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.

The landscape of somatic mutation in normal colorectal epithelial cells

2018 ◽  
Author(s):  
Henry Lee-Six ◽  
Peter Ellis ◽  
Robert J. Osborne ◽  
Mathijs A. Sanders ◽  
Luiza Moore ◽  
...  
Keyword(s):  
Normal Tissue ◽  
Somatic Mutations ◽  
Cell Lineage ◽  
Driver Mutations ◽  
Normal Cells ◽  
Genetic Changes ◽  
Adult Cell ◽  
Neoplastic Change ◽  
Cancer Types ◽  
Mutational Processes

AbstractThe colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions leading to cancer. As for most cancer types, however, understanding of the earliest phases of colorectal neoplastic change, which may occur in morphologically normal tissue, is comparatively limited because of the difficulty of detecting somatic mutations in normal cells. Each colorectal crypt is a small clone of cells derived from a single recently-existing stem cell. Here, we whole genome sequenced hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed, some ubiquitous and continuous, others only found in some individuals, in some crypts or during some phases of the cell lineage from zygote to adult cell. Likely driver mutations were present in ∼1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium.

Genomic features of primary and recurrent anal squamous cell carcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 556-556
Author(s):  
Jonathan W Pike ◽  
Kent William Mouw ◽  
Lior Zvi Braunstein ◽  
Neil E. Martin ◽  
Harvey J. Mamon ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Mutation Rate ◽  
Squamous Cell ◽  
Locally Advanced ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Anal Squamous Cell Carcinoma ◽  
Recurrent Tumors ◽  
Recurrent Mutations

556 Background: Approximately 7000 cases of anal squamous cell carcinoma (ASCC) are diagnosed annually in the US, and the incidence is increasing. Combination chemoradiotherapy (CRT) is the standard of care for locally-advanced ASCC, and the 5-year survival rate is approximately 70%. Unlike many other tumor types, no large-scale genomic studies have been reported for anal cancer. In order to characterize the mutational landscape of ASCC and identify potential therapeutic targets, we perform comprehensive genomic analysis of a pilot cohort of ASCC cases. Methods: We performed whole exome sequencing of tumor and matched germline DNA from a pilot cohort of twelve patients with locally advanced (Stage II-IVA) ASCC cases treated at Dana-Farber Cancer Institute. All patients received concurrent chemoradiotherapy (CRT): seven ‘responders’ had complete response and no evidence of recurrence with a minimum of one year follow-up, while five ‘non-responders’ had residual or recurrent disease following CRT. For non-responders, both primary and residual/recurrent tumors were analyzed. Results: The overall mutation rate was 3.7 mutations per megabase (Mb). Recurrent mutations in several known cancer genes were observed. Five of twelve cases had a hotspot mutation in FBXW7, including 3 of the 5 non-responders. Known oncogenic mutations were also observed in PIK3CA (3 tumors) and NFE2L2/KEAP1 (3 tumors). Analysis of paired primary and recurrent samples revealed surprising examples of distinct driver mutations in clonally-related tumors. Copy number analysis revealed focal amplifications of chromosome 3q. Conclusions: This study represents one of the first genome-scale analyses in ASCC. The overall mutation rate was similar to other HPV-associated squamous cell carcinomas, and recurrent mutations in several known cancer genes were observed. Analysis of paired primary and residual/recurrent tumors revealed surprising heterogeneity. To extend our findings, we are currently performing a similar analysis in a larger extension cohort of ASCC tumors.

scholarly journals EPCO-28. SPHEROID STUDY OF A GLIOBLASTOMA TUMOR IDENTIFIED A SUBCLONAL MUTATION OF EGFR T790M

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii75-ii75
Author(s):  
Shai Rosenberg ◽  
Eliana Steinberg ◽  
Adar Yaacov ◽  
Ranel Lutati ◽  
Anat Mordechai ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Ex Vivo ◽  
Resistance Mutation ◽  
Tumor Stroma ◽  
Growth Conditions ◽  
Driver Mutations ◽  
Cancer Genes ◽  
High Coverage ◽  
Parental Tumor ◽  
Egfr T790m

Abstract BACKGROUND Glioblastoma (GBM) is the most common and the most devastating primary brain cancer in adults. Precision genetic medicine approach does not provide benefit to majority of GBM patients. A major reason for this is tumor heterogeneity harboring potential resistance mechanisms. Here, we describe an approach to grow spheroids of GBM, containing tumor, stroma and vascular tissues. We show that this approach can identify undetected subclonal driver mutations that can potentially cause drug resistance later in the disease course. METHODS We grew spheroids of a GBM patient in a multi-well array and monitored them visually. Exome sequencing of the parental tumor (coverage of 557X) and of spheroids after 10 days (n=3) and 20 days (n=5) of growth was performed. In addition, we sequenced six spheroids that were grown for 10 days and treated by Temozolomide for the next 10 days. RESULTS 70 somatic mutations were detected in the parental tumor. 42/70 of the tumor’s somatic mutations were also detected in the spheroids. 192 somatic mutations were detected in the spheroids only and not in the parental tumor despite high coverage sequencing of the parental tumor. In cancer genes: six somatic mutations were identified in the parental tumor, 5/6 were also detected in the spheroids and 13 mutations were detected only in the spheroids. EGFR V774M mutation was detected in both tumor and spheroids. However – EGFR T790M was independently detected in 7/11 of the spheroids sequenced after 20 days or growth but not in the parental tumor. CONCLUSION Analysis of GBM spheroids enables detection of rare subclonal mutations not detected in parental tumor. We hypothesize that this is due to positive selection of the ex vivo growth conditions. This analysis enabled detection of EGFR T790M – an important targetable resistance mutation in lung cancer not previously described in primary GBM.

