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1.
Proc Natl Acad Sci U S A ; 120(12): e2214225120, 2023 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-36917668

RESUMO

A murine papillomavirus, MmuPV1, infects both cutaneous and mucosal epithelia of laboratory mice and can be used to model high-risk human papillomavirus (HPV) infection and HPV-associated disease. We have shown that estrogen exacerbates papillomavirus-induced cervical disease in HPV-transgenic mice. We have also previously identified stress keratin 17 (K17) as a host factor that supports MmuPV1-induced cutaneous disease. Here, we sought to test the role of estrogen and K17 in MmuPV1 infection and associated disease in the female reproductive tract. We experimentally infected wild-type and K17 knockout (K17KO) mice with MmuPV1 in the female reproductive tract in the presence or absence of exogenous estrogen for 6 mon. We observed that a significantly higher percentage of K17KO mice cleared the virus as opposed to wild-type mice. In estrogen-treated wild-type mice, the MmuPV1 viral copy number was significantly higher compared to untreated mice by as early as 2 wk postinfection, suggesting that estrogen may help facilitate MmuPV1 infection and/or establishment. Consistent with this, viral clearance was not observed in either wild-type or K17KO mice when treated with estrogen. Furthermore, neoplastic disease progression and cervical carcinogenesis were supported by the presence of K17 and exacerbated by estrogen treatment. Subsequent analyses indicated that estrogen treatment induces a systemic immunosuppressive state in MmuPV1-infected animals and that both estrogen and K17 modulate the local intratumoral immune microenvironment within MmuPV1-induced neoplastic lesions. Collectively, these findings suggest that estrogen and K17 act at multiple stages of papillomavirus-induced disease at least in part via immunomodulatory mechanisms.


Assuntos
Infecções por Papillomavirus , Camundongos , Feminino , Humanos , Animais , Infecções por Papillomavirus/genética , Queratina-17 , Camundongos Transgênicos , Imunidade , Papillomaviridae/genética , Estrogênios
2.
Nature ; 569(7758): 723-728, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043742

RESUMO

High-grade serous carcinoma has a poor prognosis, owing primarily to its early dissemination throughout the abdominal cavity. Genomic and proteomic approaches have provided snapshots of the proteogenomics of ovarian cancer1,2, but a systematic examination of both the tumour and stromal compartments is critical in understanding ovarian cancer metastasis. Here we develop a label-free proteomic workflow to analyse as few as 5,000 formalin-fixed, paraffin-embedded cells microdissected from each compartment. The tumour proteome was stable during progression from in situ lesions to metastatic disease; however, the metastasis-associated stroma was characterized by a highly conserved proteomic signature, prominently including the methyltransferase nicotinamide N-methyltransferase (NNMT) and several of the proteins that it regulates. Stromal NNMT expression was necessary and sufficient for functional aspects of the cancer-associated fibroblast (CAF) phenotype, including the expression of CAF markers and the secretion of cytokines and oncogenic extracellular matrix. Stromal NNMT expression supported ovarian cancer migration, proliferation and in vivo growth and metastasis. Expression of NNMT in CAFs led to depletion of S-adenosyl methionine and reduction in histone methylation associated with widespread gene expression changes in the tumour stroma. This work supports the use of ultra-low-input proteomics to identify candidate drivers of disease phenotypes. NNMT is a central, metabolic regulator of CAF differentiation and cancer progression in the stroma that may be therapeutically targeted.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Nicotinamida N-Metiltransferase/metabolismo , Proteômica , Fibroblastos Associados a Câncer/enzimologia , Linhagem Celular Tumoral , Células Cultivadas , Metilação de DNA , Progressão da Doença , Feminino , Histonas/química , Histonas/metabolismo , Humanos , Metástase Neoplásica , Niacinamida/análogos & derivados , Niacinamida/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Fenótipo , Prognóstico , S-Adenosil-Homocisteína/metabolismo , S-Adenosilmetionina/metabolismo
3.
Breast Cancer Res Treat ; 200(2): 225-235, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37209182

