Identification of Candidate Genes in Breast and Ovarian Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 26934

Special Issue Editors


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Guest Editor
University of Westminster, Cancer Research Group, School of Life Sciences, College of Liberal Arts & Sciences, London, United Kingdom
Interests: driver breast cancer genes; genomics; molecular pathology; systems biology

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Guest Editor
Centre Jean Perrin, INSERM 1240, Université Clermont Auvergne, France
Interests: hereditary predisposition to cancers; breast cancer; ovarian cancers

Special Issue Information

Dear Colleagues,

On a global scale, breast cancer is the most frequently diagnosed cancer in women; there were over 2 million new cases in 2018, contributing to about 11.6% of the total cancer incidence burden (Globocan 2018, International Agency for Research on Cancer). However, although the last decade has seen an increase in breast cancer incidence, there have also been great improvements in its diagnosis and survival with nearly 80% of breast cancer patients surviving for at least 10 years (Cancer Research UK). According to the International Agency for Research on Cancer, in 2018, female breast cancer ranked as the fifth leading cause of death (627,000 deaths, 6.6%) due to the prognosis being relatively favourable, at least in more developed countries.

Novel therapeutics, such as Herceptin (trastuzumab), and hormone-related biological therapies have greatly contributed to the increased survival rate, as has the knowledge acquired in cancer biology, particularly regarding the identification of candidate genes using molecular and computational approaches to interpret the “OMICs” big data generated principally by genomics and transcriptomics.

Nonetheless, as patients ultimately succumb to progressive disease, Herceptin and endocrine therapy resistance remains a major clinical challenge. Therefore, more research is required to identify genes that can act as the next generation of candidate genomic and predictive targets to improve prognosis and therapeutics. Several approaches can be used—from whole transcriptome analysis (particularly RNA seq) to whole genome/exome sequencing as well as miRNA profiling.

As well as somatic cancer analyses, in patients with breast cancer, high-throughput sequencing can explore the constitutional component, which is involved in hereditary cancer predisposition. In addition to the identification of new high-risk candidate genes for hereditary predisposition to breast cancer, the analysis of OMICS data would allow the exploration of low to moderate risk breast cancer genes, in particular multi-factorial inheritance and modifiers-risk genes, to offer at-risk patients personalized precision medicine in the future.

Thus, this Special Issue of Cancers on “Identification of candidate genes in breast and ovarian cancer ” aims to highlight the state of the current landscape in the discovery of novel breast and ovarian cancer candidate genes and to capture recent insights using genomics and transcriptomics approaches to improve diagnosis and develop therapeutic strategies for the near future.

Dr. Nadège Presneau
Prof. BIGNON Yves-Jean
Dr. Pinar Uysal-Onganer
Guest Editors

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Keywords

  • breast cancer
  • ovarian cancer
  • somatic cancer genes
  • cancer predisposition genes
  • omics
  • systems biology
  • modifying cancer risk genes
  • epigenetics

Published Papers (8 papers)

