scholarly journals Patient-derived xenografts undergo murine-specific tumor evolution

2017 ◽  
Author(s):  
Uri Ben-David ◽  
Gavin Ha ◽  
Yuen-Yi Tseng ◽  
Noah F. Greenwald ◽  
Coyin Oh ◽  
...  
Keyword(s):  
Drug Testing ◽  
Human Cancer ◽  
Genomic Stability ◽  
Molecular Characteristics ◽  
Tumor Evolution ◽  
Underlying Assumption ◽  
Primary Tumors ◽  
Specific Tumor ◽  
Pdx Models

AbstractPatient-derived xenografts (PDXs) have become a prominent model for studying human cancer in vivo. The underlying assumption is that PDXs faithfully represent the genomic features of primary tumors, retaining their molecular characteristics throughout propagation. However, the genomic stability of PDXs during passaging has not yet been evaluated systematically. Here we monitored the dynamics of copy number alterations (CNAs) in 1,110 PDX samples across 24 cancer types. We found that new CNAs accumulated quickly, such that within four passages an average of 12% of the genome was affected by newly acquired CNAs. Selection for preexisting minor clones was a major contributor to these changes, leading to both gains and losses of CNAs. The rate of CNA acquisition in PDX models was correlated with the extent of both aneuploidy and genetic heterogeneity observed in primary tumors of the same tissue. However, the specific CNAs acquired during PDX passaging differed from those acquired during tumor evolution in patients, suggesting that PDX tumors are subjected to distinct selection pressures compared to those that exist in human hosts. Specifically, several recurrent CNAs observed in primary tumors gradually disappeared in PDXs, indicating that events undergoing positive selection in humans can become dispensable during propagation in mice. Finally, we found that the genomic stability of PDX models also affected their responses to chemotherapy and targeted drugs. Our findings thus highlight the need to couple the timing of PDX molecular characterization to that of drug testing experiments. These results suggest that while PDX models are powerful tools, they should be used with caution.

scholarly journals Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts

2019 ◽  
Author(s):  
Xing Yi Woo ◽  
Jessica Giordano ◽  
Anuj Srivastava ◽  
Zi-Ming Zhao ◽  
Michael W. Lloyd ◽  
...  
Keyword(s):  
Microarray Data ◽  
Copy Number ◽  
Dynamic Range ◽  
Human Cancer ◽  
Tumor Evolution ◽  
Copy Number Alterations ◽  
Recurrence Analysis ◽  
Late Passage ◽  
Significant Enrichment ◽  
Pdx Models

ABSTRACTPatient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, impacting the accuracy of PDX modeling of human cancer. Here we exhaustively analyze copy number alterations (CNAs) in 1451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multi-region samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.

scholarly journals XenoSarc: A comprehensive platform of patient-derived xenograft (PDX) models of soft tissue sarcoma (STS) for early drug testing.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 37-37 ◽  
Author(s):  
Patrick Schoffski ◽  
Britt Van Renterghem ◽  
Jasmien Cornillie ◽  
Yannick Wang ◽  
Yemarshet Kelemework Gebreyohannes ◽  
...  
Keyword(s):  
Drug Testing ◽  
Treatment Options ◽  
Clinical Information ◽  
Tissue Microarrays ◽  
Mouse Tissue ◽  
Tissue Samples ◽  
Pdx Models ◽  
Early Drug

