scholarly journals The Genomic Landscape of Serrated Lesion of the Colorectum: Similarities and Differences With Tubular and Tubulovillous Adenomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Luigi Tornillo ◽  
Frank Serge Lehmann ◽  
Andrea Garofoli ◽  
Viola Paradiso ◽  
Charlotte K. Y. Ng ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Bioinformatic Analysis ◽  
Genetic Alterations ◽  
University Hospital ◽  
Library Preparation ◽  
Loss Of Function ◽  
Driver Genes ◽  
Cancer Driver ◽  
Genomic Landscape ◽  
Serrated Lesions

Serrated lesions of the colorectum are the precursors of 15–30% of colorectal cancers (CRCs). These lesions have a peculiar morphological appearance, and they are more difficult to detect than conventional adenomatous polyps. In this study, we sought to define the genomic landscape of these lesions using high-depth targeted sequencing. Eight sessile serrated lesions without dysplasia (SSL), three sessile serrated lesions with dysplasia (SSL/D), two traditional serrated adenomas (TSA), and three tubular adenomas (TA) were retrieved from the files of the Institute of Pathology of the University Hospital Basel and from the GILAB AG, Allschwil, Switzerland. Samples were microdissected together with the matched normal counterpart, and DNA was extracted for library preparation. Library preparation was performed using the Oncomine Comprehensive Assay targeting 161 common cancer driver genes. Somatic genetic alterations were defined using state-of-the-art bioinformatic analysis. Most SSLs, as well as all SSL/Ds and TSAs, showed the classical BRAF p.V600E mutation. The BRAF-mutant TSAs showed additional alterations in CTNNB1, NF1, TP53, NRAS, PIK3CA, while TA showed a consistently different profile, with mutations in ARID1A (two cases), SMAD4, CDK12, ERBB3, and KRAS. In conclusion, our results provide evidence that SSL/D and TSA are similar in somatic mutations with the BRAF hotspot somatic mutation as a major driver of the disease. On the other hand, TAs show a different constellation of somatic mutations such as ARID1A loss of function.

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 Non-coding mutations reveal cancer driver cistromes in luminal breast cancer

2021 ◽  
Author(s):  
Samah El Ghamrasni ◽  
Rene Quevedo ◽  
James R Hawley ◽  
Parisa Mazrooei ◽  
Youstina Hanna ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factors ◽  
Somatic Mutations ◽  
Breast Tumors ◽  
Regulatory Elements ◽  
Luminal Breast Cancer ◽  
Breast Cancers ◽  
Driver Genes ◽  
Cancer Driver ◽  
Personalized Cancer

Whole-genome sequencing of primary breast tumors enabled the identification of cancer driver genes and non-coding cancer driver plexuses from somatic mutations. However, differentiating driver and passenger events among non-coding genetic variants remains a challenge to understand the etiology of cancer and inform the delivery of personalized cancer medicine. Herein, we reveal an enrichment of non-coding mutations in cis-regulatory elements that cover a subset of transcription factors linked to tumor progression in luminal breast cancers. Using a cohort of 26 primary luminal ER+PR+ breast tumors, we compiled a catalogue of ~100,000 unique cis-regulatory elements from ATACseq data. Integrating this catalogue with somatic mutations from 350 publicly available breast tumor whole genomes, we identified four recurrently mutated individual cis-regulatory elements. By then partitioning the non-coding genome into cistromes, defined as the sum of binding sites for a transcription factor, we uncovered cancer driver cistromes for ten transcription factors in luminal breast cancer, namely CTCF, ELF1, ESR1, FOSL2, FOXA1, FOXM1 GATA3, JUND, TFAP2A, and TFAP2C in luminal breast cancer. Nine of these ten transcription factors were shown to be essential for growth in breast cancer, with four exclusive to the luminal subtype. Collectively, we present a strategy to find cancer driver cistromes relying on quantifying the enrichment of non-coding mutations over cis-regulatory elements concatenated into a functional unit drawn from an accessible chromatin catalogue derived from primary cancer tissues.

IDENTIFY CANCER DRIVER GENES THROUGH SHARED MENDELIAN DISEASE PATHOGENIC VARIANTS AND CANCER SOMATIC MUTATIONS

2016 ◽  
Author(s):  
MENG MA ◽  
CHANGCHANG WANG ◽  
BENJAMIN S. GLICKSBERG ◽  
ERIC E. SCHADT ◽  
SHUYU D. LI ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Mendelian Disease ◽  
Driver Genes ◽  
Cancer Driver ◽  
Pathogenic Variants ◽  
Cancer Driver Genes

scholarly journals DORGE: Discovery of Oncogenes and tumoR suppressor genes using Genetic and Epigenetic features

