scholarly journals Somatic mutant clones colonize the human esophagus with age

Science ◽  
2018 ◽  
Vol 362 (6417) ◽  
pp. 911-917 ◽  
Author(s):  
Iñigo Martincorena ◽  
Joanna C. Fowler ◽  
Agnieszka Wabik ◽  
Andrew R. J. Lawson ◽  
Federico Abascal ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Cancer Genes ◽  
Normal Tissues ◽  
Normal Esophagus ◽  
Human Esophagus ◽  
Age Range ◽  
Mutant Cells ◽  
Mutational Processes ◽  
Somatic Mutant ◽  
Selection Of

The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with NOTCH1 and TP53 mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of NOTCH1 mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.

scholarly journals Analysis of Mutations and Dysregulated Pathways Unravels Carcinogenic Effect and Clinical Actionability of Mutational Processes

2021 ◽  
Vol 9 ◽  
Author(s):  
Zedong Jiang ◽  
Gaoming Liao ◽  
Yiran Yang ◽  
Yujia Lan ◽  
Liwen Xu ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Strand Break ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Carcinogenic Effect ◽  
Cancer Subtypes ◽  
Recurrent Mutations ◽  
Clinical Benefits ◽  
Mutational Processes ◽  
Mutational Process

Somatic mutations accumulate over time in cancer cells as a consequence of mutational processes. However, the role of mutational processes in carcinogenesis remains poorly understood. Here, we infer the causal relationship between mutational processes and somatic mutations in 5,828 samples spanning 34 cancer subtypes. We found most mutational processes cause abundant recurrent mutations in cancer genes, while exceptionally ultraviolet exposure and altered activity of the error-prone polymerase bring a large number of recurrent non-driver mutations. Furthermore, some mutations are specifically induced by a certain mutational process, such as IDH1 p.R132H which is mainly caused by spontaneous deamination of 5-methylcytosine. At the pathway level, clock-like mutational processes extensively trigger mutations to dysregulate cancer signal transduction pathways. In addition, APOBEC mutational process destroys DNA double-strand break repair pathway, and bladder cancer patients with high APOBEC activity, though with homologous recombination proficient, show a significantly longer overall survival with platinum regimens. These findings help to understand how mutational processes act on the genome to promote carcinogenesis, and further, presents novel insights for cancer prevention and treatment, as our results showing, APOBEC mutagenesis and HRD synergistically contributed to the clinical benefits of platinum-based treatment.

scholarly journals Comprehensive analysis of clustered mutations in cancer reveals recurrent APOBEC3 mutagenesis of ecDNA

2021 ◽  
Author(s):  
Erik N Bergstrom ◽  
Jens-Christian Luebeck ◽  
Mia Petljak ◽  
Vineet Bafna ◽  
Paul S. Mischel ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Human Cancer ◽  
Cancer Genes ◽  
Base Substitutions ◽  
Cancer Genomes ◽  
Cancer Types ◽  
Mutational Processes ◽  
Comprehensive Characterization

Clustered somatic mutations are common in cancer genomes with prior analyses revealing several types of clustered single-base substitutions, including doublet- and multi-base substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. Here, we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome sequenced cancers from 30 cancer types. While only 3.7% of substitutions and 0.9% of indels were found to be clustered, they contributed 8.4% and 6.9% of substitution and indel drivers, respectively. Multiple distinct mutational processes gave rise to clustered indels including signatures enriched in tobacco smokers and homologous-recombination deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, while the majority of multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, previously attributed to the activity of APOBEC3 deaminases, accounted for a large proportion of clustered substitutions. However, only 16.2% of omikli matched APOBEC3 patterns with experimental validation confirming additional mutational processes giving rise to omikli. Kataegis was generated by multiple mutational processes with 76.1% of all kataegic events exhibiting AID/APOBEC3-associated mutational patterns. Co-occurrence of APOBEC3 kataegis and extrachromosomal-DNA (ecDNA) was observed in 31% of samples with ecDNA. Multiple distinct APOBEC3 kataegic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kataegic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fueling the evolution of ecDNA.

scholarly journals A body map of somatic mutagenesis in morphologically normal human tissues

2020 ◽  
Author(s):  
Ruoyan Li ◽  
Lin Di ◽  
Jie Li ◽  
Wenyi Fan ◽  
Yachen Liu ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Genomic Analysis ◽  
Driver Mutations ◽  
Human Tissues ◽  
Normal Tissues ◽  
Variable Extent ◽  
Normal Human ◽  
Body Map ◽  
Somatic Mutagenesis ◽  
Mutational Processes

AbstractSomatic mutations accumulated in normal tissues are associated with aging and disease. Here, we performed a comprehensive genomic analysis of 1,737 morphologically normal tissue biopsies (~ 600 cells each), mostly from the epithelia, of nine organs from five donors. We found that somatic mutation accumulations and clonal expansions are widespread, although with variable extent, in morphologically normal human tissues. Somatic copy number alterations were rarely detected, except for tissues from esophagus and cardia. Endogenous mutational processes like SBS1 and SBS5 are ubiquitous among normal tissues though exhibiting different relative activities. Exogenous mutational processes like SBS22 were found in different tissues from the same donor. We reconstructed the spatial somatic clonal architecture with sub-millimeter resolution. In epithelial tissues from esophagus and cardia, macroscopic somatic clones expanded to several millimeters were frequently seen, whereas in tissues from colon, rectum, and duodenum somatic clones were microscopic in size and evolved independently. Our study depicted a body map of somatic mutations and clonal expansions from the same individuals, and it revealed that the degree of somatic clonal expansion and enrichment of driver mutations are highly organ specific.

