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Genetic Complexity of Hormone Sensitive Cancers

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 February 2021) | Viewed by 42153

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Special Issue Editors

Dr. Jyotsna Batra

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Guest Editor

Faculty of Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
Interests: prostate cancer; miRNA; lncRNA; GWAS; SNP; genetics; transcriptomics; genomics; proteogenomics; micropeptides; biomarker
Special Issues, Collections and Topics in MDPI journals

Dr. Rupert Ecker

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Guest Editor

TissueGnostics GmbH, 1020 Vienna, Austria
Interests: personalized/precision medicine; cancer research; image cytometry; microscopy; software engineering & development of medical devices according to ISO 13485

Special Issue Information

Dear Colleagues,

The most common cancers of men and women i.e. breast and prostate cancers are well known to be dependent on hormones. Hormones have also been implicated in the genesis of uterine, ovarian, testicular, thyroid and bone as well as few other human cancers recently discovered to be hormone sensitive (e.g. lung, liver). In addition to hormones, environmental and genetic risk factors concur and mutually influence both the development of these malignancies and their progression, as well as response to treatment and the risk of recurrence. By understanding this complex interaction, we can progress means to more specifically identify the disease early, treat and ideally prevent hormone-dependent/sensitive cancers, which is of critical importance given the significant impact these malignancies have on human health.

In the recent era, our understanding of the Interplay of multiple genetic and phenotypic parameters has significantly advanced due to novel technologies that permit multiparametric analyses in the same (tissue) sample and identify molecular correlations by high-dimensional data mining. The recent advent in next-generation-sequencing and high-throughput functional genomics techniques such as single-cell sequencing, digital pathology including 4D image & tissue cytometry to retrieve spatiotemporal information about molecular interactions in regulatory networks and our ability to determine the 3D architecture of the genome in context to cellular phenotypes, permit extensive genetic fingerprinting as well as molecular profiling of the tumor cells. Similarly, high-throughput technologies such as CRISPR has skyrocketed the new knowledge in the field of molecular genetics of hormone-sensitive cancers. These recent advancements inaugurate a promising era to decipher the genetic and epigenetic basis of hormone–sensitive cancers, to help better understand their Mechanistics and histopathology and thereby, hopefully, leading to personalized and preventative medicine.

An in depth understanding of interaction of genetics as well as hormone action in regulating diverse cellular processes, cancer phenotypes and drug responsiveness is essential for the development of effective and well-tolerated treatment strategies. In this special issue of Genes, we welcome reviews, mini-reviews, new methods, and original research articles that advance our understanding of hormone-sensitive cancers using the current and emerging high-throughput approaches. While the interaction of hormones and genetics/epigenetics will be of special interest, we will also be open to any advancement exploring the genetic interactions and pleiotropy of multiple cancers.

Prof. Jyotsna Batra
Dr. Rupert Ecker
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Cancer
Hormones
Genetics
Regulatory networks
Multiplexing
Deep Learning
Artificial Intelligence
Data mining
Prostate Cancer
Breast Cancer
Ovarian Cancer
Endometrial Cancer
Bone Cancer
Testicular Cancer
Lung Cancer
Liver Cancer

Published Papers (10 papers)

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Research

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22 pages, 3963 KiB

Open AccessArticle

Identification and Characterization of Alternatively Spliced Transcript Isoforms of IRX4 in Prostate Cancer

by Achala Fernando, Chamikara Liyanage, Afshin Moradi, Panchadsaram Janaththani and Jyotsna Batra

Genes 2021, 12(5), 615; https://doi.org/10.3390/genes12050615 - 21 Apr 2021

Cited by 4 | Viewed by 4217

Abstract

Alternative splicing (AS) is tightly regulated to maintain genomic stability in humans. However, tumor growth, metastasis and therapy resistance benefit from aberrant RNA splicing. Iroquois-class homeodomain protein 4 (IRX4) is a TALE homeobox transcription factor which has been implicated in prostate cancer (PCa) as a tumor suppressor through genome-wide association studies (GWAS) and functional follow-up studies. In the current study, we characterized 12 IRX4 transcripts in PCa cell lines, including seven novel transcripts by RT-PCR and sequencing. They demonstrate unique expression profiles between androgen-responsive and nonresponsive cell lines. These transcripts were significantly overexpressed in PCa cell lines and the cancer genome atlas program (TCGA) PCa clinical specimens, suggesting their probable involvement in PCa progression. Moreover, a PCa risk-associated SNP rs12653946 genotype GG was corelated with lower IRX4 transcript levels. Using mass spectrometry analysis, we identified two IRX4 protein isoforms (54.4 kDa, 57 kDa) comprising all the functional domains and two novel isoforms (40 kDa, 8.7 kDa) lacking functional domains. These IRX4 isoforms might induce distinct functional programming that could contribute to PCa hallmarks, thus providing novel insights into diagnostic, prognostic and therapeutic significance in PCa management. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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13 pages, 1553 KiB

