical trials having patients with breast fibroepithelial neoplasms.
| S-EPMC6803552 | biostudies-literature
Project description:Malignant phyllodes tumor is a rare breast malignancy with sarcomatous overgrowth and with limited effective treatment options for recurrent and metastatic cases. Recent clinical trials indicated a potential for anti-angiogenic, anti-EGFR and immunotherapeutic approaches for patients with sarcomas, which led us to investigate these and other targetable pathways in malignant phyllodes tumor of the breast. Thirty-six malignant phyllodes tumors (including 8 metastatic tumors with two cases having matched primary and metastatic tumors) were profiled using gene sequencing, gene copy number analysis, whole genome expression, and protein expression. Whole genome expression analysis demonstrated consistent over-expression of genes involved in angiogenesis including VEGFA, Angiopoietin-2, VCAM1, PDGFRA, and PTTG1. EGFR protein overexpression was observed in 26/27 (96%) of cases with amplification of the EGFR gene in 8/24 (33%) cases. Two EGFR mutations were identified including EGFRvIII and a presumed pathogenic V774M mutation, respectively. The most common pathogenic mutations included TP53 (50%) and PIK3CA (15%). Cases with matched primary and metastatic tumors harbored identical mutations in both sites (PIK3CA/KRAS and RB1 gene mutations, respectively). Tumor expression of PD-L1 immunoregulatory protein was observed in 3/22 (14%) of cases. Overexpression of molecular biomarkers of increased angiogenesis, EGFR and immune checkpoints provides novel targeted therapy options in malignant phyllodes tumors of the breast.
| S-EPMC4811491 | biostudies-literature
Project description:PurposeTo determine molecular events involved in the tumorigenesis of phyllodes tumors (PT) and the role of each stromal (SC) and epithelial (EC) cell.MethodsFrozen breast samples enriched with epithelial and stromal cells from three fibroadenomas and 14 PT were retrieved and laser microdissected. Sanger and polymerase chain reaction-based sequencing of exon 2 MED12 and TERT promoter hotspot mutations were performed; 44K microarray platform was used to analyze gene expression.ResultsAll three fibroadenomas (FAs) presented mutations in MED12, but not in TERT, whose mutation was observed in five of the 14 PTs. EC and SC of each affected tumor displayed identical alterations. Of the total differentially expressed genes (DEG) (EC = 1,543 and SC = 850), 984 were EC-eDEGs and 291 were SC-eDEGs. We found a high similarity of diseases and functions enriched by both cell types, but dissimilarity in the number of enriched canonical pathways. Three signaling canonical pathways overlapping with EC and SC were predicted to be activated in one cell type and inactivated in the other, while no overlap in eDEGs was assigned to them. We also identified 13 EC-eDEGs and five SC-eDEGs enriched networks, in which the SC-eDEGs were able to segregate FA from PT samples.ConclusionsIdentical TERT mutations from both SC and ES origins might affect the PTs tumorigenesis. Gene expression differences suggest coordinated molecular processes between these components with determinant differences acquired by SC, able to fully distinguish PTs from FAs lesions.
| S-EPMC10695188 | biostudies-literature