Comprehensive characteristics of somatic mutations in the normal tissues of patients with cancer and existence of somatic mutant clones linked to cancer development

2020 ◽  
pp. jmedgenet-2020-106905
Author(s):  
Ji-Hye Oh ◽  
Chang Ohk Sung
Keyword(s):  
Normal Tissue ◽  
Somatic Mutations ◽  
Normal Breast ◽  
Cancer Development ◽  
Sequencing Data ◽  
Normal Tissues ◽  
Oncogenic Pathways ◽  
Whole Exome Sequencing Data ◽  
Cancer Tissues ◽  
Somatic Mutant

BackgroundSomatic mutations are a major driver of cancer development and many have now been identified in various cancer types, but the comprehensive somatic mutation status of the normal tissues matched to tumours has not been revealed.MethodWe analysed the somatic mutations of whole exome sequencing data in 392 patient tumour and normal tissue pairs based on the corresponding blood samples across 10 tumour types.ResultsMany of the mutations involved in oncogenic pathways such as PI3K, NOTCH and TP53, were identified in the normal tissues. The ageing-related mutational signature was the most prominent contributing signature found and the mutations in the normal tissues were frequently in genes involved in late replication time (p<0.0001). Variants were rarely overlapping across tissue types but shared variants between normal and matched tumour tissue were present. These shared variants were frequently pathogenic when compared with non-shared variants (p=0.001) and showed a higher variant-allele-fraction (p<0.0001). Normal tissue-specific mutated genes were frequently non-cancer-associated (p=0.009). PIK3CA mutations were identified in 6 normal tissues and were harboured by all of the matched cancer tissues. Multiple types of PIK3CA mutations were found in normal breast and matched cancer tissues. The PIK3CA mutations exclusively present in normal tissue may indicate clonal expansions unrelated to the tumour. In addition, PIK3CA mutation was appeared that they arose before the occurrence of the allelic imbalance.ConclusionOur current results suggest that somatic mutant clones exist in normal tissues and that their clonal expansion could be linked to cancer development.

scholarly journals Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alyssa L. Kennedy ◽  
Kasiani C. Myers ◽  
James Bowman ◽  
Christopher J. Gibson ◽  
Nicholas D. Camarda ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Bone Marrow Failure ◽  
Subsequent Development ◽  
Genetic Constraints ◽  
Clonal Hematopoiesis ◽  
Clinical Surveillance ◽  
Clinical Consequences ◽  
Shwachman Diamond Syndrome ◽  
Mechanistic Basis ◽  
Selection Of

AbstractTo understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.

scholarly journals Self Esteem and General Well Being in Adolescents with Low vs High Emotional Competence

2017 ◽  
Vol 4 (4) ◽  
Author(s):  
Sarvdeep Kohli ◽  
Anjali Malik ◽  
Varsha Rani
Keyword(s):  
Emotional Competence ◽  
Sample Selection ◽  
Well Being ◽  
Self Esteem ◽  
The Self ◽  
Successful Development ◽  
Emotional Evaluation ◽  
Competence Scale ◽  
Age Range ◽  
Selection Of

An essential component of youths’ successful development is learning to appropriately respond to emotions, including the ability to recognize, identify and describe one’s feelings. Emotional competence refers to one’s ability to express or release one’s inner feelings or emotions. Self-esteem reflects a person’s overall subjective emotional evaluation of his or her own worth. It is a judgment of oneself as well as an attitude toward the self. General well being refers to the harmonious functioning of the physical as well as psychological aspects of the personality, giving satisfaction to the self and benefit to the society. The present study focuses on the self esteem and general well being in adolescents with low vs high emotional competence. For this purpose, first of all emotional competence scale was administered on 260 adolescents within the age range of 15-18 years, to identify the low emotionally competent and high emotionally competent adolescents. After the sample selection of 152 subjects (76 low emotionally competent and 76 high emotionally competent) Rosenberg’s Self-esteem scale and General well being scale were administered. Results indicate that high emotionally competent adolescents have high self-esteem and better general well being than low emotionally competent adolescents.

scholarly journals A Statistical Framework for Evolutionary Analysis of Recurrent Somatic Mutations in Cancers

