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Article ; Online: Unraveling the Significance of DGCR8 and miRNAs in Thyroid Carcinoma.

Rodrigues, Lia / Da Cruz Paula, Arnaud / Soares, Paula / Vinagre, João

2024 Volume 13, Issue 7

Abstract: MicroRNAs (miRNAs) act as negative regulators for protein-coding gene expression impacting cell proliferation, differentiation, and survival. These miRNAs are frequently dysregulated in cancer and constitute classes of blood-based biomarkers useful for ... ...

Abstract	MicroRNAs (miRNAs) act as negative regulators for protein-coding gene expression impacting cell proliferation, differentiation, and survival. These miRNAs are frequently dysregulated in cancer and constitute classes of blood-based biomarkers useful for cancer detection and prognosis definition. In thyroid cancer (TC), the miRNA biogenesis pathway plays a pivotal role in thyroid gland formation, ensuring proper follicle development and hormone production. Several alterations in the miRNA biogenesis genes are reported as a causality for miRNA dysregulation. Mutations in microprocessor component genes are linked to an increased risk of developing TC; in particular, a recurrent mutation affecting
MeSH term(s)	Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; RNA-Binding Proteins/metabolism ; Thyroid Neoplasms/genetics ; Cell Differentiation ; Mutation/genetics
Chemical Substances	MicroRNAs ; RNA-Binding Proteins ; DGCR8 protein, human
Language	English
Publishing date	2024-03-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells13070561
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Article ; Online: Genomic profiling of primary and metastatic thyroid cancers.

Máximo, Valdemar / Melo, Miguel / Zhu, Yingjie / Gazzo, Andrea / Sobrinho Simões, Manuel / Da Cruz Paula, Arnaud / Soares, Paula

Endocrine-related cancer

2024 Volume 31, Issue 2

Abstract: The genetic repertoire of primary thyroid cancers (TCs) is well documented, but there is a considerable lack of molecular profiling in metastatic TCs. Here, we retrieved and analyzed the molecular and clinical features of 475 primary and metastatic TCs ... ...

Abstract	The genetic repertoire of primary thyroid cancers (TCs) is well documented, but there is a considerable lack of molecular profiling in metastatic TCs. Here, we retrieved and analyzed the molecular and clinical features of 475 primary and metastatic TCs subjected to targeted DNA sequencing, from the cBioPortal database. The cohort included primary and metastatic samples from 276 papillary thyroid carcinomas (PTCs), 5 follicular thyroid carcinomas, 22 Hürthle cell carcinomas (HCCs), 127 poorly differentiated thyroid carcinomas (PDTCs), 30 anaplastic thyroid carcinomas (ATCs) and 15 medullary thyroid carcinomas. The ATCs had the highest tumor mutational burden and the HCCs the highest fraction of the genome altered. Compared to primary PTCs, the metastases had a significantly higher frequency of genetic alterations affecting TERT (51% vs 77%, P < 0.001), CDKN2A (2% vs 10%, P < 0.01), RET (2% vs 7%, P < 0.05), CDKN2B (1% vs 6%, P < 0.05) and BCOR (0% vs 4%, P < 0.05). The distant metastases had a significantly lower frequency of BRAF (64% vs 85%, P < 0.01) and a significantly higher frequency of NRAS (13% vs 3%, P < 0.05) hotspot mutations than the lymph node metastases. Metastases from HCCs and PDTCs were found to be enriched for NF1 (29%) and TP53 (18%) biallelic alterations, respectively. The frequency of subclonal mutations in ATCs was significantly higher than in PTCs (43% vs 25%, P < 0.01) and PDTCs (43% vs 22%, P < 0.01). Metastatic TCs are enriched in clinically informative genetic alterations such as RET translocations, BRAF hotspot mutations and NF1 biallelic losses that may be explored therapeutically.
MeSH term(s)	Humans ; Proto-Oncogene Proteins B-raf/genetics ; Carcinoma, Papillary/genetics ; Carcinoma, Papillary/pathology ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/pathology ; Thyroid Carcinoma, Anaplastic/genetics ; Thyroid Cancer, Papillary/genetics ; Mutation ; Genomics
Chemical Substances	Proto-Oncogene Proteins B-raf (EC 2.7.11.1)
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1218450-0
ISSN	1479-6821 ; 1351-0088
ISSN (online)	1479-6821
ISSN	1351-0088
DOI	10.1530/ERC-23-0144
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Zs.A 4192: Show issues