2020 ◽  
Vol 6 (46) ◽  
pp. eaba6784
Author(s):  
Jie Lyu ◽  
Jingyi Jessica Li ◽  
Jianzhong Su ◽  
Fanglue Peng ◽  
Yiling Elaine Chen ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Gene Networks ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Driver Genes ◽  
Suppressor Genes ◽  
Cancer Driver ◽  
Dual Functional ◽  
Cancer Driver Genes

Data-driven discovery of cancer driver genes, including tumor suppressor genes (TSGs) and oncogenes (OGs), is imperative for cancer prevention, diagnosis, and treatment. Although epigenetic alterations are important for tumor initiation and progression, most known driver genes were identified based on genetic alterations alone. Here, we developed an algorithm, DORGE (Discovery of Oncogenes and tumor suppressoR genes using Genetic and Epigenetic features), to identify TSGs and OGs by integrating comprehensive genetic and epigenetic data. DORGE identified histone modifications as strong predictors for TSGs, and it found missense mutations, super enhancers, and methylation differences as strong predictors for OGs. We extensively validated DORGE-predicted cancer driver genes using independent functional genomics data. We also found that DORGE-predicted dual-functional genes (both TSGs and OGs) are enriched at hubs in protein-protein interaction and drug-gene networks. Overall, our study has deepened the understanding of epigenetic mechanisms in tumorigenesis and revealed previously undetected cancer driver genes.

scholarly journals OncodriveROLE classifies cancer driver genes in loss of function and activating mode of action

2014 ◽  
Vol 30 (17) ◽  
pp. i549-i555 ◽  
Author(s):  
Michael P. Schroeder ◽  
Carlota Rubio-Perez ◽  
David Tamborero ◽  
Abel Gonzalez-Perez ◽  
Nuria Lopez-Bigas
Keyword(s):  
Mode Of Action ◽  
Loss Of Function ◽  
Driver Genes ◽  
Cancer Driver ◽  
Cancer Driver Genes

scholarly journals Genomic Instability Profiles at the Single Cell Level in Mouse Colorectal Cancers of Defined Genotypes

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1267
Author(s):  
Vasilis S. Dionellis ◽  
Maxim Norkin ◽  
Angeliki Karamichali ◽  
Giacomo G. Rossetti ◽  
Joerg Huelsken ◽  
...  
Keyword(s):  
Genomic Instability ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Single Cells ◽  
Genetic Alterations ◽  
Nucleotide Substitutions ◽  
Driver Genes ◽  
Normal Cells ◽  
Cancer Driver ◽  
Intratumoural Heterogeneity

The genomes of many human CRCs have been sequenced, revealing a large number of genetic alterations. However, the molecular mechanisms underlying the accumulation of these alterations are still being debated. In this study, we examined colorectal tumours that developed in mice with Apclox/lox, LSL-KrasG12D, and Tp53lox/lox targetable alleles. Organoids were derived from single cells and the spectrum of mutations was determined by exome sequencing. The number of single nucleotide substitutions (SNSs) correlated with the age of the tumour, but was unaffected by the number of targeted cancer-driver genes. Thus, tumours that expressed mutant Apc, Kras, and Tp53 alleles had as many SNSs as tumours that expressed only mutant Apc. In contrast, the presence of large-scale (>10 Mb) copy number alterations (CNAs) correlated strongly with Tp53 inactivation. Comparison of the SNSs and CNAs present in organoids derived from the same tumour revealed intratumoural heterogeneity consistent with genomic lesions accumulating at significantly higher rates in tumour cells compared to normal cells. The rate of acquisition of SNSs increased from the early stages of cancer development, whereas large-scale CNAs accumulated later, after Tp53 inactivation. Thus, a significant fraction of the genomic instability present in cancer cells cannot be explained by aging processes occurring in normal cells before oncogenic transformation.

scholarly journals Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

2020 ◽  
Author(s):  
Alexander N. Gorelick ◽  
Minsoo Kim ◽  
Walid K. Chatila ◽  
Konnor La ◽  
A. Ari Hakimi ◽  
...  
Keyword(s):  
Mitochondrial Genome ◽  
Atp Synthesis ◽  
Loss Of Function ◽  
Sequencing Data ◽  
Mtdna Mutation ◽  
Driver Genes ◽  
Cancer Driver ◽  
Translational Machinery ◽  
Synonymous Mutations ◽  
Mtdna Mutations

AbstractMitochondrial DNA (mtDNA) encodes essential protein subunits and translational machinery for four distinct complexes of oxidative phosphorylation (OXPHOS). Using repurposed whole-exome sequencing data, we demonstrate that pathogenic mtDNA mutations arise in tumors at a rate comparable to the most common cancer driver genes. We identify OXPHOS complexes as critical determinants shaping somatic mtDNA mutation patterns across tumor lineages. Loss-of-function mutations accumulate at an elevated rate specifically in Complex I, and often arise at specific homopolymeric hotspots. In contrast, Complex V is depleted of all non-synonymous mutations, suggesting that mutations directly impacting ATP synthesis are under negative selection. Both common truncating mutations and rarer missense alleles are associated with a pan-lineage transcriptional program, even in cancer types where mtDNA mutations are comparatively rare. Pathogenic mutations of mtDNA are associated with substantial increases in overall survival of colorectal adenocarcinoma patients, demonstrating a clear functional relationship between genotype and phenotype. The mitochondrial genome is therefore frequently and functionally disrupted across many cancers, with significant implications for patient stratification, prognosis and therapeutic development.