RESUMO

PURPOSE: PAM50 profiling assigns each breast cancer to a single intrinsic subtype based on a bulk tissue sample. However, individual cancers may show evidence of admixture with an alternate subtype that could affect prognosis and treatment response. We developed a method to model subtype admixture using whole transcriptome data and associated it with tumor, molecular, and survival characteristics for Luminal A (LumA) samples. METHODS: We combined TCGA and METABRIC cohorts and obtained transcriptome, molecular, and clinical data, which yielded 11,379 gene transcripts in common and 1,178 cases assigned to LumA. We used semi-supervised non-negative matrix factorization (ssNMF) to compute the subtype admixture proportions of the four major subtypes-pLumA, pLumB, pHER2, and pBasal-for each case and measured associations with tumor characteristics, molecular features, and survival. RESULTS: Luminal A cases in the lowest versus highest quartile for pLumA transcriptomic proportion had a 27% higher prevalence of stage > 1, nearly a threefold higher prevalence of TP53 mutation, and a hazard ratio of 2.08 for overall mortality. We found positive associations between pHER2 and HER2 positivity by IHC or FISH; between pLumB and PR negativity; and between pBasal and younger age, node positivity, TP53 mutation, and EGFR expression. Predominant basal admixture, in contrast to predominant LumB or HER2 admixture, was not associated with shorter survival. CONCLUSION: Bulk sampling for genomic analyses provides an opportunity to expose intratumor heterogeneity, as reflected by subtype admixture. Our results elucidate the striking extent of diversity among LumA cancers and suggest that determining the extent and type of admixture holds promise for refining individualized therapy. LumA cancers with a high degree of basal admixture appear to have distinct biological characteristics that warrant further study.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Perfilação da Expressão Gênica
4.
Int J Gynecol Pathol ; 42(4): 376-389, 2023 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-36044323

RESUMO

Regional lymph node metastasis is a well-established negative predictive prognostic factor in endometrial carcinomas. Recently, our approach to the pathologic evaluation of lymph nodes in endometrial carcinomas has changed, mainly due to the utilization of immunohistochemical stains in the assessment of sentinel lymph nodes, which may result in the identification of previously unrecognized disease [particularly isolated tumor cells (ITCs)] on hematoxylin and eosin stained slides. However, the clinical significance of this finding is not entirely clear. Following the experience in other organs systems such as breast, the Eight Edition of the American Joint Committee on Cancer's Cancer Staging Manual has recommended utilizing the N0(i+) terminology for this finding, without impact in the final tumor stage. We performed a comparative retrospective multi-institutional survival analysis of 247 patients with endometrial carcinoma with regional lymph node metastasis of various sizes identified in nonsentinel lymphadenectomy, demonstrating that the cumulative survival of patients with isolated tumor cells in regional lymph nodes is not statistically different from patient with negative lymph nodes, and is statistically different from those with lymph nodes showing micrometastasis or larger metastatic deposits. In addition, we evaluated the prognostic implications of the number of involved regional lymph nodes, demonstrating a worsening prognosis as the number of involved lymph nodes increases from none to one, and from one to more than one. Our data suggests that regional lymph nodes with isolated tumor cells in patients with endometrial carcinoma should likely be considered, for staging purposes, as negative lymph nodes, simply indicating their presence with the (i+) terminology.


Assuntos
Neoplasias do Endométrio , Linfonodos , Feminino , Humanos , Neoplasias do Endométrio/patologia , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
5.
Int J Gynecol Pathol ; 41(2): 132-141, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33782344

