Sex Differences in Cancer Genomes: Much Learned, More Unknown

Endocrinology ◽

10.1210/endocr/bqab170 ◽

2021 ◽

Author(s):

Chenghao Zhu ◽

Paul C Boutros

Keyword(s):

Sex Differences ◽

Precision Medicine ◽

Cause Of Death ◽

Clinical Presentation ◽

Response To Treatment ◽

Critical Gap ◽

Cancer Genomes ◽

Cancer Initiation ◽

Cancer Types ◽

Key Resources

Abstract Cancer is a leading cause of death worldwide. Sex influences cancer in a bewildering variety of ways. In some cancer types it affects prevalence, in others genomic profiles, or response to treatment, or mortality. In some sex seems to have little or no influence. How and when sex influences cancer initiation and progression remain a critical gap in our understanding of cancer, with direct relevance to precision medicine. Here, we note several factors that complicate our understanding of sex differences: representativeness of large cohorts, confounding with features like ancestry, age and obesity, and variability in clinical presentation. We summarize the key resources available to study molecular sex differences, and suggest some likely directions for improving our understanding of how patient sex influences cancer behaviour.

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Cerebrovascular Hemodynamics in Women

Seminars in Neurology ◽

10.1055/s-0037-1608881 ◽

2017 ◽

Vol 37 (06) ◽

pp. 679-688

Author(s):

Cristina Duque ◽

Steven Feske ◽

Farzaneh Sorond

Keyword(s):

Sex Differences ◽

Clinical Presentation ◽

Unmet Need ◽

Response To Treatment ◽

Sex And Gender ◽

Specific Mechanism ◽

Knowledge Deficit ◽

Vascular Physiology ◽

And Gender ◽

Cerebrovascular Hemodynamics

AbstractSex and gender, as biological and social factors, significantly influence health outcomes. Among the biological factors, sex differences in vascular physiology may be one specific mechanism contributing to the observed differences in clinical presentation, response to treatment, and clinical outcomes in several vascular disorders. This review focuses on the cerebrovascular bed and summarizes the existing literature on sex differences in cerebrovascular hemodynamics to highlight the knowledge deficit that exists in this domain. The available evidence is used to generate mechanistically plausible and testable hypotheses to underscore the unmet need in understanding sex-specific mechanisms as targets for more effective therapeutic and preventive strategies.

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Predicting pathogenic non-coding SVs disrupting the 3D genome in 1646 whole cancer genomes using multiple instance learning

Scientific Reports ◽

10.1038/s41598-021-93917-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Marleen M. Nieboer ◽

Luan Nguyen ◽

Jeroen de Ridder

Keyword(s):

Multiple Instance Learning ◽

Cancer Diagnostics ◽

Common Mechanism ◽

Open Chromatin ◽

Driver Genes ◽

3D Genome ◽

Whole Genomes ◽

Cancer Genomes ◽

Cancer Types ◽

The Impact

AbstractOver the past years, large consortia have been established to fuel the sequencing of whole genomes of many cancer patients. Despite the increased abundance in tools to study the impact of SNVs, non-coding SVs have been largely ignored in these data. Here, we introduce svMIL2, an improved version of our Multiple Instance Learning-based method to study the effect of somatic non-coding SVs disrupting boundaries of TADs and CTCF loops in 1646 cancer genomes. We demonstrate that svMIL2 predicts pathogenic non-coding SVs with an average AUC of 0.86 across 12 cancer types, and identifies non-coding SVs affecting well-known driver genes. The disruption of active (super) enhancers in open chromatin regions appears to be a common mechanism by which non-coding SVs exert their pathogenicity. Finally, our results reveal that the contribution of pathogenic non-coding SVs as opposed to driver SNVs may highly vary between cancers, with notably high numbers of genes being disrupted by pathogenic non-coding SVs in ovarian and pancreatic cancer. Taken together, our machine learning method offers a potent way to prioritize putatively pathogenic non-coding SVs and leverage non-coding SVs to identify driver genes. Moreover, our analysis of 1646 cancer genomes demonstrates the importance of including non-coding SVs in cancer diagnostics.

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Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

Cells ◽

10.3390/cells9010075 ◽

2019 ◽

Vol 9 (1) ◽

pp. 75 ◽

Cited By ~ 3

Author(s):

Nicoletta Nuzziello ◽

Loredana Ciaccia ◽

Maria Liguori

Keyword(s):

Neurodegenerative Diseases ◽

Precision Medicine ◽

Target Genes ◽

Drug Disposition ◽

Therapeutic Potential ◽

Response To Treatment ◽

Therapeutic Effects ◽

Exciting Potential ◽

The Central Nervous System ◽

Effective Use

Novel insights in the development of a precision medicine approach for treating the neurodegenerative diseases (NDDs) are provided by emerging advances in the field of pharmacoepigenomics. In this context, microRNAs (miRNAs) have been extensively studied because of their implication in several disorders related to the central nervous system, as well as for their potential role as biomarkers of diagnosis, prognosis, and response to treatment. Recent studies in the field of neurodegeneration reported evidence that drug response and efficacy can be modulated by miRNA-mediated mechanisms. In fact, miRNAs seem to regulate the expression of pharmacology target genes, while approved (conventional and non-conventional) therapies can restore altered miRNAs observed in NDDs. The knowledge of miRNA pharmacoepigenomics may offers new clues to develop more effective treatments by providing novel insights into interindividual variability in drug disposition and response. Recently, the therapeutic potential of miRNAs is gaining increasing attention, and miRNA-based drugs (for cancer) have been under observation in clinical trials. However, the effective use of miRNAs as therapeutic target still needs to be investigated. Here, we report a brief review of representative studies in which miRNAs related to therapeutic effects have been investigated in NDDs, providing exciting potential prospects of miRNAs in pharmacoepigenomics and translational medicine.

