Publications by authors named "Ludmil B Alexandrov"

106 Publications

Genomic and evolutionary classification of lung cancer in never smokers.

Nat Genet 2021 09 6;53(9):1348-1359. Epub 2021 Sep 6.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Lung cancer in never smokers (LCINS) is a common cause of cancer mortality but its genomic landscape is poorly characterized. Here high-coverage whole-genome sequencing of 232 LCINS showed 3 subtypes defined by copy number aberrations. The dominant subtype (piano), which is rare in lung cancer in smokers, features somatic UBA1 mutations, germline AR variants and stem cell-like properties, including low mutational burden, high intratumor heterogeneity, long telomeres, frequent KRAS mutations and slow growth, as suggested by the occurrence of cancer drivers' progenitor cells many years before tumor diagnosis. The other subtypes are characterized by specific amplifications and EGFR mutations (mezzo-forte) and whole-genome doubling (forte). No strong tobacco smoking signatures were detected, even in cases with exposure to secondhand tobacco smoke. Genes within the receptor tyrosine kinase-Ras pathway had distinct impacts on survival; five genomic alterations independently doubled mortality. These findings create avenues for personalized treatment in LCINS.
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http://dx.doi.org/10.1038/s41588-021-00920-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432745PMC
September 2021

Significance and limitations of the use of next-generation sequencing technologies for detecting mutational signatures.

DNA Repair (Amst) 2021 Nov 5;107:103200. Epub 2021 Aug 5.

Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, 92093, USA; Department of Bioengineering, UC San Diego, La Jolla, CA, 92093, USA; Moores Cancer Center, UC San Diego, La Jolla, CA, 92037, USA. Electronic address:

Next generation sequencing technologies (NGS) have been critical in characterizing the genomic landscape and untangling the genetic heterogeneity of human cancer. Since its advent, NGS has played a pivotal role in identifying the patterns of somatic mutations imprinted on cancer genomes and in deciphering the signatures of the mutational processes that have generated these patterns. Mutational signatures serve as phenotypic molecular footprints of exposures to environmental factors as well as deficiency and infidelity of DNA replication and repair pathways. Since the first roadmap of mutational signatures in human cancer was generated from whole-genome and whole-exome sequencing data, there has been a growing interest to extract mutational signatures from other NGS technologies such as targeted panel sequencing, RNA sequencing, single-cell sequencing, duplex sequencing, reduced representation sequencing, and long-read sequencing. Many of these technologies have their inherent sequencing biases and produce technical artifacts that can confound the extraction of reliable and interpretable mutational signatures. In this review, we highlight the relevance, limitations, and prospects of using different NGS technologies for examining mutational patterns and for deciphering mutational signatures.
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http://dx.doi.org/10.1016/j.dnarep.2021.103200DOI Listing
November 2021

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

Nat Commun 2021 07 23;12(1):4496. Epub 2021 Jul 23.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.

Leiomyosarcomas (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.
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http://dx.doi.org/10.1038/s41467-021-24677-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302638PMC
July 2021

Inhibition of mTOR signaling and clinical activity of metformin in oral premalignant lesions.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Division of Cancer Prevention and.

BACKGROUNDThe aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in head and neck squamous cell carcinoma (HNSCC). Here, we conducted a single-arm, open-label phase IIa clinical trial in individuals with oral premalignant lesions (OPLs) to explore the potential of metformin to target PI3K/mTOR signaling for HNSCC prevention.METHODSIndividuals with OPLs, but who were otherwise healthy and without diabetes, underwent pretreatment and posttreatment clinical exam and biopsy. Participants received metformin for 12 weeks (week 1, 500 mg; week 2, 1000 mg; weeks 3-12, 2000 mg daily). Pretreatment and posttreatment biopsies, saliva, and blood were obtained for biomarker analysis, including IHC assessment of mTOR signaling and exome sequencing.RESULTSTwenty-three participants were evaluable for response. The clinical response rate (defined as a ≥50% reduction in lesion size) was 17%. Although lower than the proposed threshold for favorable clinical response, the histological response rate (improvement in histological grade) was 60%, including 17% complete responses and 43% partial responses. Logistic regression analysis revealed that when compared with never smokers, current and former smokers had statistically significantly increased histological responses (P = 0.016). Remarkably, a significant correlation existed between decreased mTOR activity (pS6 IHC staining) in the basal epithelial layers of OPLs and the histological (P = 0.04) and clinical (P = 0.01) responses.CONCLUSIONTo our knowledge this is the first phase II trial of metformin in individuals with OPLs, providing evidence that metformin administration results in encouraging histological responses and mTOR pathway modulation, thus supporting its further investigation as a chemopreventive agent.TRIAL REGISTRATIONNCT02581137FUNDINGNIH contract HHSN261201200031I, grants R01DE026644 and R01DE026870.
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http://dx.doi.org/10.1172/jci.insight.147096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492350PMC
September 2021

Unraveling the genomic landscape of colorectal cancer through mutational signatures.

