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

Tsang, Julia Y. S.; Hui, Yau-Kam; Lee, Michelle A.; Lacambra, Maribel D.; Ni, Yun‐Bi; Cheung, Sai‐Yin; Wu, Cherry; Kwong, Ava; Tse, Gary M.

doi:10.1038/s41598-018-22232-w

Cited by 22 publications

(18 citation statements)

References 32 publications

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“…In contrast, phyllodes tumours (PTs) are much less often diagnosed, and while they usually affect older women, younger women, particularly Asians, can be afflicted with PTs 1. Tsang et al have described differences in TERT promoter mutation patterns of PTs in Asians compared with Caucasians and have suggested that this may reflect the differences in PT pathogenesis among different ethnicities 2. Our recent work on an international cohort of fibroepithelial lesions, to be further elaborated on in this paper, has also revealed a higher frequency of KMT2D mutations in non-Asian PTs compared with Asian PTs 3.…”

Section: Introductionsupporting

confidence: 52%

Section: Tertmentioning

confidence: 92%

“…TERT promoter mutations were found at the highest frequency in borderline PTs, compared with malignant PTs, and the least in benign PTs 2 3 26. Additionally, while stromal TERT protein expression was high in both borderline and malignant PTs, it was correlated only to TERT promoter mutations in borderline PTs, suggesting that other molecular aberrations could exist in malignant PTs to increase TERT expression 2. Piscuoglio et al also reported an increase in TERT mRNA expression in PTs with TERT promoter mutations and TERT gene amplification, and the presence of a TERT promoter mutation in a malignant PT, but not in its clonally related fibroadenoma 30 46.…”

Section: Tertmentioning

confidence: 93%

“…However, TERT promoter mutations in PTs were reported only nearly two decades later and were associated with MED12 mutations, suggesting that these two may interact in the pathogenesis of PTs 26 30. Other studies also supported a high prevalence of TERT promoter mutations in PTs2 27 but not in fibroadenomas 30. This highlighted a possible explanation for the difference in behaviour of fibroadenomas compared with PTs, and the possible utility of TERT in differentiating the two in cases of diagnostic difficulties 30.…”

Section: Tertmentioning

confidence: 97%

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MED12,TERTandRARAin fibroepithelial tumours of the breast

et al. 2019

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Fibroepithelial tumours are biphasic neoplasms of the breast comprising the common benign fibroadenomas and the less common phyllodes tumours (PTs), which have recurrent potential. PTs are classified into benign, borderline or malignant, based on five histopathological criteria, with malignant PTs having the highest metastatic capability. Accurate diagnosis can be challenging due to the subjective assessment of histopathological parameters. Fibroadenomas bear morphological similarities to benign PTs, while borderline and malignant PTs can sometimes be difficult to distinguish from other spindle cell tumours of the breast. From clonality studies to whole-genome sequencing, much research has been conducted to elucidate the molecular pathogenesis of fibroepithelial tumours, which, in turn, have allowed leveraging the findings for diagnostic applications, including grading of PTs. The most noteworthy discovery was of recurrent MED12 mutations in both fibroadenomas and PTs. Subsequent studies also uncovered relatively frequent genetic mutations in TERT promoter and RARA. A customised panel of 16 most frequently mutated genes in fibroepithelial tissues has been compiled previously and has contributed to resolving a few diagnostic dilemmas. This review will introduce the 16 genes and focus on the top three that are most frequently mutated in fibroepithelial tumours: MED12, TERT, and RARA.

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Section: Introductionsupporting

confidence: 52%

Section: Tertmentioning

confidence: 92%

Section: Tertmentioning

confidence: 93%

Section: Tertmentioning

confidence: 97%

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MED12,TERTandRARAin fibroepithelial tumours of the breast

et al. 2019

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“…We noted that 18 out of 303 (6%) FAs displayed TERT promoter –124C>T (chr5:1,295,228 C>T) and –146C>T (chr5:1,295,250 C>T) mutations (see supplementary material, Table S4), while Yoshida et al discovered that four out of their 58 (7%) FAs were positive for –124C>T mutations, in contrast to none being observed in three other cohorts . PTs showed a significantly higher rate of 41% (200 out of 493 cases), especially in the borderline grade (61%), as similarly recorded by both Yoshida et al and Tsang et al . Interestingly, FELs with mutant MED12 were more likely to have TERT promoter mutation concurrently than those with wild‐type MED12 (37% versus 17%, p < 0.001), in agreement with the findings by Yoshida et al and Piscuoglio et al .…”

Section: Discussionmentioning

confidence: 77%

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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Integrating single‐cell and spatial transcriptomes reveals COL4A1/2 facilitates the spatial organisation of stromal cells differentiation in breast phyllodes tumours

Li,

Yu,

et al. 2024

Clinical & Translational Med

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BackgroundBreast phyllodes tumours (PTs) are a unique type of fibroepithelial neoplasms with metastatic potential and recurrence tendency. However, the precise nature of heterogeneity in breast PTs remains poorly understood. This study aimed to elucidate the cell subpopulations composition and spatial structure and investigate diagnostic markers in the pathogenesis of PTs.MethodsWe applied single‐cell RNA sequencing and spatial transcriptomes on tumours and adjacent normal tissues for integration analysis. Immunofluorescence experiments were conducted to verify the tissue distribution of cells. Tumour cells from patients with PTs were cultured to validate the function of genes. To validate the heterogeneity, the epithelial and stromal components of tumour tissues were separated using laser capture microdissection, and microproteomics data were obtained using data‐independent acquisition mass spectrometry. The diagnostic value of genes was assessed using immunohistochemistry staining.ResultsTumour stromal cells harboured seven subpopulations. Among them, a population of widely distributed cancer‐associated fibroblast‐like stroma cells exhibited strong communications with epithelial progenitors which underwent a mesenchymal transition. We identified two stromal subpopulations sharing epithelial progenitors and mesenchymal markers. They were inferred to further differentiate into transcriptionally active stromal subpopulations continuously expressing COL4A1/2. The binding of COL4A1/2 with ITGA1/B1 facilitated a growth pattern from the stroma towards the surrounding glands. Furthermore, we found consistent transcriptional changes between intratumoural heterogeneity and inter‐patient heterogeneity by performing microproteomics studies on 30 samples from 11 PTs. The immunohistochemical assessment of 97 independent cohorts identified that COL4A1/2 and CSRP1 could aid in accurate diagnosis and grading.ConclusionsOur study demonstrates that COL4A1/2 shapes the spatial structure of stromal cell differentiation and has important clinical implications for accurate diagnosis of breast PTs.

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

Cited by 22 publications

References 32 publications

MED12,TERTandRARAin fibroepithelial tumours of the breast

MED12,TERTandRARAin fibroepithelial tumours of the breast

Genomic characterisation of breast fibroepithelial lesions in an international cohort

Integrating single‐cell and spatial transcriptomes reveals COL4A1/2 facilitates the spatial organisation of stromal cells differentiation in breast phyllodes tumours

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