37 Background: STS is a family of rare, heterogeneous tumors with > 70 subtypes. There is an urgent need for reliable preclinical models, especially for orphan subtypes of STS, given the limited treatment options. Methods: A panel of PDX models was established by s.c. implantation of fresh tumor specimens in athymic NMRI mice. Growing pieces of tumor were re-transplanted to next generations of mice. At each passage fragments were collected for histological/molecular characterization. A model was considered “established” after observing stable features for at least 2 passages. Ex-mouse tissue samples were stored, characterized by immunohistochemistry/flow cytometry and used for in vitro drug testing. Results: Between 2011-2019, 329 samples from 301 consenting patients were transplanted; 56 models are established, 16 additional models are in early passaging. Clinical information about donor and tumor (including sensitivity to standard and experimental agents) is available. The platform includes models of dedifferentiated lipo- (10 models), myxofibro- (8), leiomyo- (7), synovial (2), intimal (2), CIC-positive round cell (1), mesenchymal chondro- (1), extraskeletal osteo- (1), myxoid lipo- (1), myxoinflammatory fibroblastic (1), rhabdomyo- (2) and high-grade undifferentiated pleomorphic sarcoma (7), as well as GIST (8), MPNST (4) and epithelioid hemangioendothelioma (1). Models are well-characterized, with molecular information on copy number changes (low-coverage whole genome sequencing) and gene expression profile (RNA-Seq) available. We also constructed tissue microarrays from the xenografts which are used for target identification and model selection for preclinical studies. Xenografts are available for in vivo testing of novel agents, and results already served as a rationale for a number of prospective clinical trials. Conclusions: XenoSarc offers opportunities for studying the biology of a variety of sarcoma subtypes including ultra-rare entities and is a valuable tool for early drug screening in preparation of clinical STS trials. The platform is well maintained and continuously expanded, and available to collaborators from academia and industry.

scholarly journals Establishment and characterization of patient-derived head and neck cancer models from surgical specimens and endoscopic biopsies

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Daniel Strüder ◽  
Theresa Momper ◽  
Nina Irmscher ◽  
Mareike Krause ◽  
Jan Liese ◽  
...  
Keyword(s):  
Head And Neck ◽  
Human Cancer ◽  
Locally Advanced ◽  
Treatment Strategies ◽  
Molecular Profile ◽  
Molecular Characteristics ◽  
Individual Response ◽  
Sample Collection ◽  
Primary Tumors ◽  
Endoscopic Biopsies

Abstract Background Head and neck squamous cell carcinoma (HNSCC) is heterogeneous in etiology, phenotype and biology. Patient-derived xenografts (PDX) maintain morphology and molecular profiling of the original tumors and have become a standard “Avatar” model for human cancer research. However, restricted availability of tumor samples hindered the widespread use of PDX. Most PDX-projects include only surgical specimens because reliable engraftment from biopsies is missing. Therefore, sample collection is limited and excludes recurrent and metastatic, non-resectable cancer from preclinical models as well as future personalized medicine. Methods This study compares the PDX-take rate, -growth, histopathology, and molecular characteristics of endoscopic specimens with surgical specimens. HNSCC samples (n = 55) were collected ad hoc, fresh frozen and implanted into NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ mice. Results Engraftment was successful in both sample types. However, engraftment rate was lower (21 vs. 52%) and growth delayed (11.2 vs. 6.7 weeks) for endoscopic biopsies. Following engraftment, growth kinetic was similar. Comparisons of primary tumors and corresponding PDX models confirmed preservation of histomorphology (HE histology) and molecular profile (Illumina Cancer Hotspot Panel) of the patients’ tumors. Accompanying flow cytometry on primary tumor specimens revealed a heterogeneous tumor microenvironment among individual cases and identified M2-like macrophages as positive predictors for engraftment. Vice versa, a high PD-L1 expression (combined positive score on tumor/immune cells) predicted PDX rejection. Conclusion Including biopsy samples from locally advanced or metastatic lesions from patients with non-surgical treatment strategies, increases the availability of PDX for basic and translational research. This facilitates (pre-) clinical studies for individual response prediction based on immunological biomarkers.

scholarly journals Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer

2016 ◽  
Vol 113 (47) ◽  
pp. E7535-E7544 ◽  
Author(s):  
Angel Diaz-Lagares ◽  
Ana B. Crujeiras ◽  
Paula Lopez-Serra ◽  
Marta Soler ◽  
Fernando Setien ◽  
...  
Keyword(s):  
Transcriptional Repression ◽  
Noncoding Rna ◽  
Regulatory Networks ◽  
Rna Binding ◽  
Human Cancer ◽  
Suppressor Activity ◽  
Primary Tumors ◽  
Epigenetic Inactivation