Adv Cancer Res 2021 27;151:385-424. Epub 2021 Mar 27.

Department of Cellular and Molecular Medicine, UC San Diego, La Jolla, CA, United States; Department of Bioengineering, UC San Diego, La Jolla, CA, United States; Moores Cancer Center, UC San Diego, La Jolla, CA, United States. Electronic address:

Colorectal cancer, along with most other cancer types, is driven by somatic mutations. Characteristic patterns of somatic mutations, known as mutational signatures, arise as a result of the activities of different mutational processes. Mutational signatures have diverse origins, including exogenous and endogenous sources. In the case of colorectal cancer, the analysis of mutational signatures has elucidated specific signatures for classically associated DNA repair deficiencies, namely mismatch repair (leading to microsatellite instability), base excision repair (due to MUTYH or NTHL1 mutations), and polymerase proofreading (due to POLE and POLD1 exonuclease domain mutations). Additional signatures also play a role in colorectal cancer, including those related to normal aging and those associated with gut microbiota, as well as a number of signatures with unknown etiologies. This chapter provides an overview of the current knowledge of mutational signatures, with a focus on colorectal cancer and on the recently reported signatures in physiologically normal and inflammatory bowel disease-affected somatic colon tissues.
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http://dx.doi.org/10.1016/bs.acr.2021.03.003DOI Listing
March 2021

Immune evasion in HPV head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss.

Proc Natl Acad Sci U S A 2021 May;118(19)

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3 and CD8 T cell microenvironments in precancer (mostly CD3, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and - codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV HNSC after anti-PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.
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http://dx.doi.org/10.1073/pnas.2022655118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8126856PMC
May 2021

Integrated mutational landscape analysis of uterine leiomyosarcomas.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

Department of Pathology, University of Brescia, Azienda Socio Sanitaria Territoriale degli Spedali Civili di Brescia, 25100 Brescia, Italy.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; = 0.002), GS-626510 (C-MYC/BETi; < 0.000001 and = 0.0005), and copanlisib (PIK3CAi; = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.
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http://dx.doi.org/10.1073/pnas.2025182118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053980PMC
April 2021

Tracing Lung Cancer Risk Factors Through Mutational Signatures in Never-Smokers.

Am J Epidemiol 2021 06;190(6):962-976

Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic "mutational signatures" that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018-ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.
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http://dx.doi.org/10.1093/aje/kwaa234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316614PMC
June 2021

Inflammation-driven deaminase deregulation fuels human pre-leukemia stem cell evolution.

Cell Rep 2021 01;34(4):108670

Division of Regenerative Medicine, Department of Medicine, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA. Electronic address:

Inflammation-dependent base deaminases promote therapeutic resistance in many malignancies. However, their roles in human pre-leukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) had not been elucidated. Comparative whole-genome and whole-transcriptome sequencing analyses of FACS-purified pre-LSCs from myeloproliferative neoplasm (MPN) patients reveal APOBEC3C upregulation, an increased C-to-T mutational burden, and hematopoietic stem and progenitor cell (HSPC) proliferation during progression, which can be recapitulated by lentiviral APOBEC3C overexpression. In pre-LSCs, inflammatory splice isoform overexpression coincides with APOBEC3C upregulation and ADAR1p150-induced A-to-I RNA hyper-editing. Pre-LSC evolution to LSCs is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown. Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching. Thus, pre-LSC evolution to LSCs is fueled by primate-specific APOBEC3C-induced pre-LSC proliferation and ADAR1-mediated splicing deregulation.
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http://dx.doi.org/10.1016/j.celrep.2020.108670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477897PMC
January 2021

St. Jude Cloud: A Pediatric Cancer Genomic Data-Sharing Ecosystem.

