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 deepBase v3.0: expression atlas and interactive analysis of ncRNAs from thousands of deep-sequencing data

2020 ◽  
Vol 49 (D1) ◽  
pp. D877-D883
Author(s):  
Fangzhou Xie ◽  
Shurong Liu ◽  
Junhao Wang ◽  
Jiajia Xuan ◽  
Xiaoqin Zhang ◽  
...  
Keyword(s):  
High Throughput Sequencing ◽  
Clinical Information ◽  
Sequencing Data ◽  
Normal Tissues ◽  
Interactive Analysis ◽  
High Throughput Sequencing Data ◽  
Expression Atlas ◽  
Expression Evolution ◽  
Noninvasive Biomarkers ◽  
Cancer Tissues

Abstract Eukaryotic genomes encode thousands of small and large non-coding RNAs (ncRNAs). However, the expression, functions and evolution of these ncRNAs are still largely unknown. In this study, we have updated deepBase to version 3.0 (deepBase v3.0, http://rna.sysu.edu.cn/deepbase3/index.html), an increasingly popular and openly licensed resource that facilitates integrative and interactive display and analysis of the expression, evolution, and functions of various ncRNAs by deeply mining thousands of high-throughput sequencing data from tissue, tumor and exosome samples. We updated deepBase v3.0 to provide the most comprehensive expression atlas of small RNAs and lncRNAs by integrating ∼67 620 data from 80 normal tissues and ∼50 cancer tissues. The extracellular patterns of various ncRNAs were profiled to explore their applications for discovery of noninvasive biomarkers. Moreover, we constructed survival maps of tRNA-derived RNA Fragments (tRFs), miRNAs, snoRNAs and lncRNAs by analyzing &gt;45 000 cancer sample data and corresponding clinical information. We also developed interactive webs to analyze the differential expression and biological functions of various ncRNAs in ∼50 types of cancers. This update is expected to provide a variety of new modules and graphic visualizations to facilitate analyses and explorations of the functions and mechanisms of various types of ncRNAs.

scholarly journals Neoantigens Derived from Recurrently Mutated Genes as Potential Immunotherapy Targets for Gastric Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Zhou ◽  
Wenyi Zhao ◽  
Jingcheng Wu ◽  
Jun Lu ◽  
Yongfeng Ding ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
T Cell ◽  
Somatic Mutations ◽  
Excision Repair ◽  
Sequencing Data ◽  
Driver Genes ◽  
Cell Immunotherapy ◽  
Whole Exome ◽  
Whole Exome Sequencing Data ◽  
Gastric Cancer Patients

Neoantigens are optimal tumor-specific targets for T-cell based immunotherapy, especially for patients with “undruggable” mutated driver genes. T-cell immunotherapy can be a “universal” treatment for HLA genotype patients sharing same oncogenic mutations. To identify potential neoantigens for therapy in gastric cancer, 32 gastric cancer patients were enrolled in our study. Whole exome sequencing data from these patients was processed by TSNAD software to detect cancer somatic mutations and predict neoantigens. The somatic mutations between different patients suggested a high interpatient heterogeneity. C>A and C>T substitutions are common, suggesting an active nucleotide excision repair. The number of predicted neoantigens was significantly higher in patients at stage T1a compared to in patients at T2 or T4b. Six genes (PIK3CA, FAT4, BRCA2, GNAQ, LRP1B, and PREX2) were found as recurrently mutated driver genes in our study. Combining with highly frequent HLA alleles, several neoantigens derived from six recurrently mutated genes were considered as potential targets for further immunotherapy.

Whole-Exome Sequencing Data – Identifying Somatic Mutations

2014 ◽  
pp. 419-427
Author(s):  
Roberta Spinelli ◽  
Rocco Piazza ◽  
Alessandra Pirola ◽  
Simona Valletta ◽  
Roberta Rostagno ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Somatic Mutations ◽  
Sequencing Data ◽  
Exome Sequencing Data ◽  
Whole Exome ◽  
Whole Exome Sequencing Data

scholarly journals Epigenetic field cancerization in breast cancer using subject-matched tumor, ipsilateral-normal, and contralateral-normal tissues

2019 ◽  
Author(s):  
Meghan E. Muse ◽  
Alexander J. Titus ◽  
Lucas A. Salas ◽  
Owen M. Wilkins ◽  
Chelsey Mullen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Breast Tumor ◽  
Normal Tissue ◽  
Tumor Tissue ◽  
Cpg Islands ◽  
Normal Breast ◽  
Field Cancerization ◽  
Breast Carcinogenesis ◽  
Normal Tissues

