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1.
J Cutan Pathol ; 2024 May 26.
Article in English | MEDLINE | ID: mdl-38797972

ABSTRACT

Cutaneous spindle cell neoplasms can be challenging to diagnose using routine histopathological techniques alone, and the growing repertoire of molecular studies can assist in diagnosis. We describe a cutaneous spindle cell neoplasm characterized by a COL3A1::PDGFRA rearrangement predicted to lead to constitutive activation of the PDGFRA kinase domain. The lesion shows some similarities to dermatofibrosarcoma protuberans and also benign and epithelioid fibrous histiocytomas but is distinct from these entities histopathologically and molecularly. This tumor is considered to represent an entity in the spectrum of PDGFR-driven cutaneous mesenchymal neoplasms.

2.
Pediatr Blood Cancer ; 71(3): e30810, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38102963

ABSTRACT

We report a unique case of high-grade B-cell lymphoma, not otherwise specified in a 5-year-old child. Whole-genome sequencing revealed a DDX3X::MLLT10 fusion, usually seen in T-cell acute lymphoblastic leukaemia (ALL). This suggests the novel idea that MLLT10 fusions are capable of driving B-cell malignancies. An IGH deletion usually only seen in adults was also found. These unique genetic findings provide novel insights into B-cell lymphomagenesis. The child remains in remission 7 year post chemotherapy, which demonstrates that novel complex molecular findings do not always denote high-risk disease.


Subject(s)
Lymphoma, B-Cell , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Adult , Humans , Child , Child, Preschool , Lymphoma, B-Cell/genetics , Lymphoma, B-Cell/pathology , B-Lymphocytes , Transcription Factors/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , DEAD-box RNA Helicases/genetics
3.
Pediatr Dev Pathol ; 27(3): 260-265, 2024.
Article in English | MEDLINE | ID: mdl-38098239

ABSTRACT

Wilms tumor (WT) is the commonest cause of renal cancer in children. In Europe, a diagnosis is made for most cases on typical clinical and radiological findings, prior to pre-operative chemotherapy. Here, we describe a case of a young boy presenting with a large abdominal tumor, associated with raised serum alpha-fetoprotein (AFP) levels at diagnosis. Given the atypical features present, a biopsy was taken, and histology was consistent with WT, showing triphasic WT, with epithelial, stromal, and blastemal elements present, and positive WT1 and CD56 immunohistochemical staining. During pre-operative chemotherapy, serial serum AFP measurements showed further increases, despite a radiological response, before a subsequent fall to normal following nephrectomy. The resection specimen was comprised of ~55% and ~45% stromal and epithelial elements, respectively, with no anaplasia, but immunohistochemistry using AFP staining revealed positive mucinous intestinal epithelium, consistent with the serum AFP observations. The lack of correlation between tumor response and serum AFP levels in this case highlights a more general clinical unmet need to identify WT-specific circulating tumor markers.


Subject(s)
Biomarkers, Tumor , Kidney Neoplasms , Wilms Tumor , alpha-Fetoproteins , Humans , Wilms Tumor/diagnosis , Wilms Tumor/pathology , Wilms Tumor/blood , alpha-Fetoproteins/analysis , alpha-Fetoproteins/metabolism , Male , Biomarkers, Tumor/blood , Biomarkers, Tumor/analysis , Kidney Neoplasms/diagnosis , Kidney Neoplasms/pathology , Kidney Neoplasms/blood , Nephrectomy
6.
Head Neck Pathol ; 17(2): 576-580, 2023 Jun.
Article in English | MEDLINE | ID: mdl-36723852

ABSTRACT

BACKGROUND: Spindle cell tumours in the sinonasal area are diagnostically challenging. We identified a neoplasm that defied histopathological classification using current criteria. METHODS: The case was subjected to histopathological, immunohistochemical and molecular analysis using a large small variant DNA panel. RESULTS: The tumour comprised cytologically bland epithelioid spindle cells with a rich vasculature, which lack expression of actin and other smooth muscle markers, CD34 and beta-catenin. An activating insertion/deletion in exon 12 of the PDGFRA gene was detected. This alteration has previously been described in gastrointestinal stromal tumours and inflammatory fibroid polyps of the GI tract, but the site, histological, and immunophenotypic features in this tumour are distinct. CONCLUSION: We describe a novel sinonasal spindle cell tumour characterised by an activating insertion/deletion in exon 12 of PDGFRA. The diagnosis of PDGFRA-activated sinonasal spindle cell tumour should be considered in difficult to classify mesenchymal lesions at this site.