RESUMO

There is increasing evidence that many endometrial cancers (EC) diagnosed as clear cell carcinoma (CCC) have substantial overlap with both serous carcinoma (SC) and endometrioid carcinoma (EmC), not only in terms of morphology and immunophenotype but also by molecular characterization. Now with use of HER2-based therapy in SC, a CCC diagnosis in serous-like tumors has the potential to exclude patients from receiving beneficial therapy. To assess HER2 in CCC in relation to other characteristics, a tissue microarray of archived CCC, EmC, and SC was stained for HER2 alongside a battery of immunostains used in EC. Cases with equivocal HER2 IHC were also assessed by in situ hybridization. HER2 status was assessed in 229 cases (23 CCC, 74 SC, 132 EmC). HER2 was positive in 48% of cases diagnosed as CCC, 19% of SC, and 0% of EmC. Rigorous morphologic and immunophenotypic review by 5 gynecologic pathologists revealed diagnostic disagreement in 8/11 HER2+ cases diagnosed as CCC, with SC as the other major diagnostic consideration. All HER2+ (n=25) cases were MMR-intact and most HER2+ EC had aberrant p53 staining (22/25, 88%); the 3 cases with a wild type pattern for p53 (12%) were all negative for ER. Based on these findings, patients with a diagnosis of CCC should be included in future clinical trials of HER2-targeted therapy. Moreover, given the diagnostic difficulty surrounding CCC, immunohistochemistry-based algorithms that include aberrant p53 and/or the absence of ER expression may provide a more objective means of establishing eligibility criteria than is currently possible using traditional histologic classification.


Assuntos
Adenocarcinoma de Células Claras , Carcinoma Endometrioide , Cistadenocarcinoma Seroso , Neoplasias do Endométrio , Adenocarcinoma de Células Claras/diagnóstico , Adenocarcinoma de Células Claras/patologia , Biomarcadores Tumorais , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/patologia , Cistadenocarcinoma Seroso/patologia , Neoplasias do Endométrio/genética , Feminino , Humanos
6.
Mod Pathol ; 33(2): 245-254, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31231127

RESUMO

Ancillary studies facilitate accurate diagnosis of morphologically challenging mesothelial proliferations. The current diagnostic algorithm proceeds from BAP1 immunohistochemistry to CDKN2A fluorescence in situ hybridization. While MTAP immunohistochemistry has recently shown promise as a surrogate for CDKN2A fluorescence in situ hybridization, it has been examined in only a few single-institution studies. Furthermore, there are no published reports on interobserver agreement or interlaboratory reproducibility for MTAP immunohistochemistry. We performed MTAP immunohistochemistry on 20 benign mesothelial lesions and 99 malignant mesotheliomas from five mesothelioma centers in four countries, and each MTAP stain was independently interpreted by four pathologists. CDKN2A fluorescence in situ hybridization data were available for a subset of cases, and a subset of cases was subjected in MTAP immunohistochemistry in multiple laboratories to assess interlaboratory reproducibility. Interobserver agreement in MTAP immunostain interpretation was excellent for all mesothelial lesions (kappa: 0.85) and for malignant mesothelioma cases only (kappa: 0.82). Interlaboratory reproducibility was also excellent (kappa values for paired protocols: 0.77-0.89). MTAP loss by immunohistochemistry was 78% sensitive and 96% specific for CDKN2A homozygous deletion. MTAP immunohistochemistry is a reliable surrogate for CDKN2A fluorescence in situ hybridization in diagnosis of malignant mesothelioma. Interobserver agreement is excellent for interpretation of MTAP staining, and protocols performed in different laboratories yield concordant MTAP staining results. Rare cases with immunohistochemical MTAP loss may retain normal CDKN2A copy number, and the MTAP staining results should be correlated with clinicopathologic findings and other ancillary studies.


Assuntos
Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Mesotelioma Maligno/enzimologia , Mesotelioma Maligno/genética , Neoplasias Pleurais/enzimologia , Neoplasias Pleurais/genética , Purina-Núcleosídeo Fosforilase/análise , França , Humanos , Mesotelioma Maligno/patologia , América do Norte , Variações Dependentes do Observador , Neoplasias Pleurais/patologia , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Tóquio
7.
Int J Gynecol Pathol ; 39(1): 8-18, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30480644