AbstractBackgroundEmerging work has demonstrated that histologically normal (non-tumor) tissue adjacent to breast tumor tissue shows evidence of molecular alterations related to tumorigenesis, referred to as field cancerization effects. Although changes in DNA methylation are known to occur early in breast carcinogenesis and the landscape of breast tumor DNA methylation is profoundly altered compared with normal tissue, there have been limited efforts to identify DNA methylation field cancerization effects in histologically normal breast tissue adjacent to tumor.MethodsMatched tumor, histologically normal tissue of the ipsilateral breast (ipsilateral-normal), and histologically normal tissue of the contralateral breast (contralateral-normal) were obtained from nine women undergoing bilateral mastectomy. Laser capture microdissection was used to select breast epithelial cells from normal tissues, and neoplastic cells from tumor specimens for genome-scale measures of DNA methylation with the Illumina HumanMethylationEPIC array.ResultsWe identified substantially more CpG loci that were differentially methylated between contralateral-normal breast and tumor tissue (63,271 CpG loci q < 0.01), than between ipsilateral-normal tissue and tumor (38,346 CpG loci q < 0.01). In addition, we identified differential methylation in ipsilateral-normal relative to contralateral-normal tissue (9,562 CpG loci p < 0.01). Hypomethylated loci in ipsilateral normal relative to contralateral were significantly enriched for breast cancer-relevant transcription factor binding sites including those for ESR1, FoxA1, and GATA3. Hypermethylated loci in ipsilateral-normal relative to contralateral-normal tissue were significantly enriched for CpG island shore regions.ConclusionsOur results indicate that early hypermethylation events in breast carcinogenesis are more likely to occur in the regions immediately surrounding CpG islands than CpG islands per se, reflecting a field effect of the tumor on surrounding histologically normal tissue. This work offers an opportunity to focus investigations of early DNA methylation alterations in breast carcinogenesis and potentially develop epigenetic biomarkers of disease risk.

scholarly journals The Cancer Epitope Trees of 23 Early Cervical Cancers in Chinese Women

2016 ◽  
Author(s):  
Xia Li ◽  
Hailiang Huang ◽  
Yanfang Guang ◽  
Yuhua Gong ◽  
Chen-Yi He ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Chinese Women ◽  
Therapeutic Targets ◽  
Sequencing Data ◽  
Phylogenic Tree ◽  
Histocompatibility Complex ◽  
Whole Exome ◽  
The Hierarchical Structure ◽  
Whole Exome Sequencing Data ◽  
Cervical Tumors

Emerging evidences suggest the heterogeneity of cancers limits the efficacy of immunotherapy. To search for optimal therapeutic targets, we used whole-exome sequencing data from 23 early cervical tumors from Chinese women to investigate the hierarchical structure of the somatic mutations and the predicted neo-epitopes based on their strong binding with major histocompatibility complex class I molecules. We found each tumor carried 117 mutations and 61 neo-epitopes in average and displayed a unique phylogenic tree and "cancer neo-epitope tree" comprising different compositions of mutations or neo-epitopes. Conceivably, the neo-epitopes at the top of the tree shared by all cancer cells are the optimal therapeutic targets that might lead to a cure. Human papillomavirus can be used as therapeutic target in only a proportion of cases where the integrated genome exits without active infection. Therefore, the "cancer neo-epitope tree" will serve as an important source to determine of the optimal immunotherapeutic target.

scholarly journals Meta-analysis of the clinicopathological significance of miRNA-145 in breast cancer

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Peng Lv ◽  
Zhenzhu Zhang ◽  
Li Hou ◽  
Yayue Zhang ◽  
Lingeng Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Patients ◽  
Human Cancer ◽  
Meta Analysis ◽  
Normal Breast ◽  
Breast Cancer Patients ◽  
Normal Tissues ◽  
Cancer Tissues ◽  
Low Expression

Abstract Low expression of tumor suppressor microRNA (miRNA) and high expression of carcinogenic miRNA promote the occurrence and progression of human cancer. Most studies show that miR-145 is a tumor suppressor miRNA, and is closely related to the clinicopathology of breast cancer. However, the results are still inconsistent. Therefore, we conducted a meta-analysis on the basis of eligible studies to summarize the possible correlation between miR-145 and the clinicopathology and prognosis of breast cancer. Using PubMed, Embase, Web of Science, Wanfang and CNKI, we searched all published papers written in either English or Chinese on miR-145 expression in breast cancer from 1990 to November 2019 for meta-analysis. We used standardized mean difference (SMD) to evaluate the differential expression of miR-145 in breast cancer tissues and adjacent normal tissues or normal breast tissues. We found that miR-145 expression was significantly lower in breast cancer tissues than that in adjacent normal tissues (SMD = −2.93, P&lt;0.0001) and in healthy women (SMD = −0.52, P=0.009). miR-145 expression was lower in breast cancer patients with ER-positive (SMD = 0.65, P&lt;0.001), HER-2-positive (SMD = −1.04, P&lt;0.001), compared with their counterparts, respectively. In addition, breast cancer patients with low expression of miR-145 had larger tumor diameters (SMD = −1.97, P&lt;0.001) and lymph node metastasis (SMD = −1.75, P&lt;0.001) that are unfavorable prognostic factors. Conclusion: Low miR-145 is observed in breast cancer, which is closely related to molecular subtypes and unfavorable factors of breast cancer. These findings indicate that miR-145 is tumor suppressor miRNA, and may be a potential diagnostic and prognostic marker in breast cancer.