Long noncoding RNAs (lncRNAs) are important regulators of cellular homeostasis. However, their contribution to the cancer phenotype still needs to be established. Herein, we have identified a p53-induced lncRNA, TP53TG1, that undergoes cancer-specific promoter hypermethylation-associated silencing. In vitro and in vivo assays identify a tumor-suppressor activity for TP53TG1 and a role in the p53 response to DNA damage. Importantly, we show that TP53TG1 binds to the multifaceted DNA/RNA binding protein YBX1 to prevent its nuclear localization and thus the YBX1-mediated activation of oncogenes. TP53TG1 epigenetic inactivation in cancer cells releases the transcriptional repression of YBX1-targeted growth-promoting genes and creates a chemoresistant tumor. TP53TG1 hypermethylation in primary tumors is shown to be associated with poor outcome. The epigenetic loss of TP53TG1 therefore represents an altered event in an lncRNA that is linked to classical tumoral pathways, such as p53 signaling, but is also connected to regulatory networks of the cancer cell.

scholarly journals A 3D Heterotypic Multicellular Tumor Spheroid Assay Platform to Discriminate Drug Effects on Stroma versus Cancer Cells

2019 ◽  
Vol 25 (3) ◽  
pp. 265-276
Author(s):  
Zoe Weydert ◽  
Madhu Lal-Nag ◽  
Lesley Mathews-Greiner ◽  
Christoph Thiel ◽  
Henrik Cordes ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Stromal Cells ◽  
High Throughput Screening ◽  
Drug Testing ◽  
Therapeutic Window ◽  
Multicellular Tumor Spheroid ◽  
Cytotoxic Effects ◽  
Primary Tumors

Three-dimensional (3D) cell culture models are thought to mimic the physiological and pharmacological properties of tissues in vivo more accurately than two-dimensional cultures on plastic dishes. For the development of cancer therapies, 3D spheroid models are being created to reflect the complex histology and physiology of primary tumors with the hopes that drug responses will be more similar to and as predictive as those obtained in vivo. The effect of additional cell types in tumors, such as stromal cells, and the resulting heterotypic cell–cell crosstalk can be investigated in these heterotypic 3D cell cultures. Here, a high-throughput screening-compatible drug testing platform based on 3D multicellular spheroid models is described that enables the parallel assessment of toxicity on stromal cells and efficacy on cancer cells by drug candidates. These heterotypic microtissue tumor models incorporate NIH3T3 fibroblasts as stromal cells that are engineered with a reporter gene encoding secreted NanoLUC luciferase. By tracking the NanoLUC signal in the media over time, a time-related measurement of the cytotoxic effects of drugs on stromal cells over the cancer cells was possible, thus enabling the identification of a therapeutic window. An in vitro therapeutic index parameter is proposed to help distinguish and classify those compounds with broad cytotoxic effects versus those that are more selective at targeting cancer cells.

scholarly journals Taxol-Loaded MSC-Derived Exosomes Provide a Therapeutic Vehicle to Target Metastatic Breast Cancer and Other Carcinoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 798 ◽  
Author(s):  
Catharina Melzer ◽  
Vanessa Rehn ◽  
Yuanyuan Yang ◽  
Heike Bähre ◽  
Juliane von der Ohe ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Human Cancer ◽  
Metastatic Breast ◽  
Carcinoma Cells ◽  
Primary Tumors ◽  
Distant Organ ◽  
In Vitro Effects ◽  
A549 Lung