RESUMO

Epithelioid trophoblastic tumor is a malignancy derived from the chorionic laeve-type intermediate trophoblast with sufficient rarity that the vast majority of literature on the topic exists in the form of case reports and small series. Classically, it is regarded as a well-circumscribed tumor with an expansile growth pattern that occurs in reproductive-aged women, usually after a normal pregnancy. However, we recently encountered a case of epithelioid trophoblastic tumor with aggressive spread throughout the abdomen and pelvis in a 68-yr-old female presenting 30 yr after her last delivery. Although to our knowledge this is the first report in a postmenopausal patient to be confirmed by molecular analysis of short tandem repeats, there are multiple similar case reports spanning a variety of clinical settings that deviate from the original description. We therefore sought to synthesize the clinicopathologic data among the available reports in the English literature, with emphasis on pathologic findings. While the overarching themes are largely unchanged, this series of 77 patients reveals a broader spectrum of disease and highlights frequent misdiagnosis. Here we present a clinicopathologic update on this rare entity, with emphasis on a practical approach to diagnosis.


Assuntos
Células Epitelioides/patologia , Neoplasias Trofoblásticas/diagnóstico , Neoplasias Trofoblásticas/patologia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologia , Adolescente , Adulto , Idoso , Feminino , Técnicas de Genotipagem , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Pós-Menopausa , Gravidez , Doenças Raras/diagnóstico , Doenças Raras/genética , Doenças Raras/patologia , Fatores de Tempo , Neoplasias Trofoblásticas/genética , Neoplasias Uterinas/genética , Adulto Jovem
8.
Mod Pathol ; 32(8): 1180-1188, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30952972

RESUMO

Uniparental disomy is an abnormal genetic condition in which both homologous chromosomes or part of the chromosome are inherited from one parent and the other parent's homologous chromosome is lost. We report three cases of gestations with paternal uniparental isodisomy at tyrosine hydroxylase or TH01 locus on chromosome 11p15.4 identified by DNA genotyping. The patients' age ranged from 32 to 35 years and all patients presented with missed abortion during the first trimester. Abnormal chorionic villi were seen in all cases with histomorphological and/or p57 immunohistochemical features simulating either partial or complete mole. While two patients had an uneventful clinical course, one patient presented with clinical complications simulating persistent gestational trophoblastic disease/neoplasia that required multiagent chemotherapy with etoposide, methotrexate, actinomycin D, vincristine, and cyclophosphamide (EMA-CO). In summary, paternal uniparental isodisomy of tyrosine hydroxylase locus at chromosome 11p15.4 may result in an abnormal gestation that simulates a hydatidiform mole both clinically and histologically. The presence of abnormal trophoblastic proliferation combined with loss of p57 expression in villous cytotrophoblast and stromal cells may be associated with an aggressive clinical behavior.


Assuntos
Biomarcadores Tumorais/genética , Loci Gênicos , Mola Hidatiforme/genética , Tirosina 3-Mono-Oxigenase/genética , Dissomia Uniparental/genética , Neoplasias Uterinas/genética , Aborto Retido , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cromossomos Humanos Par 11/genética , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Predisposição Genética para Doença , Humanos , Mola Hidatiforme/tratamento farmacológico , Mola Hidatiforme/enzimologia , Mola Hidatiforme/patologia , Masculino , Metotrexato/administração & dosagem , Fenótipo , Gravidez , Resultado do Tratamento , Neoplasias Uterinas/tratamento farmacológico , Neoplasias Uterinas/enzimologia , Neoplasias Uterinas/patologia , Vincristina/administração & dosagem
11.
Blood ; 121(9): 1534-42, 2013 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-23297135

RESUMO

The E2A transcription factors promote the development of thymus-seeding cells, but it remains unknown whether these proteins play a role in T lymphocyte lineage specification or commitment. Here, we showed that E2A proteins were required to promote T-lymphocyte commitment from DN2 thymocytes and to extinguish their potential for alternative fates. E2A proteins functioned in DN2 cells to limit expression of Gata3, which encodes an essential T-lymphocyte transcription factor whose ectopic expression can arrest T-cell differentiation. Genetic, or small interfering RNA-mediated, reduction of Gata3 rescued T-cell differentiation in the absence of E2A and restricted the development of alternative lineages by limiting the expanded self-renewal potential in E2A−/− DN2 cells. Our data support a novel paradigm in lymphocyte lineage commitment in which the E2A proteins are necessary to limit the expression of an essential lineage specification and commitment factor to restrain self-renewal and to prevent an arrest in differentiation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Diferenciação Celular/genética , Linhagem da Célula/genética , Fator de Transcrição GATA3/genética , Linfócitos T/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Cultivadas , Regulação para Baixo , Fator de Transcrição GATA3/metabolismo , Fator de Transcrição GATA3/fisiologia , Regulação da Expressão Gênica , Hematopoese/genética , Hematopoese/imunologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/fisiologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/fisiologia , Camundongos , Camundongos Transgênicos , Linfócitos T/metabolismo , Timócitos/metabolismo , Timócitos/fisiologia
12.
iScience ; 27(3): 108990, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38384837

