Genomics of Gynaecological Cancer Defining Current and Future Treatment Options

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Informatics and Big Data".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 11367

Special Issue Editors

Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research (WEHI), Melbourne, Australia; and the Department of Medical Biology, The University of Melbourne, Melbourne, Australia
Interests: gynaecological cancer; genomics; rare cancers; targeted therapies; precision medicine; pre-clinical models; metastasis; epithelial-to-mesenchymal transition; tumour microenvironment
The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London SW3 6JJ, UK
Interests: gynaecological cancers; rare cancers; PARP inhibitors; targeted therapy; clinical trials

Special Issue Information

Dear Colleagues,

Next-generation sequencing has enabled individual gynaecological cancers (ovarian, fallopian tube, endometrial (uterine), cervical, vulval or vaginal cancer) to be segregated into different molecular subtypes. Despite molecular differences, subtypes may be treated with the same standard therapies, often with poor responses.

Targeted drugs have been developed for specific molecular alterations and have had a positive impact in the treatment of some types of cancer. One example of precision medicine in gynaecological cancers was the initial implementation of PARP inhibitors for the treatment of BRCA-mutated relapsed ovarian cancer. The results from subsequent pre-clinical and clinical studies have led to PARP inhibitors being incorporated into the primary treatment of ovarian cancers. Unfortunately, precision medicine approaches in other gynaecological cancers are lagging behind.

With the increased publication of genomics and pre-clinical precision medicine studies in this area, hopefully, matched clinical trials will prove successful and treatment options for these rare diseases with often poor prognoses will improve. This Special Issue welcomes papers on the genomics of gynaecological cancers (preclinical, clinical and real-word), with a focus on the improvement of the current standard treatments through application of new targeted therapies including immunotherapy based on molecular data.

Dr. Holly Barker
Dr. Susana Banerjee
Guest Editors

Manuscript Submission Information

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Keywords

  • gynaecological cancer
  • genomics
  • precision medicine
  • targeted therapies
  • next-generation sequencing
  • pre-clinical models
  • clinical trials

Published Papers (4 papers)