Open AccessArticle

Characterization of Hormone-Dependent Pathways in Six Human Prostate-Cancer Cell Lines: A Gene-Expression Study

by Andras Franko, Lucia Berti, Alke Guirguis, Jörg Hennenlotter, Robert Wagner, Marcus O. Scharpf, Martin Hrabĕ de Angelis, Katharina Wißmiller, Heiko Lickert, Arnulf Stenzl, Andreas L. Birkenfeld, Andreas Peter, Hans-Ulrich Häring, Stefan Z. Lutz and Martin Heni

Genes 2020, 11(10), 1174; https://doi.org/10.3390/genes11101174 - 07 Oct 2020

Cited by 4 | Viewed by 2877

Abstract

Prostate cancer (PCa), the most incident cancer in men, is tightly regulated by endocrine signals. A number of different PCa cell lines are commonly used for in vitro experiments, but these are of diverse origin, and have very different cell-proliferation rates and hormone-response capacities. By analyzing the gene-expression pattern of main hormone pathways, we systematically compared six PCa cell lines and parental primary cells. We compared these cell lines (i) with each other and (ii) with PCa tissue samples from 11 patients. We found major differences in the gene-expression levels of androgen, insulin, estrogen, and oxysterol signaling between PCa tissue and cell lines, and between different cell lines. Our systematic characterization gives researchers a solid basis to choose the appropriate PCa cell model for the hormone pathway of interest. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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15 pages, 2011 KiB

Open AccessArticle

Convergence of Prognostic Gene Signatures Suggests Underlying Mechanisms of Human Prostate Cancer Progression

by Bogdan-Alexandru Luca, Vincent Moulton, Christopher Ellis, Shea P. Connell, Daniel S. Brewer and Colin S. Cooper

Genes 2020, 11(7), 802; https://doi.org/10.3390/genes11070802 - 16 Jul 2020

Cited by 6 | Viewed by 2776

Abstract

The highly heterogeneous clinical course of human prostate cancer has prompted the development of multiple RNA biomarkers and diagnostic tools to predict outcome for individual patients. Biomarker discovery is often unstable with, for example, small changes in discovery dataset configuration resulting in large alterations in biomarker composition. Our hypothesis, which forms the basis of this current study, is that highly significant overlaps occurring between gene signatures obtained using entirely different approaches indicate genes fundamental for controlling cancer progression. For prostate cancer, we found two sets of signatures that had significant overlaps suggesting important genes (p < 10⁻³⁴ for paired overlaps, hypergeometrical test). These overlapping signatures defined a core set of genes linking hormone signalling (HES6-AR), cell cycle progression (Prolaris) and a molecular subgroup of patients (PCS1) derived by Non Negative Matrix Factorization (NNMF) of control pathways, together designated as SIG-HES6. The second set (designated SIG-DESNT) consisted of the DESNT diagnostic signature and a second NNMF signature PCS3. Stratifications using SIG-HES6 (HES6, PCS1, Prolaris) and SIG-DESNT (DESNT) classifiers frequently detected the same individual high-risk cancers, indicating that the underlying mechanisms associated with SIG-HES6 and SIG-DESNT may act together to promote aggressive cancer development. We show that the use of combinations of a SIG-HES6 signature together with DESNT substantially increases the ability to predict poor outcome, and we propose a model for prostate cancer development involving co-operation between the SIG-HES6 and SIG-DESNT pathways that has implication for therapeutic design. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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17 pages, 3304 KiB

Open AccessArticle

Quantitative Proteomics of Urinary Bladder Cancer Cell Lines Identify UAP1 as a Potential Therapeutic Target

by Vinuth N. Puttamallesh, Barnali Deb, Kirti Gondkar, Ankit Jain, Bipin Nair, Akhilesh Pandey, Aditi Chatterjee, Harsha Gowda and Prashant Kumar