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Article ; Online: Ovarian RASoma With Mesonephric-like Adenocarcinoma and Mixed Mullerian Components: A Case Report With Molecular Analysis Demonstrating Multidirectional Mullerian Differentiation.

Stolnicu, Simona / Bartalis, Rolland-Jozsef / Ye, Qiqi / Da Cruz Paula, Arnaud / Weigelt, Britta / Soslow, Robert A

International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists

2023 Volume 42, Issue 6, Page(s) 620–626

Abstract: Gynecologic carcinomas with RAS mutations may show a wide spectrum of histologic types, including mixed types. We present the case of a 63-yr-old patient diagnosed with an ovarian tumor harboring a mesonephric-like adenocarcinoma in a background of mixed ...

Abstract	Gynecologic carcinomas with RAS mutations may show a wide spectrum of histologic types, including mixed types. We present the case of a 63-yr-old patient diagnosed with an ovarian tumor harboring a mesonephric-like adenocarcinoma in a background of mixed mesonephric-like, mucinous, and endometrioid components. Molecular analysis revealed that all 3 components shared the same clonal KRAS mutation (p.G12A) and chromosome 1q gain. Based on shifts in clonality, copy number gains, and acquisition of an additional mutation, our data suggest that the mucinous component likely constituted the substrate from which the mesonephric-like and endometrioid components arose.
MeSH term(s)	Female ; Humans ; Adenocarcinoma/diagnosis ; Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Endometrium/pathology ; Mutation ; Ovarian Neoplasms/diagnosis ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Middle Aged
Language	English
Publishing date	2023-01-09
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	604859-6
ISSN	1538-7151 ; 0277-1691
ISSN (online)	1538-7151
ISSN	0277-1691
DOI	10.1097/PGP.0000000000000935
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Zs.A 1814: Show issues

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Article ; Online: Adenoid cystic carcinoma of the Bartholin's gland is underpinned by MYB- and MYBL1- rearrangements.

Feinberg, Jacqueline / Da Cruz Paula, Arnaud / da Silva, Edaise M / Pareja, Fresia / Patel, Juber / Zhu, Yingjie / Selenica, Pier / Leitao, Mario M / Abu-Rustum, Nadeem R / Reis-Filho, Jorge S / Joehlin-Price, Amy / Weigelt, Britta

Gynecologic oncology

2024 Volume 185, Page(s) 58–67

Abstract: Objective: Adenoid cystic carcinoma (AdCC) of the Bartholin's gland (AdCC-BG) is a very rare gynecologic vulvar malignancy. AdCC-BGs are slow-growing but locally aggressive and are associated with high recurrence rates. Here we sought to characterize ... ...