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Effect of Obesity on Clinical Presentation and Response to Treatment in Asthma

Journal of Asthma ◽

10.1080/02770900600859123 ◽

2006 ◽

Vol 43 (7) ◽

pp. 553-558 ◽

Cited By ~ 96

Author(s):

Anne E. Dixon ◽

David M. Shade ◽

Rubin I. Cohen ◽

Gwen S. Skloot ◽

Janet T. Holbrook ◽

...

Keyword(s):

Clinical Presentation ◽

Response To Treatment

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Efficacy of local treatments in Prurigo Pigmentosa after Bariatric surgery

Journal of Clinical Research and Reports ◽

10.31579/2690-1919/141 ◽

2021 ◽

Vol 07 (02) ◽

pp. 01-03

Author(s):

Mezoun Almuhaimeed

Keyword(s):

Bariatric Surgery ◽

Clinical Presentation ◽

Response To Treatment ◽

Single Female ◽

Provisional Diagnosis ◽

Patient Response ◽

Medical City ◽

History Of ◽

Multivitamin Supplements

A 22-year-old single female presented to primary care Wazarat Health Center at Prince Sultan Military Medical City in Riyadh, with a 3 weeks history of itchy erythematous papules and vesicles and papulo-vesicles over the neck, chest, and upper back and face, which started 4 to 5 days after bariatric surgery. The patient on daily multivitamin supplements, vitamin D (50,000 IU, weekly / 2 months). The patient has lost 4kg since the operation, family history of atopy was positive regarding the mother physical examination shows erythematous papules and vesicles and papulo-vesicles over the neck with crust, chest, and upper back, Based on medical history and clinical presentation a provisional diagnosis was Prurigo Pigmentosa. The patient was prescribed topical mometasone furoate cream (BID for one week). Two -week follow-up showed improvement of the eruption. The course of the disease was shorter than usual in such cases the patient response to treatment was reactive to the topical mometasone without taking the oral minocyline, which major of such cases need in the late course of the disease The patient starts to improve within 2 weeks compared to others who need an average of 6 weeks to improve in such cases

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Eating disorders in biological males: clinical presentation and consideration of sex differences in a pediatric sample

Journal of Eating Disorders ◽

10.1186/s40337-018-0226-y ◽

2018 ◽

Vol 6 (1) ◽

Cited By ~ 3

Author(s):

Jennifer S. Coelho ◽

Tiffany Lee ◽

Priscilla Karnabi ◽

Alex Burns ◽

Sheila Marshall ◽

...

Keyword(s):

Eating Disorders ◽

Sex Differences ◽

Clinical Presentation

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P2245Sex differences in the in-vivo markers of platelet activation among patients with ischemic heart disease: insights from the EVA study

European Heart Journal ◽

10.1093/eurheartj/ehz748.0723 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

V Raparelli ◽

G F Romiti ◽

N Sperduti ◽

G F Santangelo ◽

M Vano ◽

...

Keyword(s):