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Research

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23 pages, 125196 KiB  
Article
ERAS, a Member of the Ras Superfamily, Acts as an Oncoprotein in the Mammary Gland
by Cristian Suarez-Cabrera, Isabel Ojeda-Perez, Raquel Sanchez-Baltasar, Angustias Page, Ana Bravo, Manuel Navarro and Angel Ramirez
Cancers 2021, 13(21), 5588; https://doi.org/10.3390/cancers13215588 - 8 Nov 2021
Viewed by 2489
Abstract
ERAS is a relatively uncharacterized gene of the Ras superfamily. It is expressed in ES cells and in the first stages of embryonic development; later on, it is silenced in the majority of cell types and tissues. Although there are several reports showing [...] Read more.
ERAS is a relatively uncharacterized gene of the Ras superfamily. It is expressed in ES cells and in the first stages of embryonic development; later on, it is silenced in the majority of cell types and tissues. Although there are several reports showing ERAS expression in tumoral cell lines and human tumor samples, it is unknown if ERAS deregulated expression is enough to drive tumor development. In this report, we have generated transgenic mice expressing ERAS in myoepithelial basal cells of the mammary gland and in basal cells of stratified epithelia. In spite of the low level of ERAS expression, these transgenic mice showed phenotypic alterations resembling overgrowth syndromes caused by the activation of the AKT-PI3K pathway. In addition, their mammary glands present developmental and functional disabilities accompanied by morphological and biochemical alterations in the myoepithelial cells. These mice suffer from tumoral transformation in the mammary glands with high incidence. These mammary tumors resemble, both histologically and by the expression of differentiation markers, malignant adenomyoepitheliomas. In sum, our results highlight the importance of ERAS silencing in adult tissues and define a truly oncogenic role for ERAS in mammary gland cells when inappropriately expressed. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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13 pages, 1768 KiB  
Article
In Vitro Investigations of miR-33a Expression in Estrogen Receptor-Targeting Therapies in Breast Cancer Cells
by Pelin Ozfiliz-Kilbas, Ozlem Sonmez, Pinar Obakan-Yerlikaya, Ajda Coker-Gurkan, Narcin Palavan-Ünsal, Pinar Uysal-Onganer and Elif Damla Arisan
Cancers 2021, 13(21), 5322; https://doi.org/10.3390/cancers13215322 - 23 Oct 2021
Cited by 2 | Viewed by 2596
Abstract
(1) Background: Increased fatty acid synthesis leads to the aggressive phenotype of breast cancer and renders efficiency of therapeutics. Regulatory microRNAs (miRNAs) on lipid biosynthesis pathways as miR-33a have potential to clarify the exact mechanism. (2) Methods: We determined miR-33a expression levels following [...] Read more.
(1) Background: Increased fatty acid synthesis leads to the aggressive phenotype of breast cancer and renders efficiency of therapeutics. Regulatory microRNAs (miRNAs) on lipid biosynthesis pathways as miR-33a have potential to clarify the exact mechanism. (2) Methods: We determined miR-33a expression levels following exposure of MCF-7 and MDA-MB-231 breast cancer cells to estrogen receptor (ER) activator (estradiol-17β, E2) or anti-estrogens (ICI 182,780, Fulvestrant, FUL) at non-cytotoxic concentrations. We related miR-33a expression levels in the cells to cellular lipid biosynthesis-related pathways through immunoblotting. (3) Results: miR-33a mimic treatment led to significantly downregulation of fatty acid synthase (FASN) in MCF-7 cells but not in MDA-MB-231 cells in the presence of estradiol-17β (E2) or Fulvestrant (FUL). In contrast to the miR-33a inhibitor effect, miR-33a mimic co-transfection with E2 or FUL led to diminished AMP-activated protein kinase α (AMPKα) activity in MCF-7 cells. E2 increases FASN levels in MDA-MB-231 cells regardless of miR-33a cellular levels. miR-33a inhibitor co-treatment suppressed E2-mediated AMPKα activity in MDA-MB-231 cells. (4) Conclusions: The cellular expression levels of miR-33a are critical to understanding differential responses which include cellular energy sensors such as AMPKα activation status in breast cancer cells. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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13 pages, 2866 KiB  
Article
USP19 and RPL23 as Candidate Prognostic Markers for Advanced-Stage High-Grade Serous Ovarian Carcinoma
by Haeyoun Kang, Min Chul Choi, Sewha Kim, Ju-Yeon Jeong, Ah-Young Kwon, Tae-Hoen Kim, Gwangil Kim, Won Duk Joo, Hyun Park, Chan Lee, Seung Hun Song, Sang Geun Jung, Sohyun Hwang and Hee Jung An
Cancers 2021, 13(16), 3976; https://doi.org/10.3390/cancers13163976 - 6 Aug 2021
Cited by 13 | Viewed by 2692
Abstract
Ovarian cancer is one of the leading causes of deaths among patients with gynecological malignancies worldwide. In order to identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous [...] Read more.
Ovarian cancer is one of the leading causes of deaths among patients with gynecological malignancies worldwide. In order to identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous ovarian carcinoma (HGSC). Patients with early-stage (I or II) HGSC exhibited higher immune gene expression than patients with advanced stage (III or IV) HGSC. In order to predict the prognosis of patients with HGSC, we created machine learning-based models and identified USP19 and RPL23 as candidate prognostic markers. Specifically, patients with lower USP19 mRNA levels and those with higher RPL23 mRNA levels had worse prognoses. This model was then used to analyze the data of patients with HGSC hosted on The Cancer Genome Atlas; this analysis validated the prognostic abilities of these two genes with respect to patient survival. Taken together, the transcriptome profiles of USP19 and RPL23 determined using a machine-learning model could serve as prognostic markers for patients with HGSC receiving conventional therapy. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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26 pages, 3946 KiB  
Article
Meta-Analysis of Microdissected Breast Tumors Reveals Genes Regulated in the Stroma but Hidden in Bulk Analysis
by Aurora Savino, Niccolò De Marzo, Paolo Provero and Valeria Poli
Cancers 2021, 13(13), 3371; https://doi.org/10.3390/cancers13133371 - 5 Jul 2021
Cited by 6 | Viewed by 3238
Abstract
Transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, sample heterogeneity, and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicates the [...] Read more.
Transcriptome data provide a valuable resource for the study of cancer molecular mechanisms, but technical biases, sample heterogeneity, and small sample sizes result in poorly reproducible lists of regulated genes. Additionally, the presence of multiple cellular components contributing to cancer development complicates the interpretation of bulk transcriptomic profiles. To address these issues, we collected 48 microarray datasets derived from laser capture microdissected stroma or epithelium in breast tumors and performed a meta-analysis identifying robust lists of differentially expressed genes. This was used to create a database with carefully harmonized metadata that we make freely available to the research community. As predicted, combining the results of multiple datasets improved statistical power. Moreover, the separate analysis of stroma and epithelium allowed the identification of genes with different contributions in each compartment, which would not be detected by bulk analysis due to their distinct regulation in the two compartments. Our method can be profitably used to help in the discovery of biomarkers and the identification of functionally relevant genes in both the stroma and the epithelium. This database was made to be readily accessible through a user-friendly web interface. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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15 pages, 4136 KiB  
Article
Differential Regulation of Lacto-/Neolacto- Glycosphingolipid Biosynthesis Pathway Reveals Transcription Factors as Potential Candidates in Triple-Negative Breast Cancer
by Ruichao Zeng, Ahmed Mohamed, Kum Kum Khanna and Michelle M. Hill
Cancers 2021, 13(13), 3330; https://doi.org/10.3390/cancers13133330 - 2 Jul 2021
Cited by 1 | Viewed by 2317
Abstract
Triple-negative breast cancer (TNBC) is an aggressive breast cancer with limited treatment options. Glycosylation has been implicated in cancer development, but TNBC-specific glycosylation pathways have not been examined. Here, we applied bioinformatic analyses on public datasets to discover TNBC-specific glycogenes and pathways, as [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive breast cancer with limited treatment options. Glycosylation has been implicated in cancer development, but TNBC-specific glycosylation pathways have not been examined. Here, we applied bioinformatic analyses on public datasets to discover TNBC-specific glycogenes and pathways, as well as their upstream regulatory mechanisms. Unsupervised clustering of 345 glycogene expressions in breast cancer datasets revealed a relative homogenous expression pattern in basal-like TNBC subtype. Differential expression analyses of the 345 glycogenes between basal-like TNBC (hereafter termed TNBC) and other BC subtypes, or normal controls, revealed 84 differential glycogenes in TNBC. Pathway enrichment showed two common TNBC-enriched pathways across all three datasets, cell cycle and lacto-/neolacto- glycosphingolipid (GSL) biosynthesis, while a total of four glycosylation-related pathways were significantly enriched in TNBC. We applied a selection criterion of the top 50% differential anabolic/catabolic glycogenes in the enriched pathways to define 34 TNBC-specific glycogenes. The lacto-/neolacto- GSL biosynthesis pathway was the most highly enriched, with seven glycogenes all up-regulated in TNBC. This data led us to investigate the hypothesis that a common upstream mechanism in TNBC up-regulates the lacto-/neolacto-GSL biosynthesis pathway. Using public multi-omic datasets, we excluded the involvement of copy-number alteration and DNA methylation, but identified three transcription factors (AR, GATA3 and ZNG622) that each target three candidate genes in the lacto-/neolacto- GSL biosynthesis pathway. Interestingly, a subset of TNBC has been reported to express AR and GATA3, and AR antagonists are being trialed for TNBC. Our findings suggest that AR and GATA3 may contribute to TNBC via GSL regulation, and provide a list of candidate glycogenes for further investigation. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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13 pages, 952 KiB  
Article
Causal Inference between Rheumatoid Arthritis and Breast Cancer in East Asian and European Population: A Two-Sample Mendelian Randomization
by Choonghyun Ahn, Sangjun Lee and Sue K. Park
Cancers 2020, 12(11), 3272; https://doi.org/10.3390/cancers12113272 - 5 Nov 2020
Cited by 5 | Viewed by 3069
Abstract
Previous studies have been reported that the association between rheumatoid arthritis (RA) and breast cancer remains inconclusive. A two-sample Mendelian randomization (MR) analysis can reveal the potential causal association between exposure and outcome. A two-sample MR analysis using the penalized robust inverse variance [...] Read more.
Previous studies have been reported that the association between rheumatoid arthritis (RA) and breast cancer remains inconclusive. A two-sample Mendelian randomization (MR) analysis can reveal the potential causal association between exposure and outcome. A two-sample MR analysis using the penalized robust inverse variance weighted (PRIVW) method was performed to analyze the association between RA and breast cancer risk based on the summary statistics of six genome-wide association studies (GWAS) targeting RA in an East Asian population along with summary statistics of the BioBank Japan (BBJ), Breast Cancer Association Consortium (BCAC), and Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) targeting breast cancer. We found that the direction of the effect of RA on breast cancer varied among GWAS-summary data from BBJ, BCAC, and CIMBA. Significant horizontal pleiotropy based on a penalized robust MR-Egger regression was observed only for BBJ and CIMBA BRCA2 carriers. As the results of the two-sample MR analyses were inconsistent, the causal association between RA and breast cancer was inconclusive. The biological mechanisms explaining the relationship between RA and breast cancer were unclear in Asian as well as in Caucasians. Further studies using large-scale patient cohorts are required for the validation of these results. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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Review