Abstract	Objective: Adenoid cystic carcinoma (AdCC) of the Bartholin's gland (AdCC-BG) is a very rare gynecologic vulvar malignancy. AdCC-BGs are slow-growing but locally aggressive and are associated with high recurrence rates. Here we sought to characterize the molecular underpinning of AdCC-BGs. Methods: AdCC-BGs (n = 6) were subjected to a combination of RNA-sequencing, targeted DNA-sequencing, reverse-transcription PCR, fluorescence in situ hybridization (FISH) and MYB immunohistochemistry (IHC). Clinicopathologic variables, somatic mutations, copy number alterations and chimeric transcripts were assessed. Results: All six AdCC-BGs were biphasic, composed of ductal and myoepithelial cells. Akin to salivary gland and breast AdCCs, three AdCC-BGs had the MYB::NFIB fusion gene with varying breakpoints, all of which were associated with MYB overexpression by IHC. Two AdCC-BGs were underpinned by MYBL1 fusion genes with different gene partners, including MYBL1::RAD51B and MYBL1::EWSR1 gene fusions, and showed MYB protein expression. Although the final AdCC-BG studied had MYB protein overexpression, no gene fusion was identified. AdCC-BGs harbored few additional somatic genetic alterations, and only few mutations in cancer-related genes were identified, including GNAQ, GNAS, KDM6A, AKT1 and BCL2, none of which were recurrent. Two AdCC-BGs, both with a MYB::NFIB fusion gene, developed metastatic disease. Conclusions: AdCC-BGs constitute a convergent phenotype, whereby activation of MYB or MYBL1 can be driven by the MYB::NFIB fusion gene or MYBL1 rearrangements. Our observations further support the notion that AdCCs, irrespective of organ site, constitute a genotypic-phenotypic correlation. Assessment of MYB or MYBL1 rearrangements may be used as an ancillary marker for the diagnosis of AdCC-BGs.
Language	English
Publishing date	2024-02-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	801461-9
ISSN	1095-6859 ; 0090-8258
ISSN (online)	1095-6859
ISSN	0090-8258
DOI	10.1016/j.ygyno.2024.02.015
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Zs.A 885: Show issues

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Article: Molecular profiling of primary endometrioid endometrial cancer and matched lung metastases:

Gordhandas, Sushmita / Da Cruz Paula, Arnaud / Kertowidjojo, Elizabeth C / Pareja, Fresia / Dessources, Kimberly / da Silva, Edaise M / Derakhshan, Fatemeh / Mueller, Jennifer J / Abu-Rustum, Nadeem R / Herman Chui, M / Weigelt, Britta

Gynecologic oncology reports

2024 Volume 53, Page(s) 101391

Abstract: Both primary endometrial cancers (ECs) and matched lung metastases shared a common ancestor with independent evolution at each site.•The two endometrioid ECs studied acquired additional mutations during the distant metastatic process.• ... ...

Abstract	•Both primary endometrial cancers (ECs) and matched lung metastases shared a common ancestor with independent evolution at each site.•The two endometrioid ECs studied acquired additional mutations during the distant metastatic process.•Subclonal
Language	English
Publishing date	2024-04-10
Publishing country	Netherlands
Document type	Case Reports
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2024.101391
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Article ; Online: Granular cell tumor of thyroid: a case series with molecular characterization highlighting unique pitfalls.

Srivastava, Pooja / Da Cruz Paula, Arnaud / Weigelt, Britta / Pareja, Fresia / Reis-Filho, Jorge S / Yip, Linwah / Pantanowitz, Liron / Seethala, Raja R

Endocrine

2022 Volume 76, Issue 2, Page(s) 395–406

Abstract: Primary granular cell tumors (GCTs) of the thyroid are exceptionally rare. We report the clinicopathologic and molecular features of three cases and review the literature. Two patients (20-year-old, Case 1, and 26-year-old, Case 2, black American females) ...