2020 ◽  
Author(s):  
Xun Gu
Keyword(s):  
Somatic Mutations ◽  
Cancer Genomics ◽  
Computational Procedure ◽  
The Cancer Genome Atlas ◽  
Component Model ◽  
Evolutionary Analysis ◽  
Cancer Genes ◽  
Component Mixture ◽  
Two Component ◽  
Empirical Bayesian Method

AbstractCurrent cancer genomics databases have accumulated millions of somatic mutations that remain to be further explored, faciltating enormous high throuput analyses to explore the underlying mechanisms that may contribute to malignant initiation or progression. In the context of over-dominant passenger mutations (unrelated to cancers), the challenge is to identify somatic mutations that are cancer-driving. Under the notion that carcinogenesis is a form of somatic-cell evolution, we developed a two-component mixture model that enables to accomplish the following analyses. (i) We formulated a quasi-likelihood approach to test whether the two-component model is significantly better than a single-component model, which can be used for new cancer gene predicting. (ii) We implemented an empirical Bayesian method to calculate the posterior probabilities of a site to be cancer-driving for all sites of a gene, which can be used for new driving site predicting. (iii) We developed a computational procedure to calculate the somatic selection intensity at driver sites and passenger sites, respectively, as well as site-specific profiles for all sites. Using these newly-developed methods, we comprehensively analyzed 294 known cancer genes based on The Cancer Genome Atlas (TCGA) database.

scholarly journals Nutrição enteral em sistema fechado para pediatria: escolha com base na disponibilidade no comércio brasileiro e na rotulagem

2020 ◽  
Vol 35 (1) ◽  
pp. 70-76
Author(s):  
Anelise Pigatto Bissacotti ◽  
Franceliane Jobim Benedetti
Keyword(s):  
Enteral Nutrition ◽  
Closed System ◽  
Clinical Situation ◽  
Nutritional Composition ◽  
Enteral Diet ◽  
Pediatric Nutrition ◽  
Age Range ◽  
Selection Of ◽  
Better Than

Introduction: The enteral diet (ED) for pediatric nutrition should ensure the appropriate nutritional intake for the child and/or adolescent. Therefore, during the selection of ED, in addition to the patient’s needs, the characteristics and nutritional composition of the patients should be taken into account. Thus, the objective was to identify and characterize the diets for pediatric enteral nutrition, in a closed system, currently available in the Brazilian market, in order to assist nutritionists and doctors in prescription. Methods: The descriptive and documental research consisted in the identification of the diets for pediatric enteral nutrition, in a closed system, currently available in the Brazilian market and characterization of the diets, based on labeling data. The data of interest for the development of this study were collected in catalogs and official websites of the manufacturers and suppliers and books of enteral nutrition and nutrition in pediatrics. Results: In Brazil, nine pediatric enteral nutrition diets are available in a closed system, marketed by three manufacturers. It was found that the diets for pediatric enteral nutrition can be indicated for a wide age range, from one to 10 years and patients in different pathophysiological states. There is little variation in the levels and sources of macronutrients. Four enteral diets present fibers in their composition and 5 are hypotonic. Conclusions: The Brazilian market has a limited number of diets for pediatric enteral nutrition in a closed system, which makes prescribing a challenge for nutritionists and doctors. It can not be said that a particular pediatric enteral diet in closed system is better than another, each one has specific characteristics. This makes it necessary for to carefully evaluate the professionals adequacy of the diet to the patient’s clinical situation and individuality.

scholarly journals Discovering the drivers of clonal hematopoiesis

2020 ◽  
Author(s):  
Oriol Pich ◽  
Iker Reyes-Salazar ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Positive Selection ◽  
Molecular Mechanisms ◽  
Somatic Mutations ◽  
Cancer Genomics ◽  
Variant Calling ◽  
Selective Advantage ◽  
Cancer Genes ◽  
Driver Genes ◽  
Hematopoietic Stem ◽  
Clonal Hematopoiesis

AbstractMutations in genes that confer a selective advantage to hematopoietic stem cells (HSCs) in certain conditions drive clonal hematopoiesis (CH). While some CH drivers have been identified experimentally or through epidemiological studies, the compendium of all genes able to drive CH upon mutations in HSCs is far from complete. We propose that identifying signals of positive selection in blood somatic mutations may be an effective way to identify CH driver genes, similarly as done to identify cancer genes. Using a reverse somatic variant calling approach, we repurposed whole-genome and whole-exome blood/tumor paired samples of more than 12,000 donors from two large cancer genomics cohorts to identify blood somatic mutations. The application of IntOGen, a robust driver discovery pipeline, to blood somatic mutations across both cohorts, and more than 24,000 targeted sequenced samples yielded a list of close to 70 genes with signals of positive selection in CH, available at http://www.intogen.org/ch. This approach recovers all known CH genes, and discovers novel candidates. Generating this compendium is an essential step to understand the molecular mechanisms of CH and to accurately detect individuals with CH to ascertain their risk to develop related diseases.

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