ABSTRACT
Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.
Subject(s)
DNA Copy Number Variations , DNA Mutational Analysis , Neoplasms , Aneuploidy , Chromothripsis , DNA Copy Number Variations/genetics , Haploidy , Homologous Recombination/genetics , Humans , Loss of Heterozygosity/genetics , Mutation , Neoplasms/genetics , Neoplasms/pathology , Exome SequencingABSTRACT
Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
Subject(s)
Breast Neoplasms/genetics , Cell Transformation, Neoplastic , Clonal Evolution , Mutation , Algorithms , Chromosome Aberrations , Female , Humans , Point MutationABSTRACT
All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis," was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
Subject(s)
Breast Neoplasms/genetics , DNA Mutational Analysis , Genome-Wide Association Study , Mutation , APOBEC-1 Deaminase , BRCA2 Protein/genetics , Cytidine Deaminase/metabolism , Female , Genes, BRCA1 , High-Throughput Nucleotide Sequencing , HumansABSTRACT
Li-Fraumeni syndrome is caused by inherited TP53 tumor suppressor gene mutations. MicroRNA miR-34a is a p53 target and modifier gene. Interestingly, miR-34 triple-null mice exhibit normal p53 responses and no overt cancer development, but the lack of miR-34 promotes tumorigenesis in cancer-susceptible backgrounds. miR-34 genes are highly conserved and syntenic between zebrafish and humans. Zebrafish miR-34a and miR-34b/c have similar expression timing in development, but miR-34a is more abundant. DNA damage by camptothecin led to p53-dependent induction of miR-34 genes, while miR-34a mutants were adult-viable and had normal DNA damage-induced apoptosis. Nevertheless, miR-34a-/- compound mutants with a gain-of-function tp53R217H/ R217H or tp53-/- mutants were more cancer-prone than tp53 mutants alone, confirming the tumor-suppressive function of miR-34a. Through transcriptomic comparisons at 28 hours post-fertilization (hpf), we characterized DNA damage-induced transcription, and at 8, 28 and 72 hpf we determined potential miR-34a-regulated genes. At 72 hpf, loss of miR-34a enhanced erythrocyte levels and up-regulated myb-positive hematopoietic stem cells. Overexpression of miR-34a suppressed its reporter mRNA, but not p53 target induction, and sensitized injected embryos to camptothecin but not to γ-irradiation.
Subject(s)
DNA Damage , Hematopoiesis , MicroRNAs , Tumor Suppressor Protein p53 , Zebrafish Proteins , Zebrafish , Animals , Humans , Mice , Apoptosis/genetics , Camptothecin/pharmacology , Gene Expression Regulation, Developmental , Genes, Tumor Suppressor , Hematopoiesis/genetics , Li-Fraumeni Syndrome/genetics , MicroRNAs/genetics , MicroRNAs/metabolism , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Protein p53/metabolism , Zebrafish/genetics , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
Genome sequencing (GS) is a powerful test for the diagnosis of rare genetic disorders. Although GS can enumerate most non-coding variation, determining which non-coding variants are disease-causing is challenging. RNA sequencing (RNA-seq) has emerged as an important tool to help address this issue, but its diagnostic utility remains understudied, and the added value of a trio design is unknown. We performed GS plus RNA-seq from blood using an automated clinical-grade high-throughput platform on 97 individuals from 39 families where the proband was a child with unexplained medical complexity. RNA-seq was an effective adjunct test when paired with GS. It enabled clarification of putative splice variants in three families, but it did not reveal variants not already identified by GS analysis. Trio RNA-seq decreased the number of candidates requiring manual review when filtering for de novo dominant disease-causing variants, allowing for the exclusion of 16% of gene-expression outliers and 27% of allele-specific-expression outliers. However, clear diagnostic benefit from the trio design was not observed. Blood-based RNA-seq can facilitate genome analysis in children with suspected undiagnosed genetic disease. In contrast to DNA sequencing, the clinical advantages of a trio RNA-seq design may be more limited.