Abstract	Primary granular cell tumors (GCTs) of the thyroid are exceptionally rare. We report the clinicopathologic and molecular features of three cases and review the literature. Two patients (20-year-old, Case 1, and 26-year-old, Case 2, black American females) presented with painless masses with a preoperative fine-needle aspiration biopsy (FNAB) diagnosis of "Hürthle cell neoplasm," while one additional patient, 51-year-old white American female (Case 3), presented as an incidental finding within a background of chronic lymphocytic thyroiditis. On resection, morphologic, histochemical and immunohistochemical features were typical of GCT in all cases. Cases 1 and 2 had adequate material for molecular testing and demonstrated a clonal ATP6AP1 p.G381Vfs15 frameshift mutation (Case 1) and a clonal ATP6AP2 p.L182Pfs22 frameshift mutation along with a PIK3CA H1047R hotspot mutation (Case 2). All patients showed no evidence of GCT following resection (Cases 1, 3: 96-month follow-up; Case 2: 48-month follow-up). A literature review demonstrates similar clinicopathologic features and indolent course with only rare histologically or clinically aggressive outcomes. On FNAB, lesional cells are frequently miscategorized as Hürthle cells or oncocytes. In summary, GCT of the thyroid is rare but shows similar clinical, morphologic, immunophenotypic and genetic characteristics of GCT of other sites. This unusual site poses unique differential diagnostic pitfalls by mimicking other oncocytic head and neck lesions, particularly thyroid Hürthle cell neoplasms. We confirm that thyroid GCT also harbor V-ATPase component inactivating mutations that characterize these tumors, and that additional PI3K pathway alterations may not necessarily predict aggressive behavior.
MeSH term(s)	Adenoma, Oxyphilic/diagnosis ; Adenoma, Oxyphilic/genetics ; Adenoma, Oxyphilic/pathology ; Adult ; Biopsy, Fine-Needle ; Female ; Granular Cell Tumor/pathology ; Humans ; Middle Aged ; Phosphatidylinositol 3-Kinases ; Receptors, Cell Surface ; Thyroid Neoplasms/diagnosis ; Thyroid Neoplasms/genetics ; Thyroid Neoplasms/pathology ; Vacuolar Proton-Translocating ATPases ; Young Adult
Chemical Substances	ATP6AP1 protein, human ; ATP6AP2 protein, human ; Receptors, Cell Surface ; Vacuolar Proton-Translocating ATPases (EC 3.6.1.-)
Language	English
Publishing date	2022-02-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1194484-5
ISSN	1559-0100 ; 1355-008X ; 0969-711X
ISSN (online)	1559-0100
ISSN	1355-008X ; 0969-711X
DOI	10.1007/s12020-022-03006-x
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Zs.A 3884: Show issues

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Article: Uterine washings as a novel method for early detection of ovarian cancer: Trials and tribulations.

Sia, Tiffany Y / Yaari, Zvi / Feiner, Ron / Smith, Evan / Da Cruz Paula, Arnaud / Selenica, Pier / Doddi, Sital / Chi, Dennis S / Abu-Rustum, Nadeem R / Levine, Douglas A / Weigelt, Britta / Fleisher, Martin / Ramanathan, Lakshmi V / Heller, Daniel A / Long Roche, Kara

Gynecologic oncology reports

2024 Volume 51, Page(s) 101330

Abstract: Given the tubal origin of high-grade serous ovarian cancer (HGSC), we sought to investigate intrauterine lavage (IUL) as a novel method of biomarker detection. IUL and serum samples were collected from patients with HGSC or benign pathology. Although CA- ... ...

Abstract	Given the tubal origin of high-grade serous ovarian cancer (HGSC), we sought to investigate intrauterine lavage (IUL) as a novel method of biomarker detection. IUL and serum samples were collected from patients with HGSC or benign pathology. Although CA-125 and HE4 concentrations were significantly higher in IUL samples compared to serum, they were similar between IUL samples from patients with HGSC vs benign conditions. In contrast, CA-125 and HE4 serum concentrations differed between HGSC and benign pathology (
Language	English
Publishing date	2024-02-03
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2818505-5
ISSN	2352-5789
ISSN	2352-5789
DOI	10.1016/j.gore.2024.101330
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Article ; Online: Implications of Different Cancer Stem Cell Phenotypes in Breast Cancer.

DA Cruz Paula, Arnaud / Lopes, Carlos

Anticancer research

2017 Volume 37, Issue 5, Page(s) 2173–2183

Abstract: The attempts to identify, isolate and characterize cancer stem cell populations are mostly dependent on cell-surface markers. In breast cancer, several putative breast cancer stem cell (BCSC) markers have already been reported, but the agreement on their ...