Somatic mutations in triple-negative breast carcinoma and high-grade serous ovarian carcinoma from young women.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12561-e12561
Author(s):  
Pedro Adolpho MP Serio ◽  
Glaucia Fernanda Lima Pereira ◽  
Maria Lucia Hirata Katayama ◽  
Simone Maistro ◽  
Rossana Veronica Mendoza Lopez ◽  
...  
Keyword(s):  
Ovarian Carcinoma ◽  
Somatic Mutations ◽  
Triple Negative ◽  
Young Patients ◽  
High Grade ◽  
Cancer Gene ◽  
Sequencing Data ◽  
Driver Genes ◽  
Cancer Driver ◽  
Serous Ovarian Carcinoma

e12561 Background: High grade serous ovarian carcinoma (HGSOvCa) and triple negative breast cancer (TNBC) share characteristics, such as poor prognosis, BRCA1 germline mutations and TP53 somatic mutations. Our aim was to analyze somatic mutations from HGS-OvCa and TNBC from young patients aged ≤ 40 years. Methods: Whole genome or exome sequencing data for TNBC (n = 83) or HGS-OvCa (n = 21) was recovered from COSMIC or cBioPortal. Data was searched for cancer driver genes catalogued in Cancer Gene Census (CGC) or Candidate Cancer Gene Database rank A or B (CCGD) and for DNA repair genes. Results: TNBC mainly consisted of ductal carcinomas (78/83). A median of two cancer causing genes was affected in both TNBC and HGS-OvCa and TP53 was mutated in at least 2/3 of the samples. Only 7/83 and 2/19 of TNBC and HGS-OvCa samples, respectively, did not present variants in known cancer causing genes. C > T substitutions were the most frequent events in both TNBC and HGS-OvCa, however transversions were more frequently detected in TNBC. Besides TP53, another 33 genes were mutated in both tumor types, including PIK3CA, RYR2, TARBP1, CSMD3, DNAH11, MYO3A, NF1, TNRC6A, CACNA1E, HCMN1, PRKDC. Conclusions: Although many similarities were detected, TNBC in young patients presents a higher number of transversions and almost 25% of HGSOvCa present somatic mutations in HR genes. [Table: see text]

scholarly journals Epithelial Cells of Deep Infiltrating Endometriosis Harbor Mutations in Cancer Driver Genes

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 749
Author(s):  
Agnieszka Koppolu ◽  
Radosław B. Maksym ◽  
Wiktor Paskal ◽  
Marcin Machnicki ◽  
Beata Rak ◽  
...  
Keyword(s):  
Uterine Cavity ◽  
Genetic Alterations ◽  
Deep Infiltrating Endometriosis ◽  
Driver Genes ◽  
Kras Mutations ◽  
Deep Endometriosis ◽  
Eutopic Endometrium ◽  
Cancer Driver ◽  
Cancer Driver Genes ◽  
Custom Panel

Endometriosis is an inflammatory condition manifested by the presence of endometrial-like tissue outside of the uterine cavity. The most common clinical presentations of endometriosis are dysmenorrhea, infertility, and severe pelvic pain. Few hypotheses attempt to explain the pathogenesis of endometriosis; however, none of the theories have been fully confirmed or considered universal. We examined somatic mutations in eutopic endometrium samples, deep endometriotic nodules and peripheral blood from 13 women with deep endometriosis of the rectovaginal space. Somatic variants were identified in laser microdissected samples using next-generation sequencing. A custom panel of 1296 cancer-related genes was employed, and selected genes representing cancer drivers and non-drivers for endometrial and ovarian cancer were thoroughly investigated. All 59 detected somatic variants were of low mutated allele frequency (<10%). In deep ectopic lesions, detected variants were significantly more often located in cancer driver genes, whereas in eutopic endometrium, there was no such distribution. Our results converge with other reports, where cancer-related mutations were found in endometriosis without cancer, particularly recurrent KRAS mutations. Genetic alterations located in ectopic endometriotic nodules could contribute to their formation; nevertheless, to better understand the pathogenesis of this disease, more research in this area must be performed.

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