RESUMO

Most high-grade serous ovarian cancers (HGSCs) likely initiate from fallopian tube (FT) epithelia. While epithelial subtypes have been characterized using single-cell RNA-sequencing (scRNA-Seq), heterogeneity of other compartments and their involvement in tumor progression are poorly defined. Integrated analysis of human FT scRNA-Seq and HGSC-related tissues, including tumors, revealed greater immune and stromal transcriptional diversity than previously reported. We identified abundant monocytes in FTs across two independent cohorts. The ratio of macrophages to monocytes is similar between benign FTs, ovaries, and adjacent normal tissues but significantly greater in tumors. FT-defined monocyte and macrophage signatures, cell-cell communication, and gene set enrichment analyses identified monocyte- and macrophage-specific interactions and functional pathways in paired tumors and adjacent normal tissues. Further reanalysis of HGSC scRNA-Seq identified monocyte and macrophage subsets associated with neoadjuvant chemotherapy. Taken together, our work provides data that an altered FT myeloid cell composition could inform the discovery of early detection markers for HGSC.

13.
mBio ; 15(6): e0093324, 2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38742830

RESUMO

Human papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States and are a major etiological agent of cancers in the anogenital tract and oral cavity. Growing evidence suggests changes in the host microbiome are associated with the natural history and ultimate outcome of HPV infection. We sought to define changes in the host cervicovaginal microbiome during papillomavirus infection, persistence, and pathogenesis using the murine papillomavirus (MmuPV1) cervicovaginal infection model. Cervicovaginal lavages were performed over a time course of MmuPV1 infection in immunocompetent female FVB/N mice and extracted DNA was analyzed by qPCR to track MmuPV1 viral copy number. 16S ribosomal RNA (rRNA) gene sequencing was used to determine the composition and diversity of microbial communities throughout this time course. We also sought to determine whether specific microbial communities exist across the spectrum of MmuPV1-induced neoplastic disease. We, therefore, performed laser-capture microdissection to isolate regions of disease representing all stages of neoplastic disease progression (normal, low- and high-grade dysplasia, and cancer) from female reproductive tract tissue sections from MmuPV1-infected mice and performed 16S rRNA sequencing. Consistent with other studies, we found that the natural murine cervicovaginal microbiome is highly variable across different experiments. Despite these differences in initial microbiome composition between experiments, we observed that MmuPV1 persistence, viral load, and severity of disease influenced the composition of the cervicovaginal microbiome. These studies demonstrate that papillomavirus infection can alter the cervicovaginal microbiome.IMPORTANCEHuman papillomaviruses (HPVs) are the most common sexually transmitted infection in the United States. A subset of HPVs that infect the anogenital tract (cervix, vagina, anus) and oral cavity cause at least 5% of cancers worldwide. Recent evidence indicates that the community of microbial organisms present in the human cervix and vagina, known as the cervicovaginal microbiome, plays a role in HPV-induced cervical cancer. However, the mechanisms underlying this interplay are not well-defined. In this study, we infected the female reproductive tract of mice with a murine papillomavirus (MmuPV1) and found that key aspects of papillomavirus infection and disease influence the host cervicovaginal microbiome. This is the first study to define changes in the host microbiome associated with MmuPV1 infection in a preclinical animal model of HPV-induced cervical cancer. These results pave the way for using MmuPV1 infection models to further investigate the interactions between papillomaviruses and the host microbiome.