Abstract	The attempts to identify, isolate and characterize cancer stem cell populations are mostly dependent on cell-surface markers. In breast cancer, several putative breast cancer stem cell (BCSC) markers have already been reported, but the agreement on their phenotypic characterization is still absent. In fact, it became unfeasible to obtain a universal combination of markers that could specifically identify BCSCs in all cases of breast cancer. Breast cancer heterogeneity as reflected by various histological subtypes, with variable clinical presentations and diverse molecular signatures also contributes to major drawbacks. Indeed, intra-tumor heterogeneity leads to a single tumor to contain, at any given time, tumor cell populations displaying different molecular profiles and biological properties. As a consequence, several BCSC phenotypes were described, with some being associated with aggressive forms of breast cancer. Although the validation of the CSC model remains an ongoing task, it is important to define which BCSC phenotypes have high tumorigenic potential and ability to resist therapeutic agents. For this reason, a concise review is presented here regarding the implications of the most studied BCSC markers and phenotypes in breast cancer progression and treatment.
MeSH term(s)	AC133 Antigen/metabolism ; Animals ; Breast Neoplasms/genetics ; Breast Neoplasms/metabolism ; CD24 Antigen/metabolism ; Humans ; Hyaluronan Receptors/metabolism ; Integrins/metabolism ; Isoenzymes/metabolism ; Neoplastic Stem Cells/metabolism ; Phenotype ; Retinal Dehydrogenase/metabolism ; Sequence Analysis, DNA
Chemical Substances	AC133 Antigen ; CD24 Antigen ; Hyaluronan Receptors ; Integrins ; Isoenzymes ; aldehyde dehydrogenase 1 (EC 1.2.1.-) ; Retinal Dehydrogenase (EC 1.2.1.36)
Language	English
Publishing date	2017
Publishing country	Greece
Document type	Journal Article ; Review
ZDB-ID	604549-2
ISSN	1791-7530 ; 0250-7005
ISSN (online)	1791-7530
ISSN	0250-7005
DOI	10.21873/anticanres.11552
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Zs.A 1642: Show issues

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Article ; Online: Endometrial/Endometrioid Stromal Tumors With Extensive Whorling and CTNNB1 Translocation : A Report of 3 Cases.

Boyraz, Baris / da Cruz Paula, Arnaud / Deveraux, Kelly A / Tran, Ivy / da Silva, Edaise M / Young, Robert H / Snuderl, Matija / Weigelt, Britta / Oliva, Esther

The American journal of surgical pathology

2023 Volume 47, Issue 11, Page(s) 1285–1290

Abstract: Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein ... ...