MSC-derived exosomes display, among others, an efficient biocompatibility and a reduced intrinsic immunogenicity, representing a valuable vehicle for drug delivery in a tumor-therapeutic approach. Following treatment of several human mesenchymal stroma/stem-like cell (MSC) populations with sub-lethal concentrations of taxol for 24 h, exosomes were isolated and applied to different human cancer populations including A549 lung cancer, SK-OV-3 ovarian cancer, and MDA-hyb1 breast cancer cells. While MSC control exosomes revealed little if any growth inhibition on the tumor cells, exposure to taxol-loaded MSC-derived exosomes was associated with 80–90% cytotoxicity. A similar application of taxol-loaded exosomes from HuVEC displayed much fewer effects. Quantification by LC-MS/MS analysis demonstrated a 7.6-fold reduced taxol concentration in MSC exosomes when compared to equivalent cytotoxic in vitro effects achieved with taxol substances, indicating a specific and more efficient tumor-targeting property. Consequently, MSC-derived taxol exosomes were tested in vivo. Highly metastatic MDA-hyb1 breast tumors were induced in NODscid mice, and systemic intravenous application of MSC-derived taxol exosomes revealed a more than 60% reduction of subcutaneous primary tumors. Moreover, the amount of distant organ metastases observed at least in lung, liver, spleen, and kidney was reduced by 50% with MSC taxol exosomes, similar to the effects observed with taxol, although the concentration of taxol in exosomes was about 1000-fold reduced. Together, these findings in different cancer cell populations and in vivo provide promising future perspectives for drug-loaded MSC-derived exosomes in efficiently targeting primary tumors and metastases by reducing side effects.

scholarly journals Integrative In Vivo Drug Testing Using Gene Expression Signature and Patient-Derived Xenografts from Treatment-Refractory HER2 Positive and Triple-Negative Subtypes of Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 574 ◽  
Author(s):  
Jin-Sun Ryu ◽  
Sung Hoon Sim ◽  
In Hae Park ◽  
Eun Gyeong Lee ◽  
Eun Sook Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Drug Testing ◽  
Triple Negative ◽  
Molecular Subtypes ◽  
Combined Treatment ◽  
Predictive Biomarkers ◽  
Pdx Models ◽  
Histopathologic Features

Patient-derived xenografts (PDXs) are powerful tools for translational cancer research. Here, we established PDX models from different molecular subtypes of breast cancer for in vivo drug tests and compared the histopathologic features of PDX model tumors with those of patient tumors. Predictive biomarkers were identified by gene expression analysis of PDX samples using Nanostring nCount cancer panels. Validation of predictive biomarkers for treatment response was conducted in established PDX models by in vivo drug testing. Twenty breast cancer PDX models were generated from different molecular subtypes (overall success rate, 17.5%; 3.6% for HR+/HER2−, 21.4% for HR+/HER2+, 21.9% for HR−/HER2+ and 22.5% for triple-negative breast cancer (TNBC)). The histopathologic features of original tumors were retained in the PDX models. We detected upregulated HIF1A, RAF1, AKT2 and VEGFA in TNBC cases and demonstrated the efficacy of combined treatment with sorafenib and everolimus or docetaxel and bevacizumab in each TNBC model. Additionally, we identified upregulated HIF1A in two cases of trastuzumab-exposed HR−/HER2+ PDX models and validated the efficacy of the HIF1A inhibitor, PX-478, alone or in combination with neratinib. Our results demonstrate that PDX models can be used as effective tools for predicting therapeutic markers and evaluating personalized treatment strategies in breast cancer patients with resistance to standard chemotherapy regimens.

scholarly journals Talazoparib Treatment Preferentially Depletes Cohesin-Mutant Clones in New In Vivo Models of Cohesin-Mutant Myeloid Diseases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 560-560 ◽  
Author(s):  
Mounica Vallurupalli ◽  
Rebecca Gorelov ◽  
Jacqueline S Garcia ◽  
Elizabeth A Morgan ◽  
Benjamin Ebert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Testing ◽  
Bone Marrow Cells ◽  
Mutant Mice ◽  
Hematopoietic Stem ◽  
Syngeneic Mouse Model ◽  
Stem And Progenitor Cells ◽  
Mutant Cells ◽  
Pdx Models