Genes 2020, 11(7), 763; https://doi.org/10.3390/genes11070763 - 08 Jul 2020

Cited by 10 | Viewed by 4442

Abstract

Bladder carcinoma (BC) incidence and mortality rates are increasing worldwide. The development of novel therapeutic strategies is required to improve clinical management of this cancer. Aberrant protein expression may lead to cancer initiation and progression. Therefore, the identification of these potential protein targets and limiting their expression levels would provide alternative treatment options. In this study, we utilized a liquid-chromatography tandem mass spectrometry-based global proteomics approach to identify differentially expressed proteins in bladder cancer cell lines. A total of 3913 proteins were identified in this study, of which 479 proteins were overexpressed and 141 proteins were downregulated in 4 out of 6 BC cell lines when compared with normal human urothelial cell line (TERT-NHUC). We evaluated the role of UDP-N-acetylhexosamine pyrophosphorylase (UAP1) in bladder cancer pathogenesis. The silencing of UAP1 led to reduction in proliferation, invasion, colony formation and migration capability of bladder cancer cell lines. Thus, our study reveals UAP1 as a promising therapeutic target for bladder cancer. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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13 pages, 1875 KiB

Open AccessArticle

Transcriptomic Profiling Identifies Differentially Expressed Genes in Palbociclib-Resistant ER+ MCF7 Breast Cancer Cells

by Lilibeth Lanceta, Conor O'Neill, Nadiia Lypova, Xiahong Li, Eric Rouchka, Sabine Waigel, Jorge G. Gomez-Gutierrez, Jason Chesney and Yoannis Imbert-Fernandez

Genes 2020, 11(4), 467; https://doi.org/10.3390/genes11040467 - 24 Apr 2020

Cited by 12 | Viewed by 3746

Abstract

Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition in estrogen receptor-positive (ER+) breast cancer remains a significant clinical challenge. Efforts to uncover the mechanisms underlying resistance are needed to establish clinically actionable targets effective against resistant tumors. In this study, we sought to identify differentially expressed genes (DEGs) associated with acquired resistance to palbociclib in ER+ breast cancer. We performed next-generation transcriptomic RNA sequencing (RNA-seq) and pathway analysis in ER+ MCF7 palbociclib-sensitive (MCF7/pS) and MCF7 palbociclib-resistant (MCF7/pR) cells. We identified 2183 up-regulated and 1548 down-regulated transcripts in MCF7/pR compared to MCF7/pS cells. Functional analysis of the DEGs using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database identified several pathways associated with breast cancer, including ‘cell cycle’, ‘DNA replication’, ‘DNA repair’ and ‘autophagy’. Additionally, Ingenuity Pathway Analysis (IPA) revealed that resistance to palbociclib is closely associated with deregulation of several key canonical and metabolic pathways. Further studies are needed to determine the utility of these DEGs and pathways as therapeutics targets against ER+ palbociclib-resistant breast cancer. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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Review

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11 pages, 286 KiB

Open AccessReview

Long Non-Coding RNAs at the Chromosomal Risk Loci Identified by Prostate and Breast Cancer GWAS

by Panchadsaram Janaththani, Sri Lakshmi Srinivasan and Jyotsna Batra

Genes 2021, 12(12), 2028; https://doi.org/10.3390/genes12122028 - 20 Dec 2021

Cited by 6 | Viewed by 3102

Abstract

Long non-coding RNAs (lncRNAs) are emerging as key players in a variety of cellular processes. Deregulation of the lncRNAs has been implicated in prostate and breast cancers. Recently, germline genetic variations associated with cancer risk have been correlated with lncRNA expression and/or function. In addition, single nucleotide polymorphisms (SNPs) at well-characterized cancer-associated lncRNAs have been analyzed for their association with cancer risk. These SNPs may occur within the lncRNA transcripts or spanning regions that may alter the structure, function, and expression of these lncRNA molecules and contribute to cancer progression and may have potential as therapeutic targets for cancer treatment. Additionally, some of these lncRNA have a tissue-specific expression profile, suggesting them as biomarkers for specific cancers. In this review, we highlight some of the cancer risk-associated SNPs that modulated lncRNAs with a potential role in prostate and breast cancers and speculate on how these lncRNAs may contribute to cancer development. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

27 pages, 17016 KiB

Open AccessReview

Next-Generation Digital Histopathology of the Tumor Microenvironment

by Felicitas Mungenast, Achala Fernando, Robert Nica, Bogdan Boghiu, Bianca Lungu, Jyotsna Batra and Rupert C. Ecker