Coronary Artery Disease ◽

Acute Coronary Syndrome ◽

Sex Differences ◽

Coronary Artery ◽

Coronary Stenosis ◽

Clinical Presentation ◽

Coronary Syndrome ◽

Chronic Angina ◽

Artery Disease

Abstract Background/Introduction Ischemic heart diseases (IHD) are not synonymous with obstructive flow-limiting coronary artery disease (CAD), especially in women. Platelet dysfunction is suggested as a potential mechanism favouring ischemia in non-obstructive CAD. However, it is unknown whether sex differences in platelet function of patients with non-obstructive CAD exist. Purpose We assessed for sex differences in in-vivo markers of platelet activation among patients with the acute coronary syndrome and chronic stable angina, with or without obstructive CAD Methods From the “Endocrine Vascular disease Approach” (EVA) study, we selected IHD patients undergoing urgent or elective coronary angiography with complete baseline clinical characteristics and angiographic data. Non-obstructive CAD was defined as the presence of coronary stenosis <50%. Thromboxane B2 (TxB2) and soluble P-selectin (sP-s) were measured at baseline. A sex-stratified analysis of platelet biomarkers was performed. Results Among two-hundred-seventy-seven patients (mean age 67±11, 37% women), non-obstructive CAD was documented in 25% of patients. Acute coronary syndrome (ACS) was the reason for angiography in 61% of cases. Women had more frequently ACS, as compared with men (54.8% vs 41.3%, p=0.001), with predominantly non-obstructive CAD. Median serum TxB2 (121.5 [92.7–174.0] vs 103.5 [83.0–140.2] pg/ml, p=0.005) and plasma sP-s (27.0 [18.7–35.0] vs 22.0 [16.0–30.0] ng/ml, p=0.006) levels were higher in patients with ACS as compared with the ones with stable chronic angina. The median concentration of TxB2 was significantly increased in women as compared with men, regardless of the clinical presentation and the coronary stenosis degree (all comparison, p<0.001). However, women with non-obstructive CAD were the group with the highest serum levels of TxB2 (140.0 [111.0–152.0] pg/ml). Sex differences in the plasma sP-s level were also observed among patients with stable chronic angina (women, 26 [20.0–34.0] vs men, 21 [16.6–27.7] ng/ml, p=0.002) and with non-obstructive CAD (women, 26 [20.5–34.5] vs men, 18.5 [16.6–26.0] ng/ml, p=0.003). Conclusion(s) Women with IHD and non-obstructive CAD had increased level of TxB2 and sP-s as compared with men, independently by the clinical presentation. Further investigations are warranted to verify the role of platelet hyperactivation in the pathogenesis of myocardial ischemia with non-obstructive coronary artery disease among women. Acknowledgement/Funding Scientific Independence of Young Researchers Program (RBSI14HNVT) - Ministry of Education, University and Research (MIUR)

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Microenvironmental variables need to effect intrinsic phenotypic parameters of cancer stem cells to affect tumourigenicity

10.7287/peerj.preprints.17v1 ◽

2013 ◽

Author(s):

Jacob G Scott ◽

Prakash Chinnaiyan ◽

Alexander ARA Anderson ◽

Anita Hjelmeland ◽

David Basanta

Keyword(s):

Stem Cell ◽

Therapeutic Strategy ◽

Tissue Growth ◽

Genetic Mutations ◽

Phenotypic Traits ◽

Cell Behaviour ◽

New Information ◽

Cancer Initiation ◽

Cancer Types ◽

Direct Feedback

Since the discovery of tumour initiating cells (TICs) in solid tumours, studies focussing on their role in cancer initiation and progression have abounded. The biological interrogation of these cells continues to yield volumes of information on their pro-tumourigenic behaviour, but actionable generalised conclusions have been scarce. Further, new information suggesting a dependence of tumour composition and growth on the microenvironment has yet to be studied theoretically. To address this point, we created a hybrid, discrete/continuous computational cellular automaton model of a generalised stem-cell driven tissue with a simple microenvironment. Using the model we explored the phenotypic traits inherent to the tumour initiating cells and the effect of the microenvironment on tissue growth. We identify the regions in phenotype parameter space where TICs are able to cause a disruption in homeostasis, leading to tissue overgrowth and tumour maintenance. As our parameters and model are non- specific, they could apply to any tissue TIC and do not assume specific genetic mutations. Targeting these phenotypic traits could represent a generalizable therapeutic strategy across cancer types. Further, we find that the microenvironmental variable does not strongly effect the outcomes, suggesting a need for direct feedback from the microenvironment onto stem-cell behaviour in future modelling endeavours.

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Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

10.1101/850453 ◽

2019 ◽

Cited By ~ 3

Author(s):

Harald Vöhringer ◽

Arne van Hoeck ◽

Edwin Cuppen ◽

Moritz Gerstung

Keyword(s):

Somatic Hypermutation ◽

Translesion Synthesis ◽

Strand Break ◽

Signature Analysis ◽

Transcription Start ◽

Mutational Signatures ◽

Transcription Start Sites ◽

Mutational Signature ◽

Cancer Genomes ◽

Cancer Types

AbstractMutational signature analysis is an essential part of the cancer genome analysis toolkit. Conventionally, mutational signature analysis extracts patterns of different mutation types across many cancer genomes. Here we present TensorSignatures, an algorithm to learn mutational signatures jointly across all variant categories and their genomic context. The analysis of 2,778 primary and 3,824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that practically all signatures operate dynamically in response to various genomic and epigenomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis, which is detected in 7 different cancer types. The analysis also unmasks replication- and double strand break repair-driven APOBEC mutagenesis, which manifests with differential numbers and length of mutation clusters indicating a differential processivity of the two triggers. As a fourth example, TensorSignatures detects a signature of somatic hypermutation generating highly clustered variants around the transcription start sites of active genes in lymphoid leukaemia, distinct from a more general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types.Key findingsSimultaneous inference of mutational signatures across mutation types and genomic features refines signature spectra and defines their genomic determinants.Analysis of 6,602 cancer genomes reveals pervasive intra-genomic variation of mutational processes.Distinct mutational signatures found in quiescent and active regions of the genome reveal differential repair and mutagenicity of UV- and tobacco-induced DNA damage.APOBEC mutagenesis produces two signatures reflecting highly clustered, double strand break repair-initiated and lowly clustered replication-driven mutagenesis, respectively.Somatic hypermutation in lymphoid cancers produces a strongly clustered mutational signature localised to transcription start sites, which is distinct from a weakly clustered translesion synthesis signature found in multiple tumour types.

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