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25 pages, 1931 KiB  
Review
The Genetic Analyses of French Canadians of Quebec Facilitate the Characterization of New Cancer Predisposing Genes Implicated in Hereditary Breast and/or Ovarian Cancer Syndrome Families
by Caitlin T. Fierheller, Wejdan M. Alenezi and Patricia N. Tonin
Cancers 2021, 13(14), 3406; https://doi.org/10.3390/cancers13143406 - 7 Jul 2021
Cited by 8 | Viewed by 4413
Abstract
The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in [...] Read more.
The French Canadian population of the province of Quebec has been recognized for its contribution to research in medical genetics, especially in defining the role of heritable pathogenic variants in cancer predisposing genes. Multiple carriers of a limited number of pathogenic variants in BRCA1 and BRCA2, the major risk genes for hereditary breast and/or ovarian cancer syndrome families, have been identified in French Canadians, which is in stark contrast to the array of over 2000 different pathogenic variants reported in each of these genes in other populations. As not all such cancer syndrome families are explained by BRCA1 and BRCA2, newly proposed gene candidates identified in other populations have been investigated for their role in conferring risk in French Canadian cancer families. For example, multiple carriers of distinct variants were identified in PALB2 and RAD51D. The unique genetic architecture of French Canadians has been attributed to shared ancestry due to common ancestors of early settlers of this population with origins mainly from France. In this review, we discuss the merits of genetically characterizing cancer predisposing genes in French Canadians of Quebec. We focused on genes that have been implicated in hereditary breast and/or ovarian cancer syndrome families as they have been the most thoroughly characterized cancer syndromes in this population. We describe how genetic analyses of French Canadians have facilitated: (i) the classification of variants in BRCA1 and BRCA2; (ii) the identification and classification of variants in newly proposed breast and/or ovarian cancer predisposing genes; and (iii) the identification of a new breast cancer predisposing gene candidate, RECQL. The genetic architecture of French Canadians provides a unique opportunity to evaluate new candidate cancer predisposing genes regardless of the population in which they were identified. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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16 pages, 1087 KiB  
Review
Understanding the Role of Innate Immune Cells and Identifying Genes in Breast Cancer Microenvironment
by Israa Shihab, Bariaa A. Khalil, Noha Mousaad Elemam, Ibrahim Y. Hachim, Mahmood Yaseen Hachim, Rifat A. Hamoudi and Azzam A. Maghazachi
Cancers 2020, 12(8), 2226; https://doi.org/10.3390/cancers12082226 - 9 Aug 2020
Cited by 24 | Viewed by 4340
Abstract
The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the [...] Read more.
The innate immune system is the first line of defense against invading pathogens and has a major role in clearing transformed cells, besides its essential role in activating the adaptive immune system. Macrophages, dendritic cells, NK cells, and granulocytes are part of the innate immune system that accumulate in the tumor microenvironment such as breast cancer. These cells induce inflammation in situ by secreting cytokines and chemokines that promote tumor growth and progression, in addition to orchestrating the activities of other immune cells. In breast cancer microenvironment, innate immune cells are skewed towards immunosuppression that may lead to tumor evasion. However, the mechanisms by which immune cells could interact with breast cancer cells are complex and not fully understood. Therefore, the importance of the mammary tumor microenvironment in the development, growth, and progression of cancer is widely recognized. With the advances of using bioinformatics and analyzing data from gene banks, several genes involved in NK cells of breast cancer individuals have been identified. In this review, we discuss the activities of certain genes involved in the cross-talk among NK cells and breast cancer. Consequently, altering tumor immune microenvironment can make breast tumors more responsive to immunotherapy. Full article
(This article belongs to the Special Issue Identification of Candidate Genes in Breast and Ovarian Cancer)
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