scholarly journals Iatrogenic endometriosis harbors somatic cancer-driver mutations

2018 ◽  
Vol 34 (1) ◽  
pp. 69-78 ◽  
Author(s):  
V Lac ◽  
L Verhoef ◽  
R Aguirre-Hernandez ◽  
T M Nazeran ◽  
B Tessier-Cloutier ◽  
...  
Keyword(s):  
Health Research ◽  
Somatic Mutations ◽  
Single Case ◽  
The Body ◽  
Patient Treatment ◽  
Driver Mutations ◽  
Deep Infiltrating Endometriosis ◽  
Ovarian Carcinomas ◽  
Archival Tissue ◽  
Cancer Driver

Abstract STUDY QUESTION Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? SUMMARY ANSWER We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways. WHAT IS KNOWN ALREADY Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations. STUDY DESIGN, SIZE, DURATION In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy. PARTICIPANTS/MATERIALS, SETTING, METHODS Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins. MAIN RESULTS AND THE ROLE OF CHANCE Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P > 0.05), KRAS activating mutations were more prevalent in DE. LIMITATIONS, REASONS FOR CAUTION Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established. WIDER IMPLICATIONS OF THE FINDINGS The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER Not applicable.

scholarly journals Nucleotide excision repair is impaired by binding of transcription factors to DNA

2015 ◽  
Author(s):  
Radhakrishnan Sabarinathan ◽  
Loris Mularoni ◽  
Jordi Deu-Pons ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Nucleotide Excision Repair ◽  
Mutation Rate ◽  
Binding Sites ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Replication Timing ◽  
Driver Mutations ◽  
Cancer Driver ◽  
Nucleotide Excision ◽  
Active Transcription

Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears in great variability across the genome due to chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally, such as DNA-binding proteins, are unknown. Here we demonstrate that the rate of somatic mutations in melanoma tumors is highly increased at active Transcription Factor binding sites (TFBS) and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Therefore, our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of mutations at their binding sites. This finding has important implications in our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.

scholarly journals No evidence that HLA genotype influences the driver mutations that occur in cancer patients

2021 ◽  
Author(s):  
Noor Kherreh ◽  
Siobhán Cleary ◽  
Cathal Seoighe
Keyword(s):  
Immune Responses ◽  
Somatic Mutations ◽  
Strong Relationship ◽  
Driver Mutations ◽  
Cell Surfaces ◽  
Cancer Driver ◽  
Mhc Molecules ◽  
Oncogenic Mutation ◽  
Hla Genotype ◽  
Mhc Alleles

AbstractThe major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumour. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

scholarly journals Why is cancer not more common? A changing microenvironment may help to explain why, and suggests strategies for anti-cancer therapy

2018 ◽  
Author(s):  
Xiaowei Jiang ◽  
Ian P.M. Tomlinson
Keyword(s):  
Cancer Cell ◽  
Cancer Biology ◽  
Treatment Strategies ◽  
Tumour Microenvironment ◽  
The Body ◽  
Driver Mutations ◽  
Cell Populations ◽  
Cancer Evolution ◽  
Cancer Driver ◽  
Anti Cancer

AbstractOne of the great unsolved puzzles in cancer biology is not why cancers occur, but rather, explaining why so few cancers occur compared with the theoretical number that could occur given the number of progenitor cells in the body and the normal mutation rate. We hypothesised that a contributory explanation is that the tumour microenvironment (TME) is not fixed, and that this could impair the ability of neoplastic cells to retain a high enough fitness to become a cancer. The TME has implicitly been assumed to be static in most cancer evolution models, and we therefore developed a mathematical model of spatial cancer evolution assuming that the TME, and thus the optimum cancer phenotype, change over time. Based on simulations, we show how cancer cell populations adapt to diverse changing TME conditions and fitness landscapes. Compared with static TMEs which generate neutral dynamics, changing TMEs lead to complex adaptations with spatio-temporal heterogeneity involving variable sub-clonal fitness, mixing, competition and phylogeny patterns. In many cases, cancer cell populations fail to grow or undergo spontaneous regression, and even extinction. Our analyses predict that cancer evolution in a changing TME is challenging, and can help to explain why cancer is neither inevitable nor as common as expected. Should cancer driver mutations with effects dependent of the TME exist, they are likely to be selected. Anti-cancer prevention and treatment strategies based on changing the TME are feasible and potentially effective.

scholarly journals Mutational likeliness and entropy help to identify driver mutations and their functional role in cancer

