ScalpelSig Designs Targeted Genomic Panels from Data to Detect Activity of Mutational Signatures

2022 ◽  
Author(s):  
Nicholas Franzese ◽  
Jason Fan ◽  
Roded Sharan ◽  
Mark D.M. Leiserson
Keyword(s):  
Mutational Signatures

scholarly journals Learning mutational signatures and their multidimensional genomic properties with TensorSignatures

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Harald Vöhringer ◽  
Arne Van Hoeck ◽  
Edwin Cuppen ◽  
Moritz Gerstung
Keyword(s):  
Somatic Hypermutation ◽  
Excision Repair ◽  
Metastatic Cancer ◽  
Strand Break ◽  
Lymphoid Leukaemia ◽  
Mutational Signatures ◽  
Transcription Start Sites ◽  
Nucleotide Excision ◽  
Cancer Types ◽  
Underlying Processes

AbstractWe present TensorSignatures, an algorithm to learn mutational signatures jointly across different variant categories and their genomic localisation and properties. The analysis of 2778 primary and 3824 metastatic cancer genomes of the PCAWG consortium and the HMF cohort shows that all signatures operate dynamically in response to genomic states. The analysis pins differential spectra of UV mutagenesis found in active and inactive chromatin to global genome nucleotide excision repair. TensorSignatures accurately characterises transcription-associated mutagenesis in 7 different cancer types. The algorithm also extracts distinct signatures of replication- and double strand break repair-driven mutagenesis by APOBEC3A and 3B with differential numbers and length of mutation clusters. Finally, TensorSignatures reproduces a signature of somatic hypermutation generating highly clustered variants at transcription start sites of active genes in lymphoid leukaemia, distinct from a general and less clustered signature of Polη-driven translesion synthesis found in a broad range of cancer types. In summary, TensorSignatures elucidates complex mutational footprints by characterising their underlying processes with respect to a multitude of genomic variables.

scholarly journals Current gene panels account for nearly all homologous recombination repair-associated multiple-case breast cancer families

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Thibaut S. Matis ◽  
Nadia Zayed ◽  
Bouchra Labraki ◽  
Manon de Ladurantaye ◽  
Théophane A. Matis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Homologous Recombination ◽  
Large Fraction ◽  
Homologous Recombination Repair ◽  
Mutational Signatures ◽  
Recombination Repair ◽  
Multiple Case ◽  
Gene Panels ◽  
Tumor Dna

AbstractIt was hypothesized that variants in underexplored homologous recombination repair (HR) genes could explain unsolved multiple-case breast cancer (BC) families. We investigated HR deficiency (HRD)-associated mutational signatures and second hits in tumor DNA from familial BC cases. No candidates genes were associated with HRD in 38 probands previously tested negative with gene panels. We conclude it is unlikely that unknown HRD-associated genes explain a large fraction of unsolved familial BC.

scholarly journals Analysis of the genomic landscape of yolk sac tumors reveals mechanisms of evolution and chemoresistance

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuan Zong ◽  
Ying Zhang ◽  
Xinxin Peng ◽  
Dongyan Cao ◽  
Mei Yu ◽  
...  
Keyword(s):  
Copy Number Alteration ◽  
Germ Cell Tumors ◽  
Gonadal Development ◽  
Yolk Sac ◽  
Mutational Signatures ◽  
Whole Exome ◽  
Genomic Landscape ◽  
Yolk Sac Tumors ◽  
Molecular Aberrations

AbstractYolk sac tumors (YSTs) are a major histological subtype of malignant ovarian germ cell tumors with a relatively poor prognosis. The molecular basis of this disease has not been thoroughly characterized at the genomic level. Here we perform whole-exome and RNA sequencing on 41 clinical tumor samples from 30 YST patients, with distinct responses to cisplatin-based chemotherapy. We show that microsatellite instability status and mutational signatures are informative of chemoresistance. We identify somatic driver candidates, including significantly mutated genes KRAS and KIT and copy-number alteration drivers, including deleted ARID1A and PARK2, and amplified ZNF217, CDKN1B, and KRAS. YSTs have very infrequent TP53 mutations, whereas the tumors from patients with abnormal gonadal development contain both KRAS and TP53 mutations. We further reveal a role of OVOL2 overexpression in YST resistance to cisplatin. This study lays a critical foundation for understanding key molecular aberrations in YSTs and developing related therapeutic strategies.

scholarly journals Genomic Adaption and Mutational Patterns in a HaCaT Subline Resistant to Alkylating Agents and Ionizing Radiation

2021 ◽  
Vol 22 (3) ◽  
pp. 1146
Author(s):  
Reinhard Ullmann ◽  
Benjamin Valentin Becker ◽  
Simone Rothmiller ◽  
Annette Schmidt ◽  
Horst Thiermann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Line ◽  
Copy Number ◽  
Resistant Cell ◽  
Resistant Cell Line ◽  
Chromosomal Translocations ◽  
Dna Copy Number ◽  
Mutational Signatures ◽  
Copy Number Changes ◽  
And Oxidative Stress