Cancer Discov 2021 05 6;11(5):1082-1099. Epub 2021 Jan 6.

Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Effective data sharing is key to accelerating research to improve diagnostic precision, treatment efficacy, and long-term survival in pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data-sharing ecosystem for accessing, analyzing, and visualizing genomic data from >10,000 pediatric patients with cancer and long-term survivors, and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabytes are freely available, including 12,104 whole genomes, 7,697 whole exomes, and 2,202 transcriptomes. The resource is expanding rapidly, with regular data uploads from St. Jude's prospective clinical genomics programs. Three interconnected apps within the ecosystem-Genomics Platform, Pediatric Cancer Knowledgebase, and Visualization Community-enable simultaneously performing advanced data analysis in the cloud and enhancing the Pediatric Cancer knowledgebase. We demonstrate the value of the ecosystem through use cases that classify 135 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 pediatric cancer subtypes. SIGNIFICANCE: To advance research and treatment of pediatric cancer, we developed St. Jude Cloud, a data-sharing ecosystem for accessing >1.2 petabytes of raw genomic data from >10,000 pediatric patients and survivors, innovative analysis workflows, integrative multiomics visualizations, and a knowledgebase of published data contributed by the global pediatric cancer community..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102307PMC
May 2021

Bioinformatic Methods to Identify Mutational Signatures in Cancer.

Methods Mol Biol 2021 ;2185:447-473

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.

The genome of a cancer contains somatic mutations that reflect the activities of endogenous and exogenous mutational processes, with each mutational process imprinting a characteristic mutational signature. Computational analysis of somatic mutations derived from next-generation sequencing data allows revealing the mutational signatures operative in a set of cancer genomes. In this chapter, we briefly review the concept of mutational signatures and the tools available for deciphering mutational signatures. Further, we provide a quick guide as well as an in-depth protocol for deciphering mutational signatures using the tool SigProfilerExtractor and review the results generated from an example dataset of cancer genomes.
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http://dx.doi.org/10.1007/978-1-0716-0810-4_28DOI Listing
March 2021

Generating realistic null hypothesis of cancer mutational landscapes using SigProfilerSimulator.

BMC Bioinformatics 2020 Oct 7;21(1):438. Epub 2020 Oct 7.

Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.

Background: Performing a statistical test requires a null hypothesis. In cancer genomics, a key challenge is the fast generation of accurate somatic mutational landscapes that can be used as a realistic null hypothesis for making biological discoveries.

Results: Here we present SigProfilerSimulator, a powerful tool that is capable of simulating the mutational landscapes of thousands of cancer genomes at different resolutions within seconds. Applying SigProfilerSimulator to 2144 whole-genome sequenced cancers reveals: (i) that most doublet base substitutions are not due to two adjacent single base substitutions but likely occur as single genomic events; (ii) that an extended sequencing context of ± 2 bp is required to more completely capture the patterns of substitution mutational signatures in human cancer; (iii) information on false-positive discovery rate of commonly used bioinformatics tools for detecting driver genes.

Conclusions: SigProfilerSimulator's breadth of features allows one to construct a tailored null hypothesis and use it for evaluating the accuracy of other bioinformatics tools or for downstream statistical analysis for biological discoveries. SigProfilerSimulator is freely available at https://github.com/AlexandrovLab/SigProfilerSimulator with an extensive documentation at https://osf.io/usxjz/wiki/home/ .
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http://dx.doi.org/10.1186/s12859-020-03772-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539472PMC
October 2020

The mutational signature profile of known and suspected human carcinogens in mice.

Nat Genet 2020 11 28;52(11):1189-1197. Epub 2020 Sep 28.

Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

Epidemiological studies have identified many environmental agents that appear to significantly increase cancer risk in human populations. By analyzing tumor genomes from mice chronically exposed to 1 of 20 known or suspected human carcinogens, we reveal that most agents do not generate distinct mutational signatures or increase mutation burden, with most mutations, including driver mutations, resulting from tissue-specific endogenous processes. We identify signatures resulting from exposure to cobalt and vinylidene chloride and link distinct human signatures (SBS19 and SBS42) with 1,2,3-trichloropropane, a haloalkane and pollutant of drinking water, and find these and other signatures in human tumor genomes. We define the cross-species genomic landscape of tumors induced by an important compendium of agents with relevance to human health.
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http://dx.doi.org/10.1038/s41588-020-0692-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610456PMC
November 2020

Strength of immune selection in tumors varies with sex and age.