Assuntos
Colo do Útero , Modelos Animais de Doenças , Microbiota , Papillomaviridae , Infecções por Papillomavirus , RNA Ribossômico 16S , Vagina , Feminino , Animais , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/microbiologia , Vagina/microbiologia , Vagina/virologia , Camundongos , Colo do Útero/microbiologia , Colo do Útero/virologia , RNA Ribossômico 16S/genética , Papillomaviridae/genética , Papillomaviridae/classificação , Papillomaviridae/isolamento & purificação , Carga Viral
14.
Sci Adv ; 10(17): eadl4463, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38669327

RESUMO

Slowing peritoneal spread in high-grade serous ovarian cancer (HGSOC) would improve patient prognosis and quality of life. HGSOC spreads when single cells and spheroids detach, float through the peritoneal fluid and take over new sites, with spheroids thought to be more aggressive than single cells. Using our in vitro model of spheroid collective detachment, we determine that increased substrate stiffness led to the detachment of more spheroids. We identified a mechanism where Piezo1 activity increased MMP-1/MMP-10, decreased collagen I and fibronectin, and increased spheroid detachment. Piezo1 expression was confirmed in omental masses from patients with stage III/IV HGSOC. Using OV90 and CRISPR-modified PIEZO1-/- OV90 in a mouse xenograft model, we determined that while both genotypes efficiently took over the omentum, loss of Piezo1 significantly decreased ascitic volume, tumor spheroids in the ascites, and the number of macroscopic tumors in the mesentery. These results support that slowing collective detachment may benefit patients and identify Piezo1 as a potential therapeutic target.


Assuntos
Canais Iônicos , Mecanotransdução Celular , Neoplasias Ovarianas , Esferoides Celulares , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/genética , Canais Iônicos/metabolismo , Canais Iônicos/genética , Gradação de Tumores , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/genética , Esferoides Celulares/metabolismo
15.
Pathol Res Pract ; 248: 154628, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37399589

RESUMO

BACKGROUND: Invasive breast carcinomas (IBC) that strongly express SOX10 are almost always negative for androgen receptor (AR). Furthermore, this SOX10+/AR- subset of IBC is nearly always estrogen receptor and progesterone receptor negative (ER-/PR-), being most commonly seen in triple negative breast carcinomas (TNBC), but also in a small subset of HER2+/ER-/PR- IBC. Following our previous work demonstrating the expression of SOX10 in a subset of IBC with "low positive" ER expression (i.e. 1-10 % ER+ staining based on CAP guidelines, here referred to as "ER-low"), we sought to investigate the expression of both SOX10 and AR in a larger cohort of ER-low tumors. As our previous work also revealed occasional SOX10 expression in IBC with >10 % ER+ staining, we also included tumors with any percentage of ER staining, as long as the staining intensity was weak (this subset is referred to as "ER-weak"). METHODS: We screened cases of HER2-/ER+ IBC diagnosed at our institution over a 10 year period, identified both ER-low and ER-weak tumors and stained both groups with SOX10 and AR. RESULTS: Strong SOX10 expression was seen in 12/25 (48 %) ER-low tumors and 13/24 (54 %) ER-weak tumors. ER staining in the SOX10+ subset of ER-weak tumors ranged from 15 %-80 % (median 25 %). As expected, AR was negative in all but 1 of the SOX10+ tumors in both groups. While case numbers in these groups were too small for a meaningful statistical analysis, we did note that all SOX10+/AR- tumors within both the ER-low and ER-weak groups were histologic grade 3. CONCLUSION: The presence of a SOX10+/AR- profile in a significant subset of ER-low tumors confirms the findings of our previous work and provides further support for the proposed functionally ER negative status of this group. Furthermore, the fact that the same SOX10+/AR- profile is seen in a roughly equal subset of ER-weak tumors suggests that a wider range of ER staining may be acceptable as "low positive" in SOX10+/AR- tumors, as long as the ER staining is of weak intensity. However, given the small number of cases in this single institution study, we emphasize the need for larger studies to establish the biological and clinical significance of this tumor subset.