Subject(s)
Family , Rare Diseases , Humans , Child , Base Sequence , Sequence Analysis, DNA , Exome Sequencing , Rare Diseases/genetics , Sequence Analysis, RNAABSTRACT
OBJECTIVE: Disease spectrum in pediatric sarcoma differs substantially from adults. We report a cohort of very young children with non-rhabdomyosarcoma soft tissue sarcoma (NRSTS) detailing their molecular features, treatment, and outcome. METHODS: We report features of consecutive children (age <2 years) with NRSTS (2000-2017). Archival pathological material was re-reviewed, with additional molecular techniques applied where indicated. RESULTS: Twenty-nine patients (16 females, 55%) were identified (median age 6 months; range 0-23). Most common diagnoses included infantile fibrosarcoma (IFS, n = 14, 48%), malignant rhabdoid tumor (MRT, n = 4, 14%), and undifferentiated sarcoma (n = 4, 14%). Twenty-seven of 29 (93%) had tumor molecular characterization to confirm diagnosis. Clinical presentation included a swelling/mass (n = 23, 79%). Disease extent was localized (n = 20, 69%), locoregional (n = 6, 21%), or metastatic (n = 3, 10%). Seventeen of 29 (59%) who underwent surgery achieved complete resection (R0). Other treatments included conventional chemotherapy (n = 26, 90%), molecularly targeted therapies (n = 3, 10%), and radiation (n = 5, 17%). At last follow-up (median 3 years; range 0.3-16.4), 23 (79%) were alive, disease-free and six (21%) had died of disease. All patients with IFS were alive and all those with MRT died. A cancer predisposition syndrome (CPS) was confirmed in three of 10 (30%) genetically tested patients. CONCLUSION: We recommend tumor molecular characterization in all young patients including evaluation for CPS to optimize treatment options and prognostication.
Subject(s)
Sarcoma , Soft Tissue Neoplasms , Disease-Free Survival , Female , Fibrosarcoma/diagnosis , Fibrosarcoma/therapy , Humans , Infant , Infant, Newborn , Male , Rhabdoid Tumor/diagnosis , Rhabdoid Tumor/therapy , Sarcoma/diagnosis , Sarcoma/therapy , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/therapyABSTRACT
We have optimized point mutation knock-ins into zebrafish genomic sites using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 reagents and single-stranded oligodeoxynucleotides. The efficiency of knock-ins was assessed by a novel application of allele-specific polymerase chain reaction and confirmed by high-throughput sequencing. Anti-sense asymmetric oligo design was found to be the most successful optimization strategy. However, cut site proximity to the mutation and phosphorothioate oligo modifications also greatly improved knock-in efficiency. A previously unrecognized risk of off-target trans knock-ins was identified that we obviated through the development of a workflow for correct knock-in detection. Together these strategies greatly facilitate the study of human genetic diseases in zebrafish, with additional applicability to enhance CRISPR-based approaches in other animal model systems.
Subject(s)
CRISPR-Cas Systems , Gene Editing/methods , Gene Knock-In Techniques/methods , Point Mutation/genetics , Zebrafish/genetics , Animals , Animals, Genetically Modified , Clustered Regularly Interspaced Short Palindromic Repeats , Embryo, Nonmammalian , Microinjections , Mutagenesis, Site-Directed/methods , Zebrafish/embryologySubject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Clonal Hematopoiesis , Leukemia, Myeloid, Acute/chemically induced , Myelodysplastic Syndromes/chemically induced , Neoplasms, Second Primary/chemically induced , Neuroblastoma/therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Child , Child, Preschool , Clonal Evolution , Combined Modality Therapy , Female , Hematopoietic Stem Cell Transplantation , Humans , Mutation , Myeloablative Agonists/adverse effects , Myeloablative Agonists/therapeutic use , Neoplasms, Second Primary/genetics , Neoplasms, Second Primary/physiopathology , Neuroblastoma/drug therapy , Preleukemia/chemically induced , Preleukemia/genetics , Preleukemia/physiopathology , Transplantation Conditioning/adverse effects , Transplantation, AutologousABSTRACT
Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in the pediatric age group. While RMS has been traditionally classified on the basis of its histological appearance (with embryonal and alveolar being most common), it is now clear that the PAX-FOXO1 fusion product drives prognosis. We report here a case of pelvic embryonal RMS in a 3-month-old male who was subsequently found to have developed brain metastases during the course of chemotherapy. Cytogenetic analysis of the brain metastases at the time of autopsy as well as next-generation sequencing analysis revealed a reciprocal translocation involving the SH3 domain containing ring finger 3 gene (SH3RF3, on chromosome 2q13) and the Lipase C gene (LIPC, on chromosome 15q21.3). Due to the poor quality of the pretreatment and postresection samples, cytogenetics and NGS analysis looking for the presence of this balanced translocation in these specimens could not be performed. To the authors' knowledge, this translocation has never been described in RMS. Further studies are needed to determine the biological and clinical implications of this novel translocation.