Nat Commun 2020 08 17;11(1):4128. Epub 2020 Aug 17.

Department of Medicine, Division of Medical Genetics, University of California San Diego, La Jolla, CA, 92093, USA.

Individual MHC genotype constrains the mutational landscape during tumorigenesis. Immune checkpoint inhibition reactivates immunity against tumors that escaped immune surveillance in approximately 30% of cases. Recent studies demonstrated poorer response rates in female and younger patients. Although immune responses differ with sex and age, the role of MHC-based immune selection in this context is unknown. We find that tumors in younger and female individuals accumulate more poorly presented driver mutations than those in older and male patients, despite no differences in MHC genotype. Younger patients show the strongest effects of MHC-based driver mutation selection, with younger females showing compounded effects and nearly twice as much MHC-II based selection. This study presents evidence that strength of immune selection during tumor development varies with sex and age, and may influence the availability of mutant peptides capable of driving effective response to immune checkpoint inhibitor therapy.
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http://dx.doi.org/10.1038/s41467-020-17981-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431859PMC
August 2020

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas.

Nat Commun 2020 06 18;11(1):3096. Epub 2020 Jun 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, MD, 20892, USA.

Intratumor heterogeneity (ITH) and tumor evolution have been well described for clear cell renal cell carcinomas (ccRCC), but they are less studied for other kidney cancer subtypes. Here we investigate ITH and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enable phylogenetic analysis of spatial features of clonal expansion, which shows congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of ccRCC, in pRCC, driver gene mutations and most arm-level somatic copy number alterations (SCNAs) are clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and that targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displays near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes have numerous SVs, which should be pursued for prognostic significance.
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http://dx.doi.org/10.1038/s41467-020-16546-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303129PMC
June 2020

Timing the initiation of multiple myeloma.

Nat Commun 2020 04 21;11(1):1917. Epub 2020 Apr 21.

Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

The evolution and progression of multiple myeloma and its precursors over time is poorly understood. Here, we investigate the landscape and timing of mutational processes shaping multiple myeloma evolution in a large cohort of 89 whole genomes and 973 exomes. We identify eight processes, including a mutational signature caused by exposure to melphalan. Reconstructing the chronological activity of each mutational signature, we estimate that the initial transformation of a germinal center B-cell usually occurred during the first 2-3 decades of life. We define four main patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis over time, including a subset of patients with evidence of prolonged AID activity during the pre-malignant phase, indicating antigen-responsiveness and germinal center reentry. Our findings provide a framework to study the etiology of multiple myeloma and explore strategies for prevention and early detection.
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http://dx.doi.org/10.1038/s41467-020-15740-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174344PMC
April 2020

The repertoire of mutational signatures in human cancer.

Nature 2020 02 5;578(7793):94-101. Epub 2020 Feb 5.

Wellcome Sanger Institute, Hinxton, UK.

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.
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http://dx.doi.org/10.1038/s41586-020-1943-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054213PMC
February 2020

Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice.

Nat Commun 2020 01 20;11(1):394. Epub 2020 Jan 20.

UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, 94158, USA.

Ionising radiation (IR) is a recognised carcinogen responsible for cancer development in patients previously treated using radiotherapy, and in individuals exposed as a result of accidents at nuclear energy plants. However, the mutational signatures induced by distinct types and doses of radiation are unknown. Here, we analyse the genetic architecture of mammary tumours, lymphomas and sarcomas induced by high (Fe-ions) or low (gamma) energy radiation in mice carrying Trp53 loss of function alleles. In mammary tumours, high-energy radiation is associated with induction of focal structural variants, leading to genomic instability and Met amplification. Gamma-radiation is linked to large-scale structural variants and a point mutation signature associated with oxidative stress. The genomic architecture of carcinomas, sarcomas and lymphomas arising in the same animals are significantly different. Our study illustrates the complex interactions between radiation quality, germline Trp53 deficiency and tissue/cell of origin in shaping the genomic landscape of IR-induced tumours.
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http://dx.doi.org/10.1038/s41467-019-14261-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971050PMC
January 2020

The Association of Modifiable Breast Cancer Risk Factors and Somatic Genomic Alterations in Breast Tumors: The Cancer Genome Atlas Network.