scholarly journals A Comprehensive Survey of Genomic Alterations in Gastric Cancer Reveals Recurrent Neoantigens as Potential Therapeutic Targets

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Chao Chen ◽  
Qiming Zhou ◽  
Riping Wu ◽  
Bo Li ◽  
Qiang Chen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Somatic Mutations ◽  
Sequencing Data ◽  
Cell Based Therapy ◽  
Public Resource ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Whole Exome Sequencing Data ◽  
Comprehensive Survey ◽  
Cancer Types

Immunotherapy directed against cancer-specific neoantigens derived from non-silent mutants is a promising individualized strategy for cancer treatment. Neoantigens shared across patients could be used as a public resource for developing T cell-based therapy. To identify potential public neoantigens for therapy in gastric cancer (GC), 74 GC patients were enrolled in this study. Combined with the TCGA cohort and other published studies, whole exome sequencing data from 942 GC patients were used to detect somatic mutations and predict neoantigens shared by GC patients. The mutations pattern between our study and the TCGA cohort is comparable, and C > T is the most common substitution. The number of neoantigens was significantly higher in older patients (age ≥60) compared to younger patients (age <60), both in this study and the TCGA cohort. Recurrent neoantigens were found in eight genes (TP53, PIK3CA, PGM5, ERBB3, C6, TRIM49C, OR4C16, and KRAS) in this study. The neoantigen-associated mutations PIK3CA (p.H1047R) and TP53 (p.R175H) are common across several cancer types, indicating their potential usage. Overall, our study illustrates a comprehensive genomic landscape of GC and provides the recurrent neoantigens to facilitate further immunotherapy.

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 Systematic transcriptome analysis reveals tumor-specific isoforms for ovarian cancer diagnosis and therapy

2015 ◽  
Vol 112 (23) ◽  
pp. E3050-E3057 ◽  
Author(s):  
Christian L. Barrett ◽  
Christopher DeBoever ◽  
Kristen Jepsen ◽  
Cheryl C. Saenz ◽  
Dennis A. Carson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Normal Tissue ◽  
Cell Cancer ◽  
Tissue Expression ◽  
Amino Acid Sequences ◽  
Rna Seq ◽  
Sequencing Data ◽  
Mrna Isoforms ◽  
Specific Expression ◽  
Normal Tissues

Tumor-specific molecules are needed across diverse areas of oncology for use in early detection, diagnosis, prognosis and therapy. Large and growing public databases of transcriptome sequencing data (RNA-seq) derived from tumors and normal tissues hold the potential of yielding tumor-specific molecules, but because the data are new they have not been fully explored for this purpose. We have developed custom bioinformatic algorithms and used them with 296 high-grade serous ovarian (HGS-OvCa) tumor and 1,839 normal RNA-seq datasets to identify mRNA isoforms with tumor-specific expression. We rank prioritized isoforms by likelihood of being expressed in HGS-OvCa tumors and not in normal tissues and analyzed 671 top-ranked isoforms by high-throughput RT-qPCR. Six of these isoforms were expressed in a majority of the 12 tumors examined but not in 18 normal tissues. An additional 11 were expressed in most tumors and only one normal tissue, which in most cases was fallopian or colon. Of the 671 isoforms, the topmost 5% (n = 33) ranked based on having tumor-specific or highly restricted normal tissue expression by RT-qPCR analysis are enriched for oncogenic, stem cell/cancer stem cell, and early development loci—including ETV4, FOXM1, LSR, CD9, RAB11FIP4, and FGFRL1. Many of the 33 isoforms are predicted to encode proteins with unique amino acid sequences, which would allow them to be specifically targeted for one or more therapeutic strategies—including monoclonal antibodies and T-cell–based vaccines. The systematic process described herein is readily and rapidly applicable to the more than 30 additional tumor types for which sufficient amounts of RNA-seq already exist.

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