Assuntos
Neoplasias da Mama , Carcinoma , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Receptores Androgênicos/metabolismo , Receptores de Estrogênio/metabolismo , Neoplasias da Mama/patologia , Neoplasias de Mama Triplo Negativas/patologia , Fatores de Transcrição SOXE/metabolismo , Receptores de Progesterona/metabolismo , Receptor ErbB-2/análise , Biomarcadores Tumorais/análise
16.
Cancer Res Commun ; 3(1): 54-65, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36968230

RESUMO

Chromosomal instability (CIN), the persistent reshuffling of chromosomes during mitosis, is a hallmark of human cancers that contributes to tumor heterogeneity and has been implicated in driving metastasis and altering responses to therapy. Though multiple mechanisms can produce CIN, lagging chromosomes generated from abnormal merotelic attachments are the major cause of CIN in a variety of cell lines, and are expected to predominate in cancer. Here, we quantify CIN in breast cancer using a tumor microarray, matched primary and metastatic samples, and patient-derived organoids from primary breast cancer. Surprisingly, misaligned chromosomes are more common than lagging chromosomes and represent a major source of CIN in primary and metastatic tumors. This feature of breast cancers is conserved in a majority of breast cancer cell lines. Importantly, though a portion of misaligned chromosomes align before anaphase onset, the fraction that remain represents the largest source of CIN in these cells. Metastatic breast cancers exhibit higher rates of CIN than matched primary cancers, primarily due to increases in misaligned chromosomes. Whether CIN causes immune activation or evasion is controversial. We find that misaligned chromosomes result in immune-activating micronuclei substantially less frequently than lagging and bridge chromosomes and that breast cancers with greater frequencies of lagging chromosomes and chromosome bridges recruit more stromal tumor-infiltrating lymphocytes. These data indicate misaligned chromosomes represent a major mechanism of CIN in breast cancer and provide support for differential immunostimulatory effects of specific types of CIN. Significance: We surveyed the single-cell landscape of mitotic defects that generate CIN in primary and metastatic breast cancer and relevant models. Misaligned chromosomes predominate, and are less immunostimulatory than other chromosome segregation errors.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Linhagem Celular , Cinetocoros , Mitose , Instabilidade Cromossômica/genética
17.
Bioengineering (Basel) ; 10(1)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36671664

RESUMO

Pancreatic and ampullary cancers remain highly morbid diseases for which accurate clinical predictions are needed for precise therapeutic predictions. Patient-derived cancer organoids have been widely adopted; however, prior work has focused on well-level therapeutic sensitivity. To characterize individual oligoclonal units of therapeutic response, we introduce a low-volume screening assay, including an automated alignment algorithm. The oligoclonal growth response was compared against validated markers of response, including well-level viability and markers of single-cell viability. Line-specific sensitivities were compared with clinical outcomes. Automated alignment algorithms were generated to match organoids across time using coordinates across a single projection of Z-stacked images. After screening for baseline size (50 µm) and circularity (>0.4), the match efficiency was found to be optimized by accepting the diffusion thresholded with the root mean standard deviation of 75 µm. Validated well-level viability showed a limited correlation with the mean organoid size (R = 0.408), and a normalized growth assayed by normalized changes in area (R = 0.474) and area (R = 0.486). Subclonal populations were defined by both residual growth and the failure to induce apoptosis and necrosis. For a culture with clinical resistance to gemcitabine and nab-paclitaxel, while a therapeutic challenge induced a robust effect in inhibiting cell growth (GΔ = 1.53), residual oligoclonal populations were able to limit the effect on the ability to induce apoptosis (GΔ = 0.52) and cell necrosis (GΔ = 1.07). Bioengineered approaches are feasible to capture oligoclonal heterogeneity in organotypic cultures, integrating ongoing efforts for utilizing organoids across cancer types as integral biomarkers and in novel therapeutic development.