Cancer Epidemiol Biomarkers Prev 2020 03 13;29(3):599-605. Epub 2020 Jan 13.

Channing Division of Network Medicine, Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.

Background: The link between modifiable breast cancer risk factors and tumor genomic alterations remains largely unexplored. We evaluated the association of prediagnostic body mass index (BMI), cigarette smoking, and alcohol consumption with somatic copy number variation (SCNV), total somatic mutation burden (TSMB), seven single base substitution (SBS) signatures (SBS1, SBS2, SBS3, SBS5, SBS13, SBS29, and SBS30), and nine driver mutations (, and ) in a subset of The Cancer Genome Atlas (TCGA).

Methods: Clinical and genomic data were retrieved from the TCGA database. Risk factor information was collected from four TCGA sites ( = 219 women), including BMI (1 year before diagnosis), cigarette smoking (smokers/nonsmokers), and alcohol consumption (current drinkers/nondrinkers). Multivariable regression analyses were conducted in all tumors and stratified according to estrogen receptor (ER) status.

Results: Increasing BMI was associated with increasing SCNV in all women ( = 0.039) and among women with ER tumors ( = 0.031). Smokers had higher SCNV and TSMB versus nonsmokers ( < 0.05 all women). Alcohol drinkers had higher SCNV versus nondrinkers ( < 0.05 all women and among women with ER tumors). SBS3 (defective homologous recombination-based repair) was exclusively found in alcohol drinkers with ER disease. mutation was more likely to occur in women with higher BMI. No association was significant after multiple testing correction.

Conclusions: This study provides preliminary evidence that BMI, cigarette smoking, and alcohol consumption can influence breast tumor biology, in particular, DNA alterations.

Impact: This study demonstrates a link between modifiable breast cancer risk factors and tumor genomic alterations.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060119PMC
March 2020

Genomic evidence supports a clonal diaspora model for metastases of esophageal adenocarcinoma.

Nat Genet 2020 01 6;52(1):74-83. Epub 2020 Jan 6.

MRC Cancer Unit, University of Cambridge, Cambridge, UK.

The poor outcomes in esophageal adenocarcinoma (EAC) prompted us to interrogate the pattern and timing of metastatic spread. Whole-genome sequencing and phylogenetic analysis of 388 samples across 18 individuals with EAC showed, in 90% of patients, that multiple subclones from the primary tumor spread very rapidly from the primary site to form multiple metastases, including lymph nodes and distant tissues-a mode of dissemination that we term 'clonal diaspora'. Metastatic subclones at autopsy were present in tissue and blood samples from earlier time points. These findings have implications for our understanding and clinical evaluation of EAC.
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http://dx.doi.org/10.1038/s41588-019-0551-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100916PMC
January 2020

IL-17 signaling in steatotic hepatocytes and macrophages promotes hepatocellular carcinoma in alcohol-related liver disease.

J Hepatol 2020 05 31;72(5):946-959. Epub 2019 Dec 31.

Department of Surgery, University of California San Diego, La Jolla, CA, USA. Electronic address:

Background & Aims: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA.

Methods: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens.

Results: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra and major urinary protein-urokinase-type plasminogen activator/Il-17ra mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17ra and Il-17ra mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17ra mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17ra mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17ra mice developed the fewest tumors (compared with Il-17ra mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC.

Conclusions: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC.

Lay Summary: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
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http://dx.doi.org/10.1016/j.jhep.2019.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167339PMC
May 2020

Whole-exome sequencing reveals the impact of UVA light mutagenesis in xeroderma pigmentosum variant human cells.

Nucleic Acids Res 2020 02;48(4):1941-1953

Department of Microbiology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil.

UVA-induced mutagenesis was investigated in human pol eta-deficient (XP-V) cells through whole-exome sequencing. In UVA-irradiated cells, the increase in the mutation frequency in deficient cells included a remarkable contribution of C>T transitions, mainly at potential pyrimidine dimer sites. A strong contribution of C>A transversions, potentially due to oxidized bases, was also observed in non-irradiated XP-V cells, indicating that basal mutagenesis caused by oxidative stress may be related to internal tumours in XP-V patients. The low levels of mutations involving T induced by UVA indicate that pol eta is not responsible for correctly replicating T-containing pyrimidine dimers, a phenomenon known as the 'A-rule'. Moreover, the mutation signature profile of UVA-irradiated XP-V cells is highly similar to the human skin cancer profile, revealing how studies involving cells deficient in DNA damage processing may be useful to understand the mechanisms of environmentally induced carcinogenesis.
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http://dx.doi.org/10.1093/nar/gkz1182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038989PMC
February 2020

Syngeneic animal models of tobacco-associated oral cancer reveal the activity of in situ anti-CTLA-4.

