Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations

Otsuka, Isao

doi:10.3390/ijms22094409

Cited by 18 publications

(15 citation statements)

References 139 publications

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“…Using CHIP-seq and transcriptomic studies, Lawrensen et al found that the transcription factor SOX18, which was overexpressed in tumors, induced an EMT in FTEs from patients with HGSC [21], suggesting that an EMT in FTE may represent an early molecular mechanism of HGSC development. In addition to EMT, many other genetic changes are found within the FTE of BRCA mutation carriers [22,23]. Many previous studies addressing BRCA germline mutation-associated etiologies are bulk sequencing or tissue based, and therefore unable to identify subpopulations within the FTE since all cells derived from FTE were evaluated together as a single sample.…”

Section: Introductionmentioning

confidence: 99%

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

Lin

Spirtos

et al. 2022

BMC Med

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Background High-grade serous carcinoma (HGSC) is the most frequent and lethal type of ovarian cancer. It has been proposed that tubal secretory cells are the origin of ovarian HGSC in women with familial BRCA1/2 mutations. However, the molecular changes underlying malignant transformation remain unknown. Method We performed single-cell RNA and T cell receptor sequencing of tubal fimbriated ends from 3 BRCA1 germline mutation carriers (BRCA1 carriers) and 3 normal controls with no high-risk history (non-BRCA1 carriers). Results Exploring the transcriptomes of 19,008 cells, predominantly from BRCA1+ samples, we identified 5 major cell populations in the fallopian tubal mucosae. The secretory cells of BRCA1+ samples had differentially expressed genes involved in tumor growth and regulation, chemokine signaling, and antigen presentation compared to the wild-type BRCA1 controls. There are several novel findings in this study. First, a subset of the fallopian tubal secretory cells from one BRCA1 carrier exhibited an epithelial-to-mesenchymal transition (EMT) phenotype, which was also present in the mucosal fibroblasts. Second, we identified a previously unreported phenotypic split of the EMT secretory cells with distinct evolutionary endpoints. Third, we observed increased clonal expansion among the CD8+ T cell population from BRCA1+ carriers. Among those clonally expanded CD8+ T cells, PD-1 was significantly increased in tubal mucosae of BRCA1+ patients compared with that of normal controls, indicating that T cell exhaustion may occur before the development of any premalignant or malignant lesions. Conclusion These results indicate that EMT and immune evasion in normal-looking tubal mucosae may represent early events leading to the development of HGSC in women with BRCA1 germline mutation. Our findings provide a probable molecular mechanism explaining why some, but not all, women with BRCA1 germline mutation present with early development and rapid dissemination of HGSC.

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Section: Introductionmentioning

confidence: 99%

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

Lin

Spirtos

et al. 2022

BMC Med

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“…They have also demonstrated genomic alterations in the homologous recombination repair (HRR) pathway leading to genomic instability and aneuploidy characterised by high copy number structural alterations (CNAs). CNAs can be recognised as oncogene amplifications such as CCNE1 (20%), MECOM, EMSY and MYC and deletions/breaks of tumour suppressor genes such as PTEN, RB1, RAD51B and NF1 [38,39]. Additionally, recurrent mutations have been observed in a variety of genes such as NF1 (4%-6%), RB1 (2%-6%)and PTEN (<1%) along with structural alterations/deletions can result in genes inactivation in relatively high frequency such as 20%, 17% and 7%, respectively [38,40].…”

Section: Molecular Pathology Of Ovarian High-grade Serous Carcinomasmentioning

confidence: 99%

Recent Advances in Classification and Histopathological Diagnosis of Ovarian Epithelial Malignant Tumours

Stanc¹,

Souka²,

Valavanis³

2023

Recent Advances, New Perspectives and Applications in the Treatment of Ovarian Cancer

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Ovarian tumours are a heterogeneous group of neoplasms classified based on histopathologic type and grade of differentiation. They comprise a broad range of tumours from benign and borderline to malignant histotypes characterised by different histopathological, immunophenotypic and molecular features. The purpose of this chapter is to present an overview of the recent advances in the ovarian epithelial malignant tumours classification along with the histopathological, immunophenotypic and molecular diagnostic criteria highlighting areas of terminology discrepancies or changes and diagnostic challenges. These changes provide a better understanding of the ovarian tumours nature and lead to a more efficient therapeutic management of these pathological entities.

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“…Indeed, both germline and somatic deleterious mutations in BRCA1/2 genes (referred to as gBRCA* and sBRCA* , respectively) have been shown to promote HGSOC [ 9 , 24 ]. BRCA1/2 play key roles in genome integrity maintenance and their alteration are an early event in the EOC carcinogenetic process; indeed, the loss of the first allele of BRCA1 (or BRCA2 ) is a facilitating event for TP53 loss, both of them leading to EOC development [ 25 ]. The most frequent and well-known alterations are short mutations in BRCA1/2 genes, leading to coding sequence disruption (through missense, nonsense or frameshift mutations) that subsequently inactivate proteins or result in dominant-negative mutations [ 26 ].…”

Section: From Ovarian Cancer Genetics To Homologous Recombination Def...mentioning

confidence: 99%

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

Quesada

Fabbro

Solassol

2022

Cancers

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High-grade serous ovarian cancer (HGSOC), the most frequent and lethal form of ovarian cancer, exhibits homologous recombination deficiency (HRD) in 50% of cases. In addition to mutations in BRCA1 and BRCA2, which are the best known thus far, defects can also be caused by diverse alterations to homologous recombination-related genes or epigenetic patterns. HRD leads to genomic instability (genomic scars) and is associated with PARP inhibitor (PARPi) sensitivity. HRD is currently assessed through BRCA1/2 analysis, which produces a genomic instability score (GIS). However, despite substantial clinical achievements, FDA-approved companion diagnostics (CDx) based on GISs have important limitations. Indeed, despite the use of GIS in clinical practice, the relevance of such assays remains controversial. Although international guidelines include companion diagnostics as part of HGSOC frontline management, they also underscore the need for more powerful and alternative approaches for assessing patient eligibility to PARP inhibitors. In these companion reviews, we review and present evidence to date regarding HRD definitions, achievements and limitations in HGSOC. Part 1 is dedicated to technical considerations and proposed perspectives that could lead to a more comprehensive and dynamic assessment of HR, while Part 2 provides a more integrated approach for clinicians.

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Mechanisms of High-Grade Serous Carcinogenesis in the Fallopian Tube and Ovary: Current Hypotheses, Etiologic Factors, and Molecular Alterations

Cited by 18 publications

References 139 publications

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

Dissection of transcriptome dysregulation and immune characterization in women with germline BRCA1 mutation at single-cell resolution

Recent Advances in Classification and Histopathological Diagnosis of Ovarian Epithelial Malignant Tumours

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations

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