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Research

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14 pages, 3989 KiB  
Article
Proteomic Profiling Identifies Co-Regulated Expression of Splicing Factors as a Characteristic Feature of Intravenous Leiomyomatosis
by Lukas Krasny, Chris P. Wilding, Emma Perkins, Amani Arthur, Nafia Guljar, Andrew D. Jenks, Cyril Fisher, Ian Judson, Khin Thway, Robin L. Jones and Paul H. Huang
Cancers 2022, 14(12), 2907; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122907 - 13 Jun 2022
Cited by 2 | Viewed by 1592
Abstract
Intravenous leiomyomatosis (IVLM) is a rare benign smooth muscle tumour that is characterised by intravenous growth in the uterine and pelvic veins. Previous DNA copy number and transcriptomic studies have shown that IVLM harbors unique genomic and transcriptomic alterations when compared to uterine [...] Read more.
Intravenous leiomyomatosis (IVLM) is a rare benign smooth muscle tumour that is characterised by intravenous growth in the uterine and pelvic veins. Previous DNA copy number and transcriptomic studies have shown that IVLM harbors unique genomic and transcriptomic alterations when compared to uterine leiomyoma (uLM), which may account for their distinct clinical behaviour. Here we undertake the first comparative proteomic analysis of IVLM and other smooth muscle tumours (comprising uLM, soft tissue leiomyoma and benign metastasizing leiomyoma) utilising data-independent acquisition mass spectrometry. We show that, at the protein level, IVLM is defined by the unique co-regulated expression of splicing factors. In particular, IVLM is enriched in two clusters composed of co-regulated proteins from the hnRNP, LSm, SR and Sm classes of the spliceosome complex. One of these clusters (Cluster 3) is associated with key biological processes including nascent protein translocation and cell signalling by small GTPases. Taken together, our study provides evidence of co-regulated expression of splicing factors in IVLM compared to other smooth muscle tumours, which suggests a possible role for alternative splicing in the pathogenesis of IVLM. Full article
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15 pages, 1544 KiB  
Article
Role of Homologous Recombination Repair (HRR) Genes in Uterine Leiomyosarcomas: A Retrospective Analysis
by Francesca Ciccarone, Matteo Bruno, Elisa De Paolis, Alessia Piermattei, Maria De Bonis, Domenica Lorusso, Gian Franco Zannoni, Nicola Normanno, Angelo Minucci, Giovanni Scambia and Gabriella Ferrandina
Cancers 2022, 14(8), 1934; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081934 - 12 Apr 2022
Cited by 5 | Viewed by 1794
Abstract
Uterine leiomyosarcomas (uLMS) is a very rare disease, and patients experience a dismal prognosis even when treated with chemotherapy. Therefore, a more in-depth molecular characterization of this disease could provide suitable data for the identification of potential target-based drugs. This retrospective, single institutional [...] Read more.
Uterine leiomyosarcomas (uLMS) is a very rare disease, and patients experience a dismal prognosis even when treated with chemotherapy. Therefore, a more in-depth molecular characterization of this disease could provide suitable data for the identification of potential target-based drugs. This retrospective, single institutional study aimed to define the frequencies of gene alterations in uLMS, especially regarding the somatic mutations of BRCA and Homologous Recombination Repair (HRR) genes, and the impact of molecular alterations on clinical outcomes. The 16-genes Next-Generation Sequencing (NGS) panel, Homologous Recombination Solution TM (HRS, Sophia Genetics, Saint Sulpice, Switzerland), was used for the molecular evaluation of samples. The majority of patients (66/105, 63%) carried at least one sequence alteration, with a prevalence of TP53 involvement followed by RAD51B, BRCA1/2, and FANCL. Patients with TP53 gene alterations experienced a significantly worse prognosis for progression free survival (PFS) and overall survival (OS) versus wild-type patients. Given the number of patients with the BRCA1/2 mutation (N = 12), we included them in the HRR patient group; there was no difference in clinical outcomes with HRR versus non-HRR. The Cox’s multivariate analysis showed that stage and TP53 gene alterations resulted in a significantly worse OS. The integration of gene networking data, such as tumor mutation burdens and cancer driver gene identification, could show a clearer discrimination of gene distribution patterns, and lead to the implementation of therapeutic targets. Full article
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17 pages, 5376 KiB  
Article
Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma
by Saira Khalique, Sarah Nash, David Mansfield, Julian Wampfler, Ayoma Attygale, Katherine Vroobel, Harriet Kemp, Richard Buus, Hannah Cottom, Ioannis Roxanis, Thomas Jones, Katharina von Loga, Dipa Begum, Naomi Guppy, Pradeep Ramagiri, Kerry Fenwick, Nik Matthews, Michael J. F. Hubank, Christopher J. Lord, Syed Haider, Alan Melcher, Susana Banerjee and Rachael Natrajanadd Show full author list remove Hide full author list
Cancers 2021, 13(15), 3854; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13153854 - 30 Jul 2021
Cited by 10 | Viewed by 3384
Abstract
Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low mutational burden, an intratumoural T cell response has been reported in [...] Read more.
Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low mutational burden, an intratumoural T cell response has been reported in a subset of OCCC, with ARID1A purported to be a biomarker for the response to the immune checkpoint blockade independent of micro-satellite instability (MSI). However, assessment of the different immune cell types and spatial distribution specifically within OCCC patients has not been described to date. Here, we characterised the immune landscape of OCCC by profiling a cohort of 33 microsatellite stable OCCCs at the genomic, gene expression and histological level using targeted sequencing, gene expression profiling using the NanoString targeted immune panel, and multiplex immunofluorescence to assess the spatial distribution and abundance of immune cell populations at the protein level. Analysis of these tumours and subsequent independent validation identified an immune-related gene expression signature associated with risk of recurrence of OCCC. Whilst histological quantification of tumour-infiltrating lymphocytes (TIL, Salgado scoring) showed no association with the risk of recurrence or ARID1A mutational status, the characterisation of TILs via multiplexed immunofluorescence identified spatial differences in immunosuppressive cell populations in OCCC. Tumour-associated macrophages (TAM) and regulatory T cells were excluded from the vicinity of tumour cells in low-risk patients, suggesting that high-risk patients have a more immunosuppressive microenvironment. We also found that TAMs and cytotoxic T cells were also excluded from the vicinity of tumour cells in ARID1A-mutated OCCCs compared to ARID1A wild-type tumours, suggesting that the exclusion of these immune effectors could determine the host response of ARID1A-mutant OCCCs to therapy. Overall, our study has provided new insights into the immune landscape and prognostic associations in OCCC and suggest that tailored immunotherapeutic approaches may be warranted for different subgroups of OCCC patients. Full article
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Review

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24 pages, 904 KiB  
Review
Interrogating the Genomic Landscape of Uterine Leiomyosarcoma: A Potential for Patient Benefit
by Genevieve V. Dall, Anne Hamilton, Gayanie Ratnayake, Clare Scott and Holly Barker
Cancers 2022, 14(6), 1561; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061561 - 18 Mar 2022
Cited by 5 | Viewed by 3948
Abstract
Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy. Surgical removal and chemotherapy are commonly used to treat uLMS, but recurrence rates are high. Over the last few decades, clarification of the genomic landscape of uLMS has revealed a number of recurring [...] Read more.
Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy. Surgical removal and chemotherapy are commonly used to treat uLMS, but recurrence rates are high. Over the last few decades, clarification of the genomic landscape of uLMS has revealed a number of recurring mutations, including TP53, RB1, ATRX, PTEN, and MED12. Such genomic aberrations are difficult to target therapeutically or are actively targeted in other malignancies, and their potential as targets for the treatment of uLMS remains largely unexplored. Recent identification of deficiencies in homologous recombination in a minority of these tumours, however, has provided a rationale for investigation of PARP inhibitors in this sub-set. Here, we review these mutations and the evidence for therapeutic avenues that may be applied in uLMS. We also provide a comprehensive background on diagnosis and current therapeutic strategies as well as reviewing preclinical models of uLMS, which may be employed not only in testing emerging therapies but also in understanding this challenging and deadly disease. Full article
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