Subject(s)
Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 2/genetics , Rhabdomyosarcoma, Embryonal/genetics , Translocation, Genetic , Forkhead Box Protein O1/genetics , Humans , Infant , Lipase/genetics , Male , Oncogene Proteins, Fusion/genetics , Paired Box Transcription Factors/genetics , Rhabdomyosarcoma, Embryonal/pathology , Ubiquitin-Protein Ligases/geneticsSubject(s)
Leukemia, Megakaryoblastic, Acute/pathology , Oncogene Proteins, Fusion/genetics , Polymorphism, Single Nucleotide , Promoter Regions, Genetic , RNA-Binding Proteins/genetics , Telomerase/genetics , Trans-Activators/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Fatal Outcome , Female , Humans , Infant , Leukemia, Megakaryoblastic, Acute/drug therapy , Leukemia, Megakaryoblastic, Acute/geneticsSubject(s)
Antibiotics, Antineoplastic/therapeutic use , Depsipeptides/therapeutic use , Histone Deacetylase Inhibitors/therapeutic use , Lymphoma, T-Cell, Peripheral/drug therapy , Neoplasm Recurrence, Local/drug therapy , Adolescent , Child , Child, Preschool , Female , Histone Deacetylase 1/antagonists & inhibitors , Humans , Male , Treatment FailureABSTRACT
The recessive disorder poikiloderma with neutropenia (PN) is caused by mutations in the C16orf57 gene that encodes the highly conserved USB1 protein. Here, we present the 1.1 Å resolution crystal structure of human USB1, defining it as a member of the LigT-like superfamily of 2H phosphoesterases. We show that human USB1 is a distributive 3'-5' exoribonuclease that posttranscriptionally removes uridine and adenosine nucleosides from the 3' end of spliceosomal U6 small nuclear RNA (snRNA), directly catalyzing terminal 2', 3' cyclic phosphate formation. USB1 measures the appropriate length of the U6 oligo(U) tail by reading the position of a key adenine nucleotide (A102) and pausing 5 uridine residues downstream.We show that the 3' ends of U6 snRNA in PN patient lymphoblasts are elongated and unexpectedly carry nontemplated 3' oligo(A) tails that are characteristic of nuclear RNA surveillance targets. Thus, our study reveals a novel quality control pathway in which posttranscriptional 3'-end processing by USB1 protects U6 snRNA from targeting and destruction by the nuclear exosome. Our data implicate aberrant oligoadenylation of U6 snRNA in the pathogenesis of the leukemia predisposition disorder PN.