2018 ◽  
Author(s):  
Giorgio Mattiuz ◽  
Salvatore Di Giorgio ◽  
Lorenzo Tofani ◽  
Antonio Frandi ◽  
Francesco Donati ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Cancer Evolution ◽  
Loss Of Function ◽  
Driver Genes ◽  
Cancer Driver ◽  
Cancer Genomes ◽  
Passenger Mutations ◽  
Mutational Processes

AbstractAlterations in cancer genomes originate from mutational processes taking place throughout oncogenesis and cancer progression. We show that likeliness and entropy are two properties of somatic mutations crucial in cancer evolution, as cancer-driver mutations stand out, with respect to both of these properties, as being distinct from the bulk of passenger mutations. Our analysis can identify novel cancer driver genes and differentiate between gain and loss of function mutations.

CanDriS: posterior profiling of cancer-driving sites based on two-component evolutionary model

2021 ◽  
Author(s):  
Wenyi Zhao ◽  
Jingwen Yang ◽  
Jingcheng Wu ◽  
Guoxing Cai ◽  
Yao Zhang ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Cancer Genomics ◽  
Evolutionary Model ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Driver Mutations ◽  
Component Mixture ◽  
Cancer Driver ◽  
Two Component ◽  
Potential Cancer

Abstract Current cancer genomics databases have accumulated millions of somatic mutations that remain to be further explored. Due to the over-excess mutations unrelated to cancer, the great challenge is to identify somatic mutations that are cancer-driven. Under the notion that carcinogenesis is a form of somatic-cell evolution, we developed a two-component mixture model: while the ground component corresponds to passenger mutations, the rapidly evolving component corresponds to driver mutations. Then, we implemented an empirical Bayesian procedure to calculate the posterior probability of a site being cancer-driven. Based on these, we developed a software CanDriS (Cancer Driver Sites) to profile the potential cancer-driving sites for thousands of tumor samples from the Cancer Genome Atlas and International Cancer Genome Consortium across tumor types and pan-cancer level. As a result, we identified that approximately 1% of the sites have posterior probabilities larger than 0.90 and listed potential cancer-wide and cancer-specific driver mutations. By comprehensively profiling all potential cancer-driving sites, CanDriS greatly enhances our ability to refine our knowledge of the genetic basis of cancer and might guide clinical medication in the upcoming era of precision medicine. The results were displayed in a database CandrisDB (http://biopharm.zju.edu.cn/candrisdb/).

scholarly journals vcfView: An Extensible Data Visualization and Quality Assurance Platform for Integrated Somatic Variant Analysis

2020 ◽  
Vol 19 ◽  
pp. 117693512097237
Author(s):  
Brian O’Sullivan ◽  
Cathal Seoighe
Keyword(s):  
High Throughput ◽  
High Throughput Sequencing ◽  
Somatic Mutations ◽  
Driver Mutations ◽  
Sequencing Data ◽  
Data Set ◽  
Therapeutic Implications ◽  
Cancer Driver ◽  
Sequencing Errors ◽  
The Status

Motivation: Somatic mutations can have critical prognostic and therapeutic implications for cancer patients. Although targeted methods are often used to assay specific cancer driver mutations, high throughput sequencing is frequently applied to discover novel driver mutations and to determine the status of less-frequent driver mutations. The task of recovering somatic mutations from these data is nontrivial as somatic mutations must be distinguished from germline variants, sequencing errors, and other artefacts. Consequently, bioinformatics pipelines for recovery of somatic mutations from high throughput sequencing typically involve a large number of analytical choices in the form of quality filters. Results: We present vcfView, an interactive tool designed to support the evaluation of somatic mutation calls from cancer sequencing data. The tool takes as input a single variant call format (VCF) file and enables researchers to explore the impacts of analytical choices on the mutant allele frequency spectrum, on mutational signatures and on annotated somatic variants in genes of interest. It allows variants that have failed variant caller filters to be re-examined to improve sensitivity or guide the design of future experiments. It is extensible, allowing other algorithms to be incorporated easily. Availability: The shiny application can be downloaded from GitHub ( https://github.com/BrianOSullivanGit/vcfView ). All data processing is performed within R to ensure platform independence. The app has been tested on RStudio, version 1.1.456, with base R 3.6.2 and Shiny 1.4.0. A vignette based on a publicly available data set is also available on GitHub.

scholarly journals No evidence that HLA genotype influences the driver mutations that occur in cancer patients

