Genetic analysis of uterine adenosarcomas and phyllodes tumors of the breast

Geyer, Felipe C.; Burke, Kathleen A.; Piscuoglio, Salvatore; Ng, Charlotte K.Y.; Papanastasiou, Anastasios D.; Marchiò, Caterina; Selenica, Pier; Edelweiss, Marcia; Murray, Melissa P.; Soslow, Robert A.; Rubin, Brian P.; Norton, Larry; Reis‐Filho, Jorge S.; Weigelt, Britta

doi:10.1002/1878-0261.12049

Cited by 12 publications

(13 citation statements)

References 51 publications

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“…There have also been documented reports on the presence of FA‐like areas in PTs , cases of synchronous FA and PT, along with patients with FA having subsequent PT after a period of time, albeit this remains a rare occurrence . Such findings support theories of both tumours sharing similar origin and aetiology, with recent studies unveiling their mutational and gene expression profiles .…”

Section: Introductionmentioning

confidence: 54%

Genomic characterisation of breast fibroepithelial lesions in an international cohort

Nasir

Rajasegaran

et al. 2019

The Journal of Pathology

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Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16-gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non-Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild-type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles.Conflict of interest statement: PHT, BTT, and PT jointly hold patent applications for PCT/SG2015/050107 (Breast fibroadenoma susceptibility mutations and use thereof) and PCT/SG2015/050368 (Method and kit for pathologic grading of breast neoplasms). The other authors declare no competing interests.

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Section: Introductionmentioning

confidence: 54%

Genomic characterisation of breast fibroepithelial lesions in an international cohort

Nasir

Rajasegaran

et al. 2019

The Journal of Pathology

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“…A few studies demonstrated TERT promoter mutation in PT 7 , 10 , 11 , however, TERT protein expression in PT has not been studied. We observed TERT promoter mutation in 27% of the cases, which was lower than some reported studies (35–65%) 7 , 11 .…”

Section: Discussionmentioning

confidence: 99%

“…Common somatic mutations affecting cancer associated genes, including TP53, RB1 and EGFR occur exclusively in high grade PTs 6 – 9 . In addition, frequent mutations in non-coding region of telomerase reverse transcriptase ( TERT ) promoter has also been described 7 , 10 , 11 .…”

Section: Introductionmentioning

confidence: 99%

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Association of clinicopathological features and prognosis of TERT alterations in phyllodes tumor of breast

Tsang

Hui

Lee

et al. 2018

Sci Rep

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Phyllodes tumor (PT) of the breast is a rare but clinically important fibroepithelial tumor with potential risks of recurrence and metastasis. Recent studies identified recurrent TERT promoter mutations in PTs. However, the clinical significance of this alteration has not been fully examined. Two hundred and seven PTs from two intuitions were included. All cases were subjected to immunohistochemical analysis for TERT expression. Analysis of TERT promoter mutations was further performed by Sanger sequencing targeting the hotspot mutation region on cases from one of the involved institutions. The expression of TERT was correlated with clinicopathologic features, mutation status and recurrence. There was an association of TERT expression and its promoter mutation. Both stromal TERT expression and its promoter mutation correlated with PT grading and older patient age. Recurrence free survival (RFS) of PT patients with high stromal TERT expression was shorter if the excision margin was positive. Our findings suggested a possible pathogenic role of TERT alteration in PT malignancy. Currently there is no consensus for re-excision for PT patients with positive surgical margin, particularly for low grade cases. Stromal TERT expression could be potentially useful to guide management patients with benign PTs.

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“…Moreover, several less-characterized genetic alterations (e.g. in ATRX [ 16 , 17 ], BCORL1 [ 9 ], and ZNF217 [ 11 ]) whose role in the development and progression of PTs is unknown were identified. As alterations in those genes were rarely reported they are probably not one of the key drivers in the development of PTs.…”

Section: Introductionmentioning

confidence: 99%

Two progressed malignant phyllodes tumors of the breast harbor alterations in genes frequently involved in other advanced cancers

Reinisch

Kümmel

Breit

et al. 2021

Orphanet J Rare Dis

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Background The genomic landscape of phyllodes tumors (PTs) of the breast is not well defined, especially in patients with advanced disease. To shed light on this topic, paired primary and progressed tumor samples from two patients with malignant PTs were subjected to next-generation sequencing (NGS) followed by functional analysis of genetic alterations using two prediction tools. Methods The DNA of both the primary tumor and distant metastases of Patient 1 and the primary and recurrent tumor of Patient 2 were subjected to molecular profiling. NGS with the FoundationOne® assay was performed in a commercial molecular pathology laboratory. Two in silico prediction tools were used to estimate the pathogenicity of indicated genetic alterations. Results In total, 38 genomic alterations were detected, of which 11 were predicted to be probably benign. In Patient 1, 14 aberrations were identified in the primary tumor and 17 in pulmonary metastases, 12 of which were identical. In the primary and recurrent tumor of Patient 2, 17 and 15 sequence variants, respectively, were found, with 13 overlapping findings. Affected genes included seven (TP53, TERT, APC, ARID1A, EGFR, KMT2D, and RB1) of the top 10 most frequently altered genes in other advanced cancer entities, as well as four actionable therapeutic targets (EGFR, KIT, PDGFRA, and BRIP1). Of note, seven genes coding for receptor tyrosine kinases were affected: three in Patient 1 and four in Patient 2. Several genes (e.g. EPHA3, EPHA7, and EPHB1) were shown to be altered for the first time in PTs. Conclusions The two progressed malignant PTs investigated here share some of the major genetic events occurring in other advanced cancers.

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Genetic analysis of uterine adenosarcomas and phyllodes tumors of the breast

Cited by 12 publications

References 51 publications

Genomic characterisation of breast fibroepithelial lesions in an international cohort

Genomic characterisation of breast fibroepithelial lesions in an international cohort

Association of clinicopathological features and prognosis of TERT alterations in phyllodes tumor of breast

Two progressed malignant phyllodes tumors of the breast harbor alterations in genes frequently involved in other advanced cancers

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