Cohesin is a multisubunit protein complex that is involved in sister chromatid cohesion, post-replicative DNA repair and transcriptional regulation, and is frequently mutated in cancer. STAG2 is the most recurrently mutated cohesin gene in myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML) but no STAG2-mutant disease models currently exist to study the natural evolution of cohesin-mutant myeloid disease, or to test therapeutic vulnerabilities. Our previous workimplicates PARP1 inhibition as a therapeutic vulnerability in STAG2-mutant AML cell lines, which display impaired replication fork progression and accumulation of double-strand DNA breaks.We developed a syngeneic mouse model of cohesin-mutant myeloid disease mimicking the phenotype seen in human MDS, in which STAG2 mutations arise as clonal secondary lesions in the background of clonal hematopoiesis. We used this model to test the effect of sequential acquisition of Tet2 and Stag2 mutations on mouse hematopoiesis, and in vivo therapeutic vulnerabilities including sensitivity to PARP1 inhibition. In parallel, we developed patient-derived xenograft (PDX) models of cohesin-mutant AML to extend our findings. Hematopoietic stem and progenitor cells (Lineage-, Sca1+, c-Kit+ cells) harvested from Mx1-Cre;Cas9 heterozygous C57BL.6 mice were transduced with sgRNA targeting Tet2 or non-targeting sgRNA and transplanted into lethally irradiated SJL recipient mice. Engraftment and clonal expansion of Tet2-mutant cells was confirmed with fluorescent protein reporter expression and next-generation sequencing (NGS), and was not associated with any overt phenotype, similar to human clonal hematopoiesis of indeterminate potential (CHIP). c-Kit enriched bone marrow cells from mice with Tet2-mutant CHIP were subsequently transduced with sgRNA targeting Stag2 or non-targeting sgRNAs and re-transplanted into recipient mice. Mice were serially followed for up to 9 months and showed increased clonal expansion of Tet2/Stag2-mutant cells over Tet2-only mutant cells. In contrast to Tet2-only mutant mice, Tet2/Stag2-mutant mice developed leukocytosis, absolute monocytosis, anemia, and thrombocytopenia. Bone marrow evaluation of Tet2/Stag2 mice demonstrated increased hemophagocytosis and fewer megakaryocytes in comparison to Tet2-only mice and NGS confirmed predicted loss of function frameshift mutations in Tet2 and Stag2. We therefore generated a new model of cohesin-mutant myeloid disease recapitulating sequential acquisition of Stag2mutations in the context of an initiating epigenetic lesion as seen in patients with cohesin-mutant MDS. Tet2/Stag2 andTet2-mutant clones and the associated hematologic phenotypes were serially transplantable and allowed for genotype-specific in vivo drug testing of the PARP1 inhibitor talazoparib. Forty recipient mice transplanted with Tet2 or Tet2/Stag2 mutant bone marrow cells were stratified into treatment groups with talazoparib or vehicle. Expression of congenic markers and fluorescent reporters linked to Tet2 and Stag2 sgRNA expression were used to monitor mice during 4 weeks of treatment. We observed normalization of leukocytosis, monocytosis and thrombocytopenia in Tet2/Stag2 mutant mice treated with talazoparib. In addition, Tet2/Stag2-mutant mice but not Tet2-only mice treated with talazoparib demonstrated a significant loss of mutant clones as determined by flow cytometry and NGS. To further extend these findings in primary human cells, we developed serially transplantable PDX models of cohesin-mutant AML and performed in vivo drug testing with talazoparib. We noted increased survival of cohesin-mutant PDX models treated with talazoparib as compared to vehicle. We demonstrate the development of a syngeneic mouse model of Stag2-mutated myeloid disease through sequential introduction of Tet2 or Stag2 mutations in primary mouse hematopoietic stem and progenitor cells. Mice with loss of Tet2 and Stag2 recapitulate hematologic parameters mimicking myelodysplastic/myeloproliferative neoplasms in humans. In vivo treatment with talazoparib demonstrates selective depletion of cohesin mutations in syngeneic and PDX models. The effect of talazoparib monotherapy in cohesin-mutated AML or MDS with excess blasts is under investigation in a pilot proof-of-concept study (ClinicalTrials.gov Identifier NCT03974217). Disclosures Garcia: Abbvie: Research Funding; Genentech: Research Funding.