Sulfur mustard (SM) is a chemical warfare agent that can damage DNA via alkylation and oxidative stress. Because of its genotoxicity, SM is cancerogenic and the progenitor of many chemotherapeutics. Previously, we developed an SM-resistant cell line via chronic exposure of the popular keratinocyte cell line HaCaT to increasing doses of SM over a period of 40 months. In this study, we compared the genomic landscape of the SM-resistant cell line HaCaT/SM to its sensitive parental line HaCaT in order to gain insights into genetic changes associated with continuous alkylation and oxidative stress. We established chromosome numbers by cytogenetics, analyzed DNA copy number changes by means of array Comparative Genomic Hybridization (array CGH), employed the genome-wide chromosome conformation capture technique Hi-C to detect chromosomal translocations, and derived mutational signatures by whole-genome sequencing. We observed that chronic SM exposure eliminated the initially prevailing hypotetraploid cell population in favor of a hyperdiploid one, which contrasts with previous observations that link polyploidization to increased tolerance and adaptability toward genotoxic stress. Furthermore, we observed an accumulation of chromosomal translocations, frequently flanked by DNA copy number changes, which indicates a high rate of DNA double-strand breaks and their misrepair. HaCaT/SM-specific single-nucleotide variants showed enrichment of C > A and T > A transversions and a lower rate of deaminated cytosines in the CpG dinucleotide context. Given the frequent use of HaCaT in toxicology, this study provides a valuable data source with respect to the original genotype of HaCaT and the mutational signatures associated with chronic alkylation and oxidative stress.

scholarly journals Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Nathaniel D. Anderson ◽  
Yael Babichev ◽  
Fabio Fuligni ◽  
Federico Comitani ◽  
Mehdi Layeghifard ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Therapeutic Strategy ◽  
Genetic Factors ◽  
Phylogenetic Reconstruction ◽  
Mutational Signatures ◽  
Multiple Tumor ◽  
Dystrophin Expression ◽  
Genome Wide ◽  
Damage Response ◽  
Disease Site

AbstractLeiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis.

scholarly journals Distinct genomic features across cytolytic subgroups in skin melanoma

2021 ◽  
Author(s):  
Constantinos Roufas ◽  
Ilias Georgakopoulos-Soares ◽  
Apostolos Zaravinos
Keyword(s):  
Immune Checkpoint ◽  
Cytolytic Activity ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Skin Melanoma ◽  
Related Gene ◽  
Mutational Signatures ◽  
Genomic Features ◽  
Immune Related Gene ◽  
Gene Sets

Abstract Background Skin melanoma is a highly immunogenic cancer. The intratumoral immune cytolytic activity (CYT) reflects the ability of cytotoxic T and NK cells to eliminate cancer cells, and is associated with improved patient survival. Despite the enthusiastic clinical results seen in advanced-stage metastatic melanoma patients treated with immune checkpoint inhibitors, a subgroup of them will later relapse and develop acquired resistance. We questioned whether CYT associates with different genomic profiles and thus, patient outcome, in skin melanoma. Methods We explored the TCGA-SKCM dataset and stratified patients to distinct subgroups of cytolytic activity. The tumor immune contexture, somatic mutations and recurrent copy number aberrations were calculated using quanTIseq, MutSigCV and GISTIC2. Chromothriptic events were explored using CTLPScanner and cancer neoepitopes were predicted with antigen garnish. Each tumor's immunophenoscore was calculated using Immunophenogram. Mutational signatures and kataegis were explored using SigProfiler and compared to the known single or doublet base substitution signatures from COSMIC. Results Metastatic skin melanomas had significantly higher CYT levels compared to primary tumors. We assessed enrichment for immune-related gene sets within CYT-high tumors, whereas, CYT-low tumors were enriched for non-immune related gene sets. In addition, distinct mutational and neoantigen loads, primarily composed of C > T transitions, along with specific types of copy number aberrations, characterized each cytolytic subgroup. We found a broader pattern of chromothripsis across CYT-low tumors, where chromosomal regions harboring chromothriptic events, contained a higher number of cancer genes. SBS7a/b, SBS5 and SBS1 were the most prevalent mutational signatures across both cytolytic subgroups, but SBS1 differed significantly between them. SBS7a/b was mutually exclusive with SBS5 and SBS1 in both CYT subgroups. CYT-high patients had markedly higher immunophenoscore, suggesting that they should display a clinical benefit upon treatment with immune checkpoint inhibition therapy, compared to CYT-low patients. Conclusions Overall, our data highlight the existence of distinct genomic features across cytolytic subgroups in skin melanoma, which might affect the patients' relapse rate or their acquisition of resistance to immune checkpoint inhibition therapies.

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