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 Whole-genome sequencing of follicular thyroid carcinomas reveal recurrent mutations in microRNA processing subunit DGCR8

2021 ◽  
Author(s):  
Johan O Paulsson ◽  
Nima Rafati ◽  
Sebastian DiLorenzo ◽  
Yi Chen ◽  
Felix Haglund ◽  
...  
Keyword(s):  
Copy Number ◽  
Somatic Mutations ◽  
Whole Genome ◽  
Cancer Genes ◽  
Copy Number Alterations ◽  
Thyroid Carcinomas ◽  
Future Studies ◽  
Recurrent Mutations ◽  
Microrna Processing ◽  
Widely Invasive

Abstract Background The genomic and transcriptomic landscape of widely invasive follicular thyroid carcinomas (wiFTCs) and Hürthle cell carcinoma (HCC) are poorly characterized and subsets of these tumors lack information on genetic driver events. The aim of this study was to bridge this gap. Methods We performed whole-genome and RNA sequencing and subsequent bioinformatic analyses of 11 wiFTCs and 2 HCCs with a particularly poor prognosis, and matched normal tissue. Results All wiFTCs exhibited one or several mutations in established thyroid cancer genes, including TERT (n=4), NRAS (n=3), HRAS, KRAS, AKT, PTEN, PIK3CA, MUTYH, TSHR and MEN1 (n=1 each). MutSig2CV analysis revealed recurrent somatic mutations in FAM72D (n=3, in two wiFTCs and in a single HCC), TP53 (n=3, in two wiFTCs and a single HCC) and EIF1AX (n=3), with DGCR8 (n=2) as borderline significant. The DGCR8 mutations were recurrent p.E518K missense alterations, known to cause familial multinodular goiter via disruption of microRNA processing. Expression analyses showed reduced DGCR8 mRNA expression in FTCs in general, and the two DGCR8 mutants displayed a distinct miRNA profile compared to DGCR8 wildtypes. Copy number analyses revealed recurrent gains on chromosomes 4, 6 and 10, and fusiongene analyses revealed 27 high-quality events. Both HCCs displayed hyperploidy, which was fairly unusual in the FTC cohort. Based on the transcriptome data tumors amassed in two principal clusters. Conclusion We describe the genomic and transcriptomic landscape in wiFTCs and HCCs and identify novel recurrent mutations and copy number alterations with possible driver properties and lay the foundation for future studies.

scholarly journals Molecular characterization of non-small cell lung cancer tumors in Latin American patients from Brazil, Chile and Peru uncovers novel potentially driver mutations

2020 ◽  
Author(s):  
Gonzalo Sepulveda ◽  
Alejandro Blanco ◽  
Matias Freire ◽  
Rodrigo Lizana ◽  
Javier Caceres-Molina ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Latin American ◽  
Somatic Mutations ◽  
Nsclc Patient ◽  
Driver Mutations ◽  
Cancer Genes ◽  
Genomic Databases ◽  
Dna And Rna ◽  
Nsclc Patients ◽  
First Time

Introduction Therapies that target activating Egfr, Alk, Ros1 and other mutations have become first-line treatments that improve NSCLC patient life expectancy. Latin-American patients are poorly represented in clinical trials and in genomic databases, thus little is known about the prevalence of actionable mutations in this population. This study characterizes, for the first time, the somatic mutations found in 52 actionable genes, and describe a novel set of potentially actionable mutations, in NSCLC patients from Chile, Brazil and Peru, while correlating these genomic occurrences with relevant clinical, demographic and pathology aspects. Methods 1732 subjects diagnosed with NSCLC were analyzed. DNA and RNA were sequenced using a 52 genes NGS panel. Mutations were annotated using the Variant Effect Predictor, COSMIC, OncoKB and the Cancer Genome Interpreter to categorize somatic mutations. Results We found a total of 1713 mutations with 626 (36.5%) novel, potentially driver mutations. 66.1% of these novel mutations were predicted as Tier 1 driver mutations. Actionable mutations for Ret and Alk were more prevalent in Brazil than in Chile, whereas Met exon-14 skipping was significantly enriched in Chile. In Peru, Egfr is higher while Kras is lower. A high number of novels potentially driver mutations in know NSCLC actionable genes, such as Alk, Erbb2, Ret, Met, and Ros1, was found. Conclusions The analysis of many Latin America subjects revealed a significant number of clinically actionable but also novel somatic mutations in cancer genes highlighting the importance of including less-represented populations in clinical trials and molecular studies.

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.

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 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.

scholarly journals Clonal status of actionable driver events and the timing of mutational processes in cancer evolution

2015 ◽  
Vol 7 (283) ◽  
pp. 283ra54-283ra54 ◽  
Author(s):  
Nicholas McGranahan ◽  
Francesco Favero ◽  
Elza C. de Bruin ◽  
Nicolai Juul Birkbak ◽  
Zoltan Szallasi ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Tumor Cells ◽  
Mitogen Activated Protein Kinase ◽  
Driver Mutations ◽  
Intratumor Heterogeneity ◽  
Tumor Evolution ◽  
Cancer Genes ◽  
Cancer Evolution ◽  
Signaling Axis ◽  
Mutational Processes

Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal “actionable” mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)–AKT–mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS–MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.

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