scholarly journals Genomic analysis of patient-derived xenograft models reveals intra-tumor heterogeneity in endometrial cancer and can predict tumor growth inhibition with talazoparib

2021 ◽  
Author(s):  
Vanessa F. Bonazzi ◽  
Olga Kondrashova ◽  
Deborah Smith ◽  
Katia Nones ◽  
Asmerom T. Sengal ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Primary Tumor ◽  
Tumor Heterogeneity ◽  
Molecular Subtypes ◽  
Molecular Subtype ◽  
Primary Tumors ◽  
Patient Derived Xenograft ◽  
Wide Range ◽  
Pdx Models

Background: Endometrial cancer (EC) is a major gynecological cancer with increasing incidence. It comprised of four molecular subtypes with differing etiology, prognoses, and response to chemotherapy. In the future, clinical trials testing new single agents or combination therapies will be targeted to the molecular subtype most likely to respond. Pre-clinical models that faithfully represent the molecular subtypes of EC are urgently needed, we sought to develop and characterize a panel of novel EC patient-derived xenograft (PDX) models. Methods: Here, we report whole exome or whole genome sequencing of 11 PDX models and the matched primary tumor. Analysis of multiple PDX lineages and passages was performed to study tumor heterogeneity across lineages and/or passages. Based on recent reports of frequent defects in the homologous recombination (HR) pathway in EC, we assessed mutational signatures and HR deficiency scores and correlated these with in vivo responses to the PARP inhibitor (PARPi) talazoparib in six PDXs representing the different molecular subtypes of EC. Results: PDX models were successfully generated from all four molecular subtypes of EC and uterine carcinosarcomas, and they recapitulated morphology and the molecular landscape of primary tumors without major genomic drift. We also observed a wide range of inter-tumor and intra-tumor heterogeneity, well captured by different PDX lineages, which could lead to different treatment responses. An in vivo response to talazoparib was detected in two p53mut models consistent with stable disease, however both lacked the HR deficiency genomic signature. Conclusions: EC PDX models represent the four molecular subtypes of disease and can capture intra-tumoral heterogeneity of the original primary tumor. PDXs of the p53mut molecular subtype showed sensitivity to PARPi, however, deeper and more durable responses will likely require combination of PARPi with other agents.

scholarly journals 5-Fluorouracil treatment induces characteristic T>G mutations in human cancer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sharon Christensen ◽  
Bastiaan Van der Roest ◽  
Nicolle Besselink ◽  
Roel Janssen ◽  
Sander Boymans ◽  
...  
Keyword(s):  
Human Cancer ◽  
Whole Genome Sequencing Data ◽  
Tumor Evolution ◽  
Breast Cancer Patients ◽  
Sequencing Data ◽  
Nucleotide Synthesis ◽  
Mutational Pattern ◽  
Treatment Naïve ◽  
Strong Resemblance

Abstract 5-Fluorouracil (5-FU) is a chemotherapeutic drug commonly used for the treatment of solid cancers. It is proposed that 5-FU interferes with nucleotide synthesis and incorporates into DNA, which may have a mutational impact on both surviving tumor and healthy cells. Here, we treat intestinal organoids with 5-FU and find a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Tumor whole genome sequencing data confirms that this signature is also identified in vivo in colorectal and breast cancer patients who have received 5-FU treatment. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures.

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