18.
Viruses ; 15(9)2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37766356

RESUMO

Approximately 40% of vulvar squamous cell carcinoma (vSCC) cases are etiologically associated with high-risk human papillomaviruses (HPVs) of the alpha genera (α-HPV) that cause other anogenital cancers; however, the etiology of α-HPV-negative vSCC is poorly understood. HPVs of the beta genera (ß-HPV) are risk factors for cutaneous squamous cell carcinoma (cSCC) and may be related to carcinomas originating in other cutaneous sites such as the vulva. In this study, we investigate the presence of ß-HPVs, with an emphasis on p16-negative squamous lesions adjacent to vSCC. We subjected 28 vulvar squamous intraepithelial lesions adjacent to vSCC for comprehensive HPV genotyping, p16 and p53 immunohistochemistry, and consensus morphology review. Selected cases were subjected to qPCR and RNA in situ hybridization. Clinical data were obtained from medical records. ß-HPV DNA was detected in eight of ten p16-negative lesions and three of fourteen p16-positive high-grade squamous intraepithelial lesions. The HPV DNA loads in vulvar squamous intraepithelial lesions ranged between less than 1 HPV DNA copy per cell to more than 100 HPV DNA copies per cell. This is, to the best of our knowledge, the first report of the association of p16-negative vulvar intraepithelial squamous lesions with detection of ß-HPVs. These findings expand possible etiologic mechanisms that may contribute to p16-negative lesions of the vulva.


Assuntos
Betapapillomavirus , Carcinoma in Situ , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias Cutâneas , Lesões Intraepiteliais Escamosas , Neoplasias Vulvares , Feminino , Humanos , Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , Neoplasias Vulvares/etiologia , Neoplasias Vulvares/patologia , Papillomavirus Humano , Lesões Intraepiteliais Escamosas/complicações , Papillomaviridae/genética
19.
Semin Diagn Pathol ; 29(1): 2-11, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22372201

RESUMO

The diagnosis of acute lymphoblastic leukemia (ALL) is made by evaluating morphology and immunophenotype. However, appropriate risk stratification and decisions regarding the intensity of therapy are influenced by additional clinical and laboratory testing that reflect the biology of the disease. Recent years have seen tremendous progress in uncovering genetic lesions that influence the biology of ALL. In recognition of these advances, the 2008 WHO classification incorporated the category of B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities into the classification of precursor lymphoid neoplasms. Based on the knowledge available at the time, genetic lesions associated with distinct clinical features, immunophenotype, prognosis, or other unique biological characteristics were included in this category. Not surprisingly, significant novel genetic lesions that profoundly affect the biology of ALL have since been identified and will have a major impact on risk stratification and may ultimately be incorporated into future classification schemes. After establishing an initial diagnosis and treatment regimen, hematopathologists must also evaluate for minimal residual disease (MRD) to determine the need for additional intervention because MRD remains the most useful clinical indicator of disease progression and response to treatment. Doing so requires familiarity with not only morphology, but also flow cytometry and molecular genetics. Although not all of these applications are handled directly by the hematopathologist, it is our strong belief that meaningful involvement in patient care dictates that hematopathologists appreciate all aspects of ALL diagnosis and disease monitoring. This review covers the salient aspects of recent advances in the biology of ALL and evaluation of MRD, placing emphasis on how this information may ultimately be used to improve risk stratification and, as a result, patient outcomes.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Técnicas de Laboratório Clínico , Análise Citogenética , Humanos , Imunofenotipagem , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Organização Mundial da Saúde
20.
Methods Mol Biol ; 2424: 11-40, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34918285

RESUMO

Optimal use of human tissue for research requires an understanding of basic pathologic principles. Given that the physical assessment of tissue must occur as part of standard clinical examination, it cannot be handled directly by investigators unless they are also a part of the care team. The purpose of this chapter is to provide an overview of the clinical analytic process, from initial gross handling to histologic examination by light microscopy and the use of ancillary studies, in order to provide context for samples that are used in research and to highlight specific considerations that are relevant for obtaining appropriate tissue for experimental purposes. Given that they comprise >95% of ovarian malignancies, there is an emphasis on epithelial tumors.


Assuntos
Neoplasias Ovarianas , Carcinoma Epitelial do Ovário , Feminino , Humanos , Neoplasias Epiteliais e Glandulares
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