Genes 2021, 12(4), 538; https://doi.org/10.3390/genes12040538 - 07 Apr 2021

Cited by 18 | Viewed by 9678

Abstract

Progress in cancer research is substantially dependent on innovative technologies that permit a concerted analysis of the tumor microenvironment and the cellular phenotypes resulting from somatic mutations and post-translational modifications. In view of a large number of genes, multiplied by differential splicing as well as post-translational protein modifications, the ability to identify and quantify the actual phenotypes of individual cell populations in situ, i.e., in their tissue environment, has become a prerequisite for understanding tumorigenesis and cancer progression. The need for quantitative analyses has led to a renaissance of optical instruments and imaging techniques. With the emergence of precision medicine, automated analysis of a constantly increasing number of cellular markers and their measurement in spatial context have become increasingly necessary to understand the molecular mechanisms that lead to different pathways of disease progression in individual patients. In this review, we summarize the joint effort that academia and industry have undertaken to establish methods and protocols for molecular profiling and immunophenotyping of cancer tissues for next-generation digital histopathology—which is characterized by the use of whole-slide imaging (brightfield, widefield fluorescence, confocal, multispectral, and/or multiplexing technologies) combined with state-of-the-art image cytometry and advanced methods for machine and deep learning. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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22 pages, 3389 KiB

Open AccessReview

Genetic Drivers of Head and Neck Squamous Cell Carcinoma: Aberrant Splicing Events, Mutational Burden, HPV Infection and Future Targets

by Zodwa Dlamini, Mohammed Alaouna, Sikhumbuzo Mbatha, Ahmed Bhayat, Mzubanzi Mabongo, Aristotelis Chatziioannou and Rodney Hull

Genes 2021, 12(3), 422; https://doi.org/10.3390/genes12030422 - 15 Mar 2021

Cited by 4 | Viewed by 2935

Abstract

Head and neck cancers include cancers that originate from a variety of locations. These include the mouth, nasal cavity, throat, sinuses, and salivary glands. These cancers are the sixth most diagnosed cancers worldwide. Due to the tissues they arise from, they are collectively named head and neck squamous cell carcinomas (HNSCC). The most important risk factors for head and neck cancers are infection with human papillomavirus (HPV), tobacco use and alcohol consumption. The genetic basis behind the development and progression of HNSCC includes aberrant non-coding RNA levels. However, one of the most important differences between healthy tissue and HNSCC tissue is changes in the alternative splicing of genes that play a vital role in processes that can be described as the hallmarks of cancer. These changes in the expression profile of alternately spliced mRNA give rise to various protein isoforms. These protein isoforms, alternate methylation of proteins, and changes in the transcription of non-coding RNAs (ncRNA) can be used as diagnostic or prognostic markers and as targets for the development of new therapeutic agents. This review aims to describe changes in alternative splicing and ncRNA patterns that contribute to the development and progression of HNSCC. It will also review the use of the changes in gene expression as biomarkers or as the basis for the development of new therapies. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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16 pages, 2869 KiB

Open AccessReview

Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

by Flavia Zita Francies, Sheynaz Bassa, Aristotelis Chatziioannou, Andreas Martin Kaufmann and Zodwa Dlamini

Genes 2021, 12(2), 130; https://doi.org/10.3390/genes12020130 - 20 Jan 2021

Cited by 13 | Viewed by 3985

Abstract

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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12 pages, 525 KiB

Open AccessReview

The Genetic Complexity of Prostate Cancer

by Eva Compérat, Gabriel Wasinger, André Oszwald, Renate Kain, Geraldine Cancel-Tassin and Olivier Cussenot

Genes 2020, 11(12), 1396; https://doi.org/10.3390/genes11121396 - 25 Nov 2020

Cited by 9 | Viewed by 3039

Abstract

Prostate cancer (PCa) is a major concern in public health, with many genetically distinct subsets. Genomic alterations in PCa are extraordinarily complex, and both germline and somatic mutations are of great importance in the development of this tumor. The aim of this review is to provide an overview of genetic changes that can occur in the development of PCa and their role in potential therapeutic approaches. Various pathways and mechanisms proposed to play major roles in PCa are described in detail to provide an overview of current knowledge. Full article

(This article belongs to the Special Issue Genetic Complexity of Hormone Sensitive Cancers)

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