Nat Commun 2019 12 5;10(1):5546. Epub 2019 Dec 5.

Moores Cancer Center, University of California San Diego, 3855 Health Sciences Drive, La Jolla, CA, USA.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately mimic the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report a mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we find that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform to accelerate the development of immunotherapeutic options for HNSCC.
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http://dx.doi.org/10.1038/s41467-019-13471-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895221PMC
December 2019

Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia.

Blood 2020 01;135(1):41-55

Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Shanghai Children's Medical Center-National Children's Medical Center, and.

To study the mechanisms of relapse in acute lymphoblastic leukemia (ALL), we performed whole-genome sequencing of 103 diagnosis-relapse-germline trios and ultra-deep sequencing of 208 serial samples in 16 patients. Relapse-specific somatic alterations were enriched in 12 genes (NR3C1, NR3C2, TP53, NT5C2, FPGS, CREBBP, MSH2, MSH6, PMS2, WHSC1, PRPS1, and PRPS2) involved in drug response. Their prevalence was 17% in very early relapse (<9 months from diagnosis), 65% in early relapse (9-36 months), and 32% in late relapse (>36 months) groups. Convergent evolution, in which multiple subclones harbor mutations in the same drug resistance gene, was observed in 6 relapses and confirmed by single-cell sequencing in 1 case. Mathematical modeling and mutational signature analysis indicated that early relapse resistance acquisition was frequently a 2-step process in which a persistent clone survived initial therapy and later acquired bona fide resistance mutations during therapy. In contrast, very early relapses arose from preexisting resistant clone(s). Two novel relapse-specific mutational signatures, one of which was caused by thiopurine treatment based on in vitro drug exposure experiments, were identified in early and late relapses but were absent from 2540 pan-cancer diagnosis samples and 129 non-ALL relapses. The novel signatures were detected in 27% of relapsed ALLs and were responsible for 46% of acquired resistance mutations in NT5C2, PRPS1, NR3C1, and TP53. These results suggest that chemotherapy-induced drug resistance mutations facilitate a subset of pediatric ALL relapses.
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http://dx.doi.org/10.1182/blood.2019002220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6940198PMC
January 2020

Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy.

Proc Natl Acad Sci U S A 2019 11 17;116(45):22730-22736. Epub 2019 Oct 17.

Institute of Obstetrics and Gynecology, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.

The prognosis of advanced/recurrent cervical cancer patients remains poor. We analyzed 54 fresh-frozen and 15 primary cervical cancer cell lines, along with matched-normal DNA, by whole-exome sequencing (WES), most of which harboring Human-Papillomavirus-type-16/18. We found recurrent somatic missense mutations in 22 genes (including PIK3CA, ERBB2, and GNAS) and a widespread APOBEC cytidine deaminase mutagenesis pattern (TCW motif) in both adenocarcinoma (ACC) and squamous cell carcinomas (SCCs). Somatic copy number variants (CNVs) identified 12 copy number gains and 40 losses, occurring more often than expected by chance, with the most frequent events in pathways similar to those found from analysis of single nucleotide variants (SNVs), including the ERBB2/PI3K/AKT/mTOR, apoptosis, chromatin remodeling, and cell cycle. To validate specific SNVs as targets, we took advantage of primary cervical tumor cell lines and xenografts to preclinically evaluate the activity of pan-HER (afatinib and neratinib) and PIK3CA (copanlisib) inhibitors, alone and in combination, against tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway (71%). Tumors harboring (5.8%) domain mutations were significantly more sensitive to single agents afatinib or neratinib when compared to wild-type tumors in preclinical in vitro and in vivo models ( = 0.001). In contrast, pan-HER and PIK3CA inhibitors demonstrated limited in vitro activity and were only transiently effective in controlling in vivo growth of PIK3CA-mutated cervical cancer xenografts. Importantly, combinations of copanlisib and neratinib were highly synergistic, inducing long-lasting regression of tumors harboring alterations in the ERBB2/PI3K/AKT/mTOR pathway. These findings define the genetic landscape of cervical cancer, suggesting that a large subset of cervical tumors might benefit from existing ERBB2/PIK3CA/AKT/mTOR-targeted drugs.
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http://dx.doi.org/10.1073/pnas.1911385116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842590PMC
November 2019

SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events.