Subject(s)
Gastrointestinal Stromal Tumors , Head and Neck Neoplasms , Soft Tissue Neoplasms , Humans , Mutation , Proto-Oncogene Proteins c-kit/genetics , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Receptor Protein-Tyrosine Kinases/genetics
7.
J Pathol ; 259(2): 119-124, 2023 02.
Article in English | MEDLINE | ID: mdl-36426824

ABSTRACT

The FOS gene family has been implicated in tumourigenesis across several tumour types, particularly mesenchymal tumours. The rare fibrous tumour desmoplastic fibroblastoma is characterised by overexpression of FOSL1. However, previous studies using cytogenetic and molecular techniques did not identify an underlying somatic change involving the FOSL1 gene to explain this finding. Prompted by an unusual index case, we report the discovery of a novel FOSL1 rearrangement in desmoplastic fibroblastoma using whole-genome and targeted RNA sequencing. We investigated 15 desmoplastic fibroblastomas and 15 fibromas of tendon sheath using immunohistochemistry, in situ hybridisation and targeted RNA sequencing. Rearrangements in FOSL1 and FOS were identified in 10/15 and 2/15 desmoplastic fibroblastomas respectively, which mirrors the pattern of FOS rearrangements observed in benign bone and vascular tumours. Fibroma of tendon sheath, which shares histological features with desmoplastic fibroblastoma, harboured USP6 rearrangements in 9/15 cases and did not demonstrate rearrangements in any of the four FOS genes. The overall concordance between FOSL1 immunohistochemistry and RNA sequencing results was 90%. These findings illustrate that FOSL1 and FOS rearrangements are a recurrent event in desmoplastic fibroblastoma, establishing this finding as a useful diagnostic adjunct and expanding the spectrum of tumours driven by FOS gene family alterations. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Subject(s)
Fibroma, Desmoplastic , Fibroma , Soft Tissue Neoplasms , Humans , Fibroma, Desmoplastic/diagnosis , Fibroma, Desmoplastic/genetics , Fibroma, Desmoplastic/pathology , Fibroma/genetics , Gene Rearrangement , In Situ Hybridization , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/pathology , Ubiquitin Thiolesterase/genetics
9.
Front Endocrinol (Lausanne) ; 13: 1066208, 2022.
Article in English | MEDLINE | ID: mdl-36440187

ABSTRACT

There is increasing evidence to support the use of temozolomide therapy for the treatment of metastatic phaeochromocytoma/paraganglioma (PPGL) in adults, particularly in patients with SDHx mutations. In children however, very little data is available. In this report, we present the case of a 12-year-old female with a SDHB-related metastatic paraganglioma treated with surgery followed by temozolomide therapy. The patient presented with symptoms of palpitations, sweating, flushing and hypertension and was diagnosed with a paraganglioma. The primary mass was surgically resected six weeks later after appropriate alpha- and beta-blockade. During the surgery extensive nodal disease was identified that had been masked by the larger paraganglioma. Histological review confirmed a diagnosis of a metastatic SDHB-deficient paraganglioma with nodal involvement. Post-operatively, these nodal lesions demonstrated tracer uptake on 18F-FDG PET-CT. Due to poor tumour tracer uptake on 68Ga-DOTATATE and 123I-MIBG functional imaging studies radionuclide therapy was not undertaken as a potential therapeutic option for this patient. Due to the low tumour burden and lack of clinical symptoms, the multi-disciplinary team opted for close surveillance for the first year, during which time the patient continued to thrive and progress through puberty. 13 months after surgery, evidence of radiological and biochemical progression prompted the decision to start systemic monotherapy using temozolomide. The patient has now completed ten cycles of therapy with limited adverse effects and has benefited from a partial radiological and biochemical response.