Abstract	Endometrial/endometrioid stromal tumors are rare and morphologically heterogenous, and their diagnosis may be challenging. We identified 3 endometrial/endometrioid stromal tumors with identical and previously undescribed histologic features and herein report their morphologic, immunohistochemical, and molecular profiles. Patients were 53, 62, and 79 years. Tumors were well-circumscribed, tan-yellow solid masses measuring 10.0, 11.0, and 18.7 cm, and were intramyometrial (n=2) or in the broad ligament (n=1). All showed small, tight whorls of epithelioid to slightly spindled tumor cells with minimal cytoplasm and negligible mitoses, multifocally associated with hyalinization and myxoid change set in a loose fibroblastic background with small, delicate vessels. This morphology was seen throughout in 1 tumor and in ∼20% and 70% of the 2 others with the remaining areas showing sex cord-like differentiation. Tumor cells expressed CD10 (3/3, 1 focal), calretinin (3/3 diffuse), WT1 (3/3 diffuse), estrogen receptor (1/1, diffuse). RNA-sequencing was successful in 1 tumor and revealed a GREB1-CTNNB1 in-frame fusion. All 3 tumors harbored a CTNNB1 translocation by fluorescence in situ hybridization correlating with nuclear β-catenin expression. Whole-genome DNA methylation analysis classified all 3 tumors within the low-grade endometrial stromal sarcoma reference class with flat copy number profiles. One patient (79-y-old) died of unrelated causes 2 months after surgery and the other 2 were alive without disease after 13 and 75 months. We have described a rare subset of endometrial/endometrioid stromal tumors with extensive whorling and a CTNNB1 translocation, expanding the morphologic and molecular spectrum of these neoplasms.
MeSH term(s)	Female ; Humans ; beta Catenin/genetics ; In Situ Hybridization, Fluorescence ; Endometrial Stromal Tumors/pathology ; Mitosis ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/surgery ; Endometrial Neoplasms/metabolism ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/analysis ; Sarcoma, Endometrial Stromal/genetics ; Sarcoma, Endometrial Stromal/surgery ; Sarcoma, Endometrial Stromal/pathology
Chemical Substances	beta Catenin ; Biomarkers, Tumor ; CTNNB1 protein, human
Language	English
Publishing date	2023-08-15
Publishing country	United States
Document type	Case Reports ; Journal Article
ZDB-ID	752964-8
ISSN	1532-0979 ; 0147-5185
ISSN (online)	1532-0979
ISSN	0147-5185
DOI	10.1097/PAS.0000000000002094
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Zs.A 1356: Show issues

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Article ; Online: Decreased HER2 expression in endometrial cancer following anti-HER2 therapy.

Chui, M Herman / Brown, David N / Da Cruz Paula, Arnaud / da Silva, Edaise M / Momeni-Boroujeni, Amir / Reis-Filho, Jorge S / Zhang, Yanming / Makker, Vicky / Ellenson, Lora Hedrick / Weigelt, Britta

The Journal of pathology

2023 Volume 262, Issue 2, Page(s) 129–136

Abstract: Trastuzumab has demonstrated clinical efficacy in the treatment of HER2-positive serous endometrial cancer (EC), which led to its incorporation into standard-of-care management of this aggressive disease. Acquired resistance remains an important ... ...

Abstract	Trastuzumab has demonstrated clinical efficacy in the treatment of HER2-positive serous endometrial cancer (EC), which led to its incorporation into standard-of-care management of this aggressive disease. Acquired resistance remains an important challenge, however, and its underlying mechanisms in EC are unknown. To define the molecular changes that occur in response to anti-HER2 therapy in EC, targeted next-generation sequencing (NGS), HER2 immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) were performed on pre- and post-treatment tumour samples from 14 patients with EC treated with trastuzumab or trastuzumab emtansine. Recurrent tumours after anti-HER2 therapy acquired additional genetic alterations compared with matched pre-treatment ECs and frequently showed decreased HER2 protein expression by IHC (7/14, 50%). Complete/near-complete absence of HER2 protein expression (score 0/1+) observed post-treatment (4/14, 29%) was associated with retained HER2 gene amplification (n = 3) or copy number neutral status (n = 1). Whole-exome sequencing performed on primary and recurrent tumours from the latter case, which exhibited genetic heterogeneity of HER2 amplification in the primary tumour, revealed selection of an early HER2-non-amplified clone following therapy. Our findings demonstrate that loss of target expression, by selection of HER2-non-amplified clones or, more commonly, by downregulation of expression, may constitute a mechanism of resistance to anti-HER2 therapy in HER2-positive EC. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
MeSH term(s)	Female ; Humans ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; In Situ Hybridization, Fluorescence ; Neoplasm Recurrence, Local/genetics ; Trastuzumab/therapeutic use ; Endometrial Neoplasms/drug therapy ; Endometrial Neoplasms/genetics ; Endometrial Neoplasms/pathology ; Gene Amplification
Chemical Substances	Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
Language	English
Publishing date	2023-11-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3119-7
ISSN	1096-9896 ; 0022-3417
ISSN (online)	1096-9896
ISSN	0022-3417
DOI	10.1002/path.6230
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