2021 ◽  
Author(s):  
Noor Kherreh ◽  
Siobhán Cleary ◽  
Cathal Seoighe
Keyword(s):  
Immune Responses ◽  
Somatic Mutations ◽  
Strong Relationship ◽  
Driver Mutations ◽  
Cell Surfaces ◽  
Cancer Driver ◽  
Mhc Molecules ◽  
Oncogenic Mutation ◽  
Hla Genotype ◽  
Mhc Alleles

AbstractThe major histocompatibility (MHC) molecules are capable of presenting neoantigens resulting from somatic mutations on cell surfaces, potentially directing immune responses against cancer. This led to the hypothesis that cancer driver mutations may occur in gaps in the capacity to present neoantigens that are dependent on MHC genotype. If this is correct, it has important implications for understanding oncogenesis and may help to predict driver mutations based on genotype data. In support of this hypothesis, it has been reported that driver mutations that occur frequently tend to be poorly presented by common MHC alleles and that the capacity of a patient’s MHC alleles to present the resulting neoantigens is predictive of the driver mutations that are observed in their tumor. Here we show that these reports of a strong relationship between driver mutation occurrence and patient MHC alleles are a consequence of unjustified statistical assumptions. Our reanalysis of the data provides no evidence of an effect of MHC genotype on the oncogenic mutation landscape.

Fictions of the Human Right to Health: Writing Against the Postcolonial Exotic in Western Medicine

2018 ◽  
Author(s):  
Rosemary J. Jolly
Keyword(s):  
Health Research ◽  
Western Medicine ◽  
Scientific Method ◽  
Medical Humanities ◽  
Right To Health ◽  
The Body ◽  
Health And Wellness ◽  
Human Right ◽  
Cultural Specificity ◽  
The Social

The last decade has witnessed far greater attention to the social determinants of health in health research, but literary studies have yet to address, in a sustained way, how narratives addressing issues of health across postcolonial cultural divides depict the meeting – or non-meeting – of radically differing conceptualisations of wellness and disease. This chapter explores representations of illness in which Western narrators and notions of the body are juxtaposed with conceptualisations of health and wellness entirely foreign to them, embedded as the former are in assumptions about Cartesian duality and the superiority of scientific method – itself often conceived of as floating (mysteriously) free from its own processes of enculturation and their attendant limits. In this respect my work joins Volker Scheid’s, in this volume, in using the capacity of critical medical humanities to reassert the cultural specificity of what we have come to know as contemporary biomedicine, often assumed to be

scholarly journals Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

2013 ◽  
Vol 98 (2) ◽  
pp. E364-E369 ◽  
Author(s):  
Nishant Agrawal ◽  
Yuchen Jiao ◽  
Mark Sausen ◽  
Rebecca Leary ◽  
Chetan Bettegowda ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Somatic Mutations ◽  
Medullary Thyroid Cancer ◽  
Driver Mutations ◽  
High Confidence ◽  
Kras Mutations ◽  
Protein Coding ◽  
Medullary Thyroid ◽  
Oncogenic Mutations ◽  
Independent Cohort

Abstract Context: Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. Objective: To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. Patients and Design: We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. Results: We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. Conclusions: Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

scholarly journals Clonal approaches to understanding the impact of mutations on hematologic disease development

Blood ◽  
2019 ◽  
Vol 133 (13) ◽  
pp. 1436-1445 ◽  
Author(s):  
Jyoti Nangalia ◽  
Emily Mitchell ◽  
Anthony R. Green
Keyword(s):  
Somatic Mutations ◽  
Clonal Selection ◽  
Single Cells ◽  
Driver Mutations ◽  
Great Promise ◽  
Tumor Evolution ◽  
Disease Development ◽  
Hematopoietic Tissue ◽  
The Impact

Abstract Interrogation of hematopoietic tissue at the clonal level has a rich history spanning over 50 years, and has provided critical insights into both normal and malignant hematopoiesis. Characterization of chromosomes identified some of the first genetic links to cancer with the discovery of chromosomal translocations in association with many hematological neoplasms. The unique accessibility of hematopoietic tissue and the ability to clonally expand hematopoietic progenitors in vitro has provided fundamental insights into the cellular hierarchy of normal hematopoiesis, as well as the functional impact of driver mutations in disease. Transplantation assays in murine models have enabled cellular assessment of the functional consequences of somatic mutations in vivo. Most recently, next-generation sequencing–based assays have shown great promise in allowing multi-“omic” characterization of single cells. Here, we review how clonal approaches have advanced our understanding of disease development, focusing on the acquisition of somatic mutations, clonal selection, driver mutation cooperation, and tumor evolution.

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