Subject(s)
Adrenal Gland Neoplasms , Brain Neoplasms , Neoplasms, Second Primary , Paraganglioma , Pheochromocytoma , Adult , Female , Humans , Child , Pheochromocytoma/genetics , Temozolomide/therapeutic use , Positron Emission Tomography Computed Tomography , Paraganglioma/drug therapy , Paraganglioma/genetics , Adrenal Gland Neoplasms/drug therapy
10.
Br J Cancer ; 127(1): 137-144, 2022 07.
Article in English | MEDLINE | ID: mdl-35449451

ABSTRACT

BACKGROUND: Whole-genome sequencing (WGS) of cancers is becoming an accepted component of oncological care, and NHS England is currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share the experience of the East of England Genomic Medicine Centre (East-GMC), reporting the feasibility and clinical utility of centralised WGS for individual children locally. METHODS: Non-consecutive children with solid tumours were recruited into the pilot 100 K project at our Genomic Medicine Centre. Variant catalogues were returned for local scrutiny and appraisal at dedicated genomic tumour advisory boards with an emphasis on a detailed exploration of potential clinical value. RESULTS: Thirty-six children, representing one-sixth of the national 100 K cohort, were recruited through our Genomic Medicine Centre. The diagnoses encompassed 23 different solid tumour types and WGS provided clinical utility, beyond standard-of-care assays, by refining (2/36) or changing (4/36) diagnoses, providing prognostic information (8/36), defining pathogenic germline mutations (1/36) or revealing novel therapeutic opportunities (8/36). CONCLUSION: Our findings demonstrate the feasibility and clinical value of centralised WGS for children with cancer. WGS offered additional clinical value, especially in diagnostic terms. However, our experience highlights the need for local expertise in scrutinising and clinically interpreting centrally derived variant calls for individual children.


Subject(s)
Neoplasms , State Medicine , Child , Feasibility Studies , Germ-Line Mutation , Humans , Neoplasms/genetics , Whole Genome Sequencing
11.
Eur J Hum Genet ; 30(4): 420-427, 2022 04.
Article in English | MEDLINE | ID: mdl-34992252

ABSTRACT

ZNF711 is one of eleven zinc-finger genes on the X chromosome that have been associated with X-linked intellectual disability. This association is confirmed by the clinical findings in 20 new cases in addition to 11 cases previously reported. No consistent growth aberrations, craniofacial dysmorphology, malformations or neurologic findings are associated with alterations in ZNF711. The intellectual disability is typically mild and coexisting autism occurs in half of the cases. Carrier females show no manifestations. A ZNF711-specific methylation signature has been identified which can assist in identifying new cases and in confirming the pathogenicity of variants in the gene.


Subject(s)
Autistic Disorder , Intellectual Disability , Autistic Disorder/genetics , DNA Methylation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Genes, X-Linked , Humans , Intellectual Disability/genetics
12.
Neuropathol Appl Neurobiol ; 47(6): 882-888, 2021 10.
Article in English | MEDLINE | ID: mdl-33534137

ABSTRACT

In a case of astroblastoma, methylation analysis was uninformative, with no clustering with known CNS-HGNET-MN1 cases. Whole genome sequencing however identified a novel MN1-GTSE1 gene fusion (image), confirming the diagnosis of astroblastoma, as well as an EWSR1-PATZ1 gene fusion. Whole genome sequencing, alongside methylation profiling and conventional neuropathology, will continue to lead to improved diagnostics and prognostication for children with brain tumours.


Subject(s)
Brain Neoplasms/genetics , Gene Fusion/genetics , Kruppel-Like Transcription Factors/genetics , Microtubule-Associated Proteins/genetics , Neoplasms, Neuroepithelial/genetics , Repressor Proteins/genetics , Trans-Activators/genetics , Tumor Suppressor Proteins/genetics , Adolescent , Brain Neoplasms/diagnosis , Brain Neoplasms/pathology , Female , Humans , Neoplasms, Neuroepithelial/diagnosis , Neoplasms, Neuroepithelial/pathology
13.
Nature ; 580(7805): 640-646, 2020 04.
Article in English | MEDLINE | ID: mdl-32350471

ABSTRACT

All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium1,2. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.