Subject(s)
Mutation , Neutropenia/genetics , Phosphoric Diester Hydrolases/genetics , RNA, Small Nuclear/genetics , Skin Abnormalities/genetics , 3' Untranslated Regions/genetics , Adenine Nucleotides/genetics , Adenine Nucleotides/metabolism , Amino Acid Sequence , Base Sequence , Catalytic Domain , Cell Line , Crystallography, X-Ray , Genetic Complementation Test , Humans , Models, Genetic , Models, Molecular , Molecular Sequence Data , Neutropenia/metabolism , Oligoribonucleotides/genetics , Oligoribonucleotides/metabolism , Phosphoric Diester Hydrolases/chemistry , Phosphoric Diester Hydrolases/metabolism , RNA Processing, Post-Transcriptional , RNA, Small Nuclear/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/growth & development , Sequence Homology, Amino Acid , Skin Abnormalities/metabolism , Spliceosomes/genetics , Spliceosomes/metabolism , Uridine/genetics , Uridine/metabolismABSTRACT
Myelodysplastic syndromes (MDS) are a heterogeneous group of chronic hematological malignancies characterized by dysplasia, ineffective hematopoiesis and a variable risk of progression to acute myeloid leukemia. Sequencing of MDS genomes has identified mutations in genes implicated in RNA splicing, DNA modification, chromatin regulation, and cell signaling. We sequenced 111 genes across 738 patients with MDS or closely related neoplasms (including chronic myelomonocytic leukemia and MDS-myeloproliferative neoplasms) to explore the role of acquired mutations in MDS biology and clinical phenotype. Seventy-eight percent of patients had 1 or more oncogenic mutations. We identify complex patterns of pairwise association between genes, indicative of epistatic interactions involving components of the spliceosome machinery and epigenetic modifiers. Coupled with inferences on subclonal mutations, these data suggest a hypothesis of genetic "predestination," in which early driver mutations, typically affecting genes involved in RNA splicing, dictate future trajectories of disease evolution with distinct clinical phenotypes. Driver mutations had equivalent prognostic significance, whether clonal or subclonal, and leukemia-free survival deteriorated steadily as numbers of driver mutations increased. Thus, analysis of oncogenic mutations in large, well-characterized cohorts of patients illustrates the interconnections between the cancer genome and disease biology, with considerable potential for clinical application.
Subject(s)
Mutation , Myelodysplastic Syndromes/genetics , Aged , Aged, 80 and over , Cohort Studies , Disease Progression , Epistasis, Genetic , Female , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Male , Middle Aged , Myelodysplastic-Myeloproliferative Diseases/genetics , Oncogenes , Prognosis , RNA Splicing/genetics , Spliceosomes/geneticsABSTRACT
BACKGROUND: High-risk neuroblastoma is a complex genetic disease that is lethal in more than 50% of patients despite intense multimodal therapy. Through genome-wide association studies (GWAS) and next-generation sequencing, we have identified common single nucleotide polymorphisms and rare, pathogenic or likely pathogenic germline loss-of-function variants in BARD1 enriched in neuroblastoma patients. The functional implications of these findings remain poorly understood. METHODS: We correlated BARD1 genotype with expression in normal tissues and neuroblastomas, along with the burden of DNA damage in tumors. To validate the functional consequences of germline pathogenic or likely pathogenic BARD1 variants, we used CRISPR-Cas9 to generate isogenic neuroblastoma (IMR-5) and control (RPE1) cellular models harboring heterozygous BARD1 loss-of-function variants (R112*, R150*, E287fs, and Q564*) and quantified genomic instability in these cells via next-generation sequencing and with functional assays measuring the efficiency of DNA repair. RESULTS: Both common and rare neuroblastoma-associated BARD1 germline variants were associated with lower levels of BARD1 mRNA and an increased burden of DNA damage. Using isogenic heterozygous BARD1 loss-of-function variant cellular models, we functionally validated this association with inefficient DNA repair. BARD1 loss-of-function variant isogenic cells exhibited reduced efficiency in repairing Cas9-induced DNA damage, ineffective RAD51 focus formation at DNA double-strand break sites, and enhanced sensitivity to cisplatin and poly (ADP-ribose) polymerase (PARP) inhibition both in vitro and in vivo. CONCLUSIONS: Taken together, we demonstrate that germline BARD1 variants disrupt DNA repair fidelity. This is a fundamental molecular mechanism contributing to neuroblastoma initiation that may have important therapeutic implications.
Subject(s)
Neuroblastoma , Tumor Suppressor Proteins , Humans , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Genome-Wide Association Study , Haploinsufficiency , Ubiquitin-Protein Ligases/genetics , BRCA1 Protein/genetics , DNA Repair/genetics , Neuroblastoma/pathologyABSTRACT
Germline pathogenic TP53 variants predispose individuals to a high lifetime risk of developing multiple cancers and are the hallmark feature of Li-Fraumeni syndrome (LFS). Our group has previously shown that LFS patients harbor shorter plasma cell-free DNA fragmentation; independent of cancer status. To understand the functional underpinning of cfDNA fragmentation in LFS, we conducted a fragmentomic analysis of 199 cfDNA samples from 82 TP53 mutation carriers and 30 healthy TP53-wildtype controls. We find that LFS individuals exhibit an increased prevalence of A/T nucleotides at fragment ends, dysregulated nucleosome positioning at p53 binding sites, and loci-specific changes in chromatin accessibility at development-associated transcription factor binding sites and at cancer-associated open chromatin regions. Machine learning classification resulted in robust differentiation between TP53 mutant versus wildtype cfDNA samples (AUC-ROC = 0.710-1.000) and intra-patient longitudinal analysis of ctDNA fragmentation signal enabled early cancer detection. These results suggest that cfDNA fragmentation may be a useful diagnostic tool in LFS patients and provides an important baseline for cancer early detection.