BMC Genomics 2019 Aug 30;20(1):685. Epub 2019 Aug 30.

Department of Cellular and Molecular Medicine and Department of Bioengineering and Moores Cancer Center, University of California, San Diego, La Jolla, CA, 92093, USA.

Background: Cancer genomes are peppered with somatic mutations imprinted by different mutational processes. The mutational pattern of a cancer genome can be used to identify and understand the etiology of the underlying mutational processes. A plethora of prior research has focused on examining mutational signatures and mutational patterns from single base substitutions and their immediate sequencing context. We recently demonstrated that further classification of small mutational events (including substitutions, insertions, deletions, and doublet substitutions) can be used to provide a deeper understanding of the mutational processes that have molded a cancer genome. However, there has been no standard tool that allows fast, accurate, and comprehensive classification for all types of small mutational events.

Results: Here, we present SigProfilerMatrixGenerator, a computational tool designed for optimized exploration and visualization of mutational patterns for all types of small mutational events. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment. SigProfilerMatrixGenerator produces fourteen distinct matrices by considering transcriptional strand bias of individual events and by incorporating distinct classifications for single base substitutions, doublet base substitutions, and small insertions and deletions. While the tool provides a comprehensive classification of mutations, SigProfilerMatrixGenerator is also faster and more memory efficient than existing tools that generate only a single matrix.

Conclusions: SigProfilerMatrixGenerator provides a standardized method for classifying small mutational events that is both efficient and scalable to large datasets. In addition to extending the classification of single base substitutions, the tool is the first to provide support for classifying doublet base substitutions and small insertions and deletions. SigProfilerMatrixGenerator is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/ .
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http://dx.doi.org/10.1186/s12864-019-6041-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717374PMC
August 2019

Somatic evolution and global expansion of an ancient transmissible cancer lineage.

Science 2019 08;365(6452)

Universidade Vila Velha, Vila Velha, Brazil.

The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by "metastasizing" between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage's worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer's evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.
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http://dx.doi.org/10.1126/science.aau9923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116271PMC
August 2019

Insights into BRCA Cancer Predisposition from Integrated Germline and Somatic Analyses in 7632 Cancers.

JNCI Cancer Spectr 2019 Jun 19;3(2):pkz028. Epub 2019 Apr 19.

Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.

Background: It is often assumed any cancer in a germline or (collectively termed BRCA) mutation carrier was caused by that mutation. It is also often assumed the occurrence of breast or ovarian cancer in an individual with a variant of uncertain significance (VUS) suggests the VUS is pathogenic. These assumptions have profound management implications for cancer patients and healthy individuals.

Methods: We compared the frequency of BRCA mutations, allele loss, and Signature 3 in 7632 individuals with 28 cancers and 1000 population controls. Because only increased frequency was the focus of the study, all statistical tests were one-sided.

Results: Individuals with breast or ovarian cancer had increased germline BRCA pathogenic mutation frequencies compared to controls ( = 1.0x10 and  = 1.4x10, respectively). There was no increase in other cancer types. Wild-type allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers with BRCA mutations compared with other cancers with BRCA mutations ( = 5.1x10 and  = 3.7x10) and cancers without BRCA mutations ( = 2.8x10 and  = 1.0x10). There was no difference between non-breast and non-ovarian cancers with BRCA mutations and cancers without BRCA mutations. Allele loss and Signature 3 were statistically significantly higher in breast and ovarian cancers in individuals with BRCA pathogenic mutations compared to those with VUS ( = 3.8x10 and  = 1.6x10) or benign variants ( = 1.2x10 and  = 2.2x10). There was no difference between individuals with BRCA VUS and those with benign variants.

Conclusions: These data show that non-breast and non-ovarian cancers in individuals with germline BRCA pathogenic mutations are often not causally related to the mutation and that BRCA VUS are highly unlikely to be pathogenic. These results should reduce inappropriate management of germline BRCA information.
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http://dx.doi.org/10.1093/jncics/pkz028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649772PMC
June 2019
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