Subject(s)
DNA Mutational Analysis , Endometrium/cytology , Endometrium/metabolism , Epithelium/metabolism , Health , Mutation , Adult , Age of Onset , Aged , Aged, 80 and over , Aging/genetics , Carcinogenesis/genetics , Clone Cells/cytology , Endometrial Neoplasms/genetics , Endometrium/pathology , Epithelial Cells/cytology , Epithelial Cells/metabolism , Epithelial Cells/pathology , Epithelium/pathology , Female , Humans , Middle Aged , Parity/genetics , Time Factors , Young Adult
14.
Science ; 366(6470): 1247-1251, 2019 12 06.
Article in English | MEDLINE | ID: mdl-31806814

ABSTRACT

Adult cancers often arise from premalignant clonal expansions. Whether the same is true of childhood tumors has been unclear. To investigate whether Wilms tumor (nephroblastoma; a childhood kidney cancer) develops from a premalignant background, we examined the phylogenetic relationship between tumors and corresponding normal tissues. In 14 of 23 cases studied (61%), we found premalignant clonal expansions in morphologically normal kidney tissues that preceded tumor development. These clonal expansions were defined by somatic mutations shared between tumor and normal tissues but absent from blood cells. We also found hypermethylation of the H19 locus, a known driver of Wilms tumor development, in 58% of the expansions. Phylogenetic analyses of bilateral tumors indicated that clonal expansions can evolve before the divergence of left and right kidney primordia. These findings reveal embryonal precursors from which unilateral and multifocal cancers develop.


Subject(s)
Clone Cells , DNA Methylation , Kidney Neoplasms/genetics , Kidney/pathology , Precancerous Conditions/pathology , Wilms Tumor/genetics , Child , Humans , Kidney/embryology , Kidney Neoplasms/pathology , Mutation , Phylogeny , Wilms Tumor/pathology
15.
Cancer Cell ; 35(3): 441-456.e8, 2019 03 18.
Article in English | MEDLINE | ID: mdl-30889380

ABSTRACT

Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis.


Subject(s)
DNA Methylation , Gene Expression Profiling/methods , Sarcoma/genetics , Sequence Analysis, DNA/methods , Evolution, Molecular , Gene Duplication , Humans , Mutation , Ploidies , Prognosis
16.
Mol Genet Genomic Med ; 7(4): e00569, 2019 04.
Article in English | MEDLINE | ID: mdl-30729724

ABSTRACT

BACKGROUND: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. METHODS: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. RESULTS: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. CONCLUSIONS: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.


Subject(s)
Craniofacial Abnormalities/genetics , Mediator Complex/genetics , Mental Retardation, X-Linked/genetics , Mutation, Missense , Adult , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Bone Morphogenetic Protein 4/genetics , Bone Morphogenetic Protein 4/metabolism , Cells, Cultured , Craniofacial Abnormalities/pathology , Cyclic AMP Response Element-Binding Protein A/genetics , Cyclic AMP Response Element-Binding Protein A/metabolism , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Humans , Male , Mediator Complex/chemistry , Mediator Complex/metabolism , Mental Retardation, X-Linked/pathology , Middle Aged , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Pedigree , Protein Domains , Signal Transduction
17.
Cancer Discov ; 8(12): 1548-1565, 2018 12.
Article in English | MEDLINE | ID: mdl-30322867

ABSTRACT

Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. SIGNIFICANCE: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494.


Subject(s)
Biomarkers, Tumor/genetics , Lung Neoplasms/genetics , Mesothelioma/genetics , Mutation , Pleural Neoplasms/genetics , Aged , Female , Histone-Lysine N-Methyltransferase , Humans , Kaplan-Meier Estimate , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Male , Mesothelioma/pathology , Mesothelioma/therapy , Middle Aged , Pleural Neoplasms/pathology , Pleural Neoplasms/therapy , Prognosis , Protein Methyltransferases/genetics , Tumor Suppressor Proteins/genetics , Ubiquitin Thiolesterase/genetics
18.
Sci Rep ; 8(1): 13537, 2018 09 10.
Article in English | MEDLINE | ID: mdl-30202034

ABSTRACT

Anaplastic meningioma is a rare and aggressive brain tumor characterised by intractable recurrences and dismal outcomes. Here, we present an integrated analysis of the whole genome, transcriptome and methylation profiles of primary and recurrent anaplastic meningioma. A key finding was the delineation of distinct molecular subgroups that were associated with diametrically opposed survival outcomes. Relative to lower grade meningiomas, anaplastic tumors harbored frequent driver mutations in SWI/SNF complex genes, which were confined to the poor prognosis subgroup. Aggressive disease was further characterised by transcriptional evidence of increased PRC2 activity, stemness and epithelial-to-mesenchymal transition. Our analyses discern biologically distinct variants of anaplastic meningioma with prognostic and therapeutic significance.


Subject(s)
Gene Expression Regulation, Neoplastic , Meningeal Neoplasms/genetics , Meningioma/genetics , Neoplasm Recurrence, Local/genetics , Transcriptome/genetics , Aged , DNA Methylation/genetics , Disease Progression , Female , Gene Expression Profiling , Genomics/methods , Humans , Male , Meningeal Neoplasms/mortality , Meningeal Neoplasms/pathology , Meningeal Neoplasms/surgery , Meningioma/mortality , Meningioma/pathology , Meningioma/surgery , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/mortality , Neoplasm Recurrence, Local/pathology , Prognosis , Survival Analysis , Whole Genome Sequencing
19.
Cell Death Dis ; 9(9): 894, 2018 08 30.
Article in English | MEDLINE | ID: mdl-30166531

ABSTRACT

Improving early detection of colorectal cancer (CRC) is a key public health priority as adenomas and stage I cancer can be treated with minimally invasive procedures. Population screening strategies based on detection of occult blood in the feces have contributed to enhance detection rates of localized disease, but new approaches based on genetic analyses able to increase specificity and sensitivity could provide additional advantages compared to current screening methodologies. Recently, circulating cell-free DNA (cfDNA) has received much attention as a cancer biomarker for its ability to monitor the progression of advanced disease, predict tumor recurrence and reflect the complex genetic heterogeneity of cancers. Here, we tested whether analysis of cfDNA is a viable tool to enhance detection of colon adenomas. To address this, we assessed a cohort of patients with adenomas and healthy controls using droplet digital PCR (ddPCR) and mutation-specific assays targeted to trunk mutations. Additionally, we performed multiregional, targeted next-generation sequencing (NGS) of adenomas and unmasked extensive heterogeneity, affecting known drivers such as APC, KRAS and mismatch repair (MMR) genes. However, tumor-related mutations were undetectable in patients' plasma. Finally, we employed a preclinical mouse model of Apc-driven intestinal adenomas and confirmed the inability to identify tumor-related alterations via cfDNA, despite the enhanced disease burden displayed by this experimental cancer model. Therefore, we conclude that benign colon lesions display extensive genetic heterogeneity, that they are not prone to release DNA into the circulation and are unlikely to be reliably detected with liquid biopsies, at least with the current technologies.


Subject(s)
Adenoma/diagnosis , Circulating Tumor DNA/isolation & purification , Colonic Neoplasms/diagnosis , Early Detection of Cancer/methods , Adenoma/blood , Adenoma/genetics , Adenomatous Polyposis Coli Protein/genetics , Aged , Aged, 80 and over , Animals , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Colonic Neoplasms/blood , Colonic Neoplasms/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Liquid Biopsy/methods , Male , Mice , Mice, Knockout , Middle Aged , Polymerase Chain Reaction , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras)/genetics
20.
Nat Commun ; 9(1): 3363, 2018 08 22.
Article in English | MEDLINE | ID: mdl-30135448

ABSTRACT

We analyzed whole genomes of unique paired samples from smoldering multiple myeloma (SMM) patients progressing to multiple myeloma (MM). We report that the genomic landscape, including mutational profile and structural rearrangements at the smoldering stage is very similar to MM. Paired sample analysis shows two different patterns of progression: a "static progression model", where the subclonal architecture is retained as the disease progressed to MM suggesting that progression solely reflects the time needed to accumulate a sufficient disease burden; and a "spontaneous evolution model", where a change in the subclonal composition is observed. We also observe that activation-induced cytidine deaminase plays a major role in shaping the mutational landscape of early subclinical phases, while progression is driven by APOBEC cytidine deaminases. These results provide a unique insight into myelomagenesis with potential implications for the definition of smoldering disease and timing of treatment initiation.


Subject(s)
Gene Expression Regulation, Neoplastic , Smoldering Multiple Myeloma/genetics , Aged , Databases, Genetic , Disease Progression , Female , Gene Expression Profiling , Genomics , Humans , Male , Middle Aged , Multiple Myeloma/genetics , Multiple Myeloma/pathology , Mutation/genetics , Risk Factors , Smoldering Multiple Myeloma/pathology
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