Subject(s)
Cell-Free Nucleic Acids , DNA Fragmentation , Germ-Line Mutation , Li-Fraumeni Syndrome , Tumor Suppressor Protein p53 , Humans , Tumor Suppressor Protein p53/genetics , Male , Female , Li-Fraumeni Syndrome/genetics , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/blood , Adult , Young Adult , Middle Aged , Circulating Tumor DNA/genetics , Circulating Tumor DNA/blood , Adolescent , Neoplasms/genetics , Neoplasms/pathology , Chromatin/genetics , Chromatin/metabolism , Machine Learning , Heterozygote , Child , Nucleosomes/metabolism , Nucleosomes/genetics , Early Detection of CancerABSTRACT
Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to American College of Medical Genetics/Association for Molecular Pathology criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes are poorly understood. We identified 168 rare CSSVs in blood-expressed genes in 112 individuals using genome sequencing, and studied their impact on splicing using RNA sequencing (RNA-seq). There was no evidence of a frameshift, nor of reduced expression consistent with nonsense-mediated decay, for 25.6% of CSSVs: 17.9% had wildtype splicing only and normal junction depths, 3.6% resulted in cryptic splice site usage and in-frame insertions or deletions, 3.6% resulted in full exon skipping (in frame), and 0.6% resulted in full intron inclusion (in frame). Blind to these RNA-seq data, we attempted to predict the precise impact of CSSVs by applying in silico tools and the ClinGen Sequence Variant Interpretation Working Group 2018 guidelines for applying PVS1 criterion. The predicted impact on splicing using (1) SpliceAI, (2) MaxEntScan, and (3) AutoPVS1, an automatic classification tool for PVS1 interpretation of null variants that utilizes Ensembl Variant Effect Predictor and MaxEntScan, was concordant with RNA-seq analyses for 65%, 63%, and 61% of CSSVs, respectively. In summary, approximately one in four rare CSSVs did not show evidence for LoF based on analysis of RNA-seq data. Predictions from in silico methods were often discordant with findings from RNA-seq. More caution may be warranted in applying PVS1-level evidence to CSSVs in the absence of functional data.
Subject(s)
Computer Simulation , RNA Splice Sites , RNA Splicing , Humans , RNA Splice Sites/genetics , RNA Splicing/genetics , Computational Biology/methods , Exons/genetics , Genetic Variation/geneticsABSTRACT
CIC::DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of patient tumor samples and cell lines. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous soft tissue tumors and disseminated disease in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic Cic function and the distance between adjacent loxP sites. Characterization of soft tissue and presumed metastatic tumors showed that they consistently expressed the CIC::DUX4 fusion protein and many downstream markers of the disease credentialing the models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-sequencing maps, validate CIC::DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS.
Subject(s)
Sarcoma, Small Cell , Sarcoma , Soft Tissue Neoplasms , Animals , Mice , Alleles , Biomarkers, Tumor , Oncogene Proteins, Fusion/genetics , Oncogene Proteins, Fusion/metabolism , Proto-Oncogene Proteins c-ets , Sarcoma/genetics , Sarcoma/metabolism , Sarcoma, Small Cell/chemistry , Sarcoma, Small Cell/genetics , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/pathology , HumansABSTRACT
SUMMARY: We are building the world's first Virtual Child-a computer model of normal and cancerous human development at the level of each individual cell. The Virtual Child will "develop cancer" that we will subject to unlimited virtual clinical trials that pinpoint, predict, and prioritize potential new treatments, bringing forward the day when no child dies of cancer, giving each one the opportunity to lead a full and healthy life.
Subject(s)
Neoplasms , Humans , Neoplasms/geneticsABSTRACT
DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature.