[Malignant rhabdoid tumor of the lung].

Rev Mal Respir. 2016 Nov;33(9):808-811

Authors: Zysman M, Clement-Duchene C, Bastien C, Vaillant P, Martinet Y

Abstract
INTRODUCTION: Rhabdoid tumours usually develop in brain and spinal cord or kidney; they are highly malignant neoplasms that typically arise in infancy and early childhood. However, rare cases of pulmonary localization have been described, particularly among young adults.
CASE REPORT: A 26-year-old man, smoker, had a right apical lung mass associated with a Pancoast syndrome leading to haemoptysis. There was also a tumour of the left thigh and scalp. Histological samples taken at these three locations were in favour of an undifferentiated carcinoma. The lack of nuclear integrase interactor 1 expression, and immunohistochemical appearance supported the diagnosis of rhabdoid tumour. Despite treatment, unfavourable progression confirmed this hypothesis, doubling time was less than six weeks with development of multiple metastases resulted in death within only three months after diagnosis.
CONCLUSION: The lack of expression of integrase interactor 1 should suggest the diagnosis of rhabdoid tumour, especially when there is quick progression. The prognosis of these tumours remains poor and therapeutic options are limited.

PMID: 27595391 [PubMed - indexed for MEDLINE]

A rare occurrence of intramasseteric schwannoma - case report and literature review.

Rev Stomatol Chir Maxillofac Chir Orale. 2016 Jun;117(3):170-2

Authors: Wang HK, Gong YL, Wang RX, Zheng XT, Huang SY, Zhang DS

Abstract
A schwannoma is a benign, solitary, well-defined, painless, slowly-enlarging nerve sheath tumor, composed of Schwann cells. Intramasseteric localization is very unusual. We report the case of a 33-year-old male who developed an intramasseteric schwannoma. Tumor could be completely removed under general anesthesia. Histopathological examination made the diagnosis of intramasseteric schwannoma through the presence of Antoni A areas and Verocay bodies. The diagnosis of schwannoma should be taken into consideration in case of parotideomasseteric tumors.

PMID: 27155941 [PubMed - indexed for MEDLINE]

[NK/T-cell Lymphoma of nasal-type: A rare affection with a poor prognosis].

Rev Stomatol Chir Maxillofac Chir Orale. 2016 Jun;117(3):167-9

Authors: Doh K, Tagba E, Thiam I, Sarr A, Woto-Gaye G

Abstract
INTRODUCTION: NK/T cell lymphoma of nasal-type was described in 1933 as a malignant midfacial granuloma. The diagnosis of this rare affection is clinical and immunohistopathological. We report a case of NK/T cell lymphoma diagnosed at an advanced stage.
OBSERVATION: A 60-year-old man with no particular medical history presented since seven months with a left nasal obstruction associated with a purulent and fetid rhinorrhea followed by a centrifugal midfacial necrosis. Blood tests showed an inflammatory syndrome. The CT-scan of the face showed a filling of the nose and sinus by a tissular process and a lysis of the bone walls. Three series of biopsies (le last being performed under general anesthesia) were necessary to get the diagnosis of NK/T cell lymphoma. The standard histology showed a malignant proliferation made of round and spindle-shaped lymphoid-like cells and angiocentric arrangement. The cells were CD 2+, CD 3+, CD 5+ and CD 56+. The spontaneous evolution was fatal one month after diagnosis in a context of septic shock.
CONCLUSION: NK/T cell lymphoma of nasal-type is a rare disease but should be evocated in patient with midfacial necrosis of centrifugal evolution. The diagnosis certainty is made on immunohistopathological analysis. Multiple biopsies, made at distance from necrotic areas and under general anesthesia may be necessary.

PMID: 26972561 [PubMed - indexed for MEDLINE]

Precision medicine and pharmacogenetics: what does oncology have that addiction medicine does not?

Addiction. 2017 Apr 21;:

Authors: Kranzler HR, Smith RV, Schnoll R, Moustafa A, Greenstreet-Akman E

Abstract
BACKGROUND AND AIMS: Precision, personalized or stratified medicine, which promises to deliver the right treatment to the right patient, is a topic of international interest in both the lay press and the scientific literature. A key aspect of precision medicine is the identification of biomarkers that predict the response to medications (i.e. pharmacogenetics). We examined why, despite the great strides that have been made in biomarker identification in many areas of medicine, only in oncology has there been substantial progress in their clinical implementation. We also considered why progress in this effort has lagged in addiction medicine.
METHODS: We compared the development of pharmacogenetic biomarkers in oncology, cardiovascular medicine (where developments are also promising) and addictive disorders.
RESULTS: The first major reason for the success of oncologic pharmacogenetics is ready access to tumor tissue, which allows in-vitro testing and insights into cancer biology. The second major reason is funding, with cancer research receiving, by far, the largest allocation by the National Institutes of Health (NIH) during the past two decades. The second largest allocation of research funding has gone to cardiovascular disease research. Addictions research received a much smaller NIH funding allocation, despite the major impact that tobacco use, alcohol consumption and illicit drug use have on the public health and healthcare costs.
CONCLUSIONS: Greater support for research on the personalized treatment of addictive disorders can be expected to yield disproportionately large benefits to the public health and substantial reductions in healthcare costs.

PMID: 28431457 [PubMed - as supplied by publisher]

Risk stratification for venous thromboembolism in patients with testicular germ cell tumors.

PLoS One. 2017;12(4):e0176283

Authors: Bezan A, Posch F, Ploner F, Bauernhofer T, Pichler M, Szkandera J, Hutterer GC, Pummer K, Gary T, Samonigg H, Beyer J, Winder T, Hermanns T, Fankhauser CD, Gerger A, Stotz M

Abstract
BACKGROUND: Patients with testicular germ cell tumors (TGCT) have an increased risk for venous thromboembolism (VTE). We identified risk factors for VTE in this patient cohort and developed a clinical risk model.
METHODS: In this retrospective cohort study at the Medical University of Graz we included 657 consecutive TGCT patients across all clinical stages. A predictive model for VTE was developed and externally validated in 349 TGCT patients treated at the University Hospital Zurich.
RESULTS: Venous thromboembolic events occurred in 34 (5.2%) patients in the Graz cohort. In univariable competing risk analysis, higher clinical stage (cS) and a retroperitoneal lymphadenopathy (RPLN) were the strongest predictors of VTE (p<0.0001). As the presence of a RPLN with more than 5cm in greatest dimension without coexisting visceral metastases is classified as cS IIC, we constructed an empirical VTE risk model with the following four categories (12-month-cumulative incidence): cS IA-B 8/463 patients (1.7%), cS IS-IIB 5/86 patients (5.9%), cS IIC 3/21 patients (14.3%) and cS IIIA-C 15/70 patients (21.4%). This risk model was externally validated in the Zurich cohort (12-month-cumulative incidence): cS IA-B (0.5%), cS IS-IIB (6.0%), cS IIC (11.1%) and cS IIIA-C (19.1%). Our model had a significantly higher discriminatory performance than a previously published classifier (RPLN-VTE-risk-classifier) which is based on the size of RPLN alone (AUC-ROC: 0.75 vs. 0.63, p = 0.007).
CONCLUSIONS: According to our risk stratification, TGCT patients with cS IIC and cS III disease have a very high risk of VTE and may benefit from primary thromboprophylaxis for the duration of chemotherapy.

PMID: 28430804 [PubMed - in process]

ABCG2 and NCF4 polymorphisms are associated with clinical outcomes in diffuse large B-cell lymphoma patients treated with R-CHOP.

Oncotarget. 2017 Apr 06;:

Authors: Liu D, Wu N, Sun H, Dong M, Guo T, Chi P, Li G, Sun D, Jin Y

Abstract
The impact of pharmacogenetics on predicting survival in diffuse large B-cell lymphoma (DLBCL) remains unclear. We tested 337 DLBCL patients treated with rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for 9 single nucleotide polymorphisms from 6 genes (CD20, FCGR2A, NAD(P)H, ABCC2, ABCG2 and CYP3A5). Patients who carried the NCF4 rs1883112 GG genotype showed significantly shorter progression-free survival (PFS) (P = 0.023) and event-free survival (EFS) (P < 0.001) comparing with A allele. A significantly shortened PFS (P = 0.013) and EFS (P = 0.002) was also observed in the patients with ABCG2 rs2231137 GG genotype. Furthermore, the elder (> 60 years old) or male patients with ABCG2 rs2231137 GG genotype had poorer PFS and EFS than A allele. Moreover, CD20 rs2070770 CC and RAC2 rs13058338 AT genotypes were independent predictors of chemotherapy-induced toxicity. Cox proportional hazards analyses demonstrated that the GG genotype of ABCG2 rs2231137 and NCF4 rs1883112 were risk factors in DLBCL patients. In conclusion, the identified polymorphisms provide guide for the identification of DLBCL patients who are likely to benefit from chemotherapy.

PMID: 28430649 [PubMed - as supplied by publisher]

Nanodiscs for INPHARMA NMR Characterization of GPCRs: Ligand Binding to the Human A2A Adenosine Receptor.

Angew Chem Int Ed Engl. 2017 Apr 21;:

Authors: Fredriksson K, Lottmann P, Hinz S, Onila I, Shymanets A, Harteneck C, Müller CE, Griesinger C, Exner TE

Abstract
G-protein-coupled-receptors (GPCRs) are of fundamental importance for signal transduction through cell membranes. This makes them important drug targets, but structure-based drug design (SBDD) is still hampered by the limitations for structure determination of unmodified GPCRs. We show that the interligand NOEs for pharmacophore mapping (INPHARMA) method can provide valuable information on ligand poses inside the binding site of the unmodified human A2A adenosine receptor reconstituted in nanodiscs. By comparing experimental INPHARMA spectra with back-calculated spectra based on ligand poses obtained from molecular dynamics simulations, a complex structure for A2A R with the low-affinity ligand 3-pyrrolidin-1-ylquinoxalin-2-amine was determined based on the X-ray structure of ligand ZM-241,358 in complex with a modified A2A R.

PMID: 28429411 [PubMed - as supplied by publisher]

The association between GGCX, miR-133 genetic polymorphisms and warfarin stable dosage in Han Chinese patients with mechanical heart valve replacement.

J Clin Pharm Ther. 2017 Apr 21;:

Authors: Tang XY, Zhang J, Peng J, Tan SL, Zhang W, Song GB, Liu LM, Li CL, Ren H, Zeng L, Liu ZQ, Chen XP, Zhou XM, Zhou HH, Hu JX, Li Z

Abstract
WHAT IS KNOWN AND OBJECTIVE: Warfarin is a widely used anticoagulant with a narrow therapeutic index. Polymorphisms in the VKORC1, CYP2C9 and CYP4F2 genes have been verified to correlate with warfarin stable dosage (WSD). Whether any other genes or variants affect the dosage is unknown. The aim of our study was to investigate the relationship between GGCX, miR-133 variants and the WSD in Han Chinese patients with mechanical heart valve replacement (MHVR).
METHODS: A total of 231 patients were enrolled in the study. Blood samples were collected for genotyping. The average WSD among subjects with different GGCX or miR-133 genotypes was compared. Regression analyses were performed to test for any association of genetic polymorphisms with WSD.
RESULTS AND DISCUSSION: The warfarin dosage in patients with the GGCX rs699664 TT and rs12714145 TT genotypes was 3.77±0.93 (95% CI: 3.35-4.19) mg/d and 3.70±1.00 (95% CI: 3.32-4.09) mg/d, respectively. The GGCX rs699664 and rs12714145 genotypes were significantly associated with WSD (P<.05). But they were ruled out in the multivariate regression analysis. There were no significant differences in the average warfarin stable dosage between subjects with MIR133B rs142410335 wild-type and variant genotypes (P>.05).
WHAT IS NEW AND CONCLUSION: The genotypes of GGCX rs699644 and rs12714145 were significantly associated with WSD (P<.05), but their contributions were not significant after accounting for other factors. MIR133B rs142410335 makes no significant contributions to warfarin stable dosage in Han Chinese patients with MHVR neither in univariate regression nor in multivariate regression analyses.

PMID: 28429387 [PubMed - as supplied by publisher]

Pregnane X Receptor Regulates the AhR/Cyp1A1 Pathway and Protects Liver Cells from Benzo-[α]-Pyrene-induced DNA Damage.

Toxicol Lett. 2017 Apr 17;:

Authors: Cui H, Gu X, Chen J, Xie Y, Ke S, Wu J, Golovko A, Morpurgo B, Yan C, Phillips TD, Xie W, Luo J, Zhou Z, Tian Y

Abstract
Pregnane X receptor (PXR) plays an important role in protecting cells from mutagenic DNA damages induced by endogenous and exogenous toxicants. This protective function is often attributed to the PXR-regulated metabolic detoxification. Here we report a novel potential mechanism that PXR reduces benzo-[α]-pyrene(BaP)-induced DNA damage through inhibiting the transcriptional activity of aryl hydrocarbon receptor (AhR) which plays a pivotal role in the bioactivation of BaP. We have utilized three well-characterized cell lines, i.e. Hepa1c1c7, AhR +/+; Bpr lacks AhR obligatory partner ARNT; Tao, lacks AhR, to analyze pivotal role of AhR/ARNT complex in mediating the BaP-induced DNA damages using comet assay (single-cell gel electrophoresis). We found that PXR activation could significantly inhibit BaP-induced DNA damage in the HepG2 cells as well as mouse hepatocytes. Using PXR-null and wild type mouse hepatocytes we showed that PXR activation by pregnenolone 16α-carbonitrile (PCN) significantly inhibited BaP-induced DNA damage and this protective effect was abolished in PXR-null hepatocytes. Mechanistically, PXR activation inhibited expression of AhR-target genes for CYP1A1, CYP1B1 and CYP1A2 that are required for BaP biotransformation in cultured liver cells, or in the livers of C57BL/6J mice. Using an AhR-responsive reporter assay as well as chromatin immunoprecipitation assay we found that PXR activation transcriptionally represses AhR-regulated gene expression. Furthermore, we found that PXR directly bound AhR at its DNA-binding domain, and this association may play a role in preventing of the AhR from binding to its target genes as shown in the ChIP assay. Taken together, our study has revealed a novel mechanism by which PXR protects liver cells from BaP-induced DNA damage through inhibiting the BaP biotransformation.

PMID: 28428138 [PubMed - as supplied by publisher]

Polymorphisms in CYP2C8 and CYP3A5 genes in the Nigerian population.

Drug Metab Pharmacokinet. 2016 Sep 14;:

Authors: Adehin A, Bolaji OO, Kennedy MA

Abstract
Polymorphisms in CYP2C8 and CYP3A5 genes have implications for responses elicited by the ingestion of some xenobiotics, the metabolism of which are mediated by these enzymes. CYP2C8*2, CYP2C8*3, CYP3A5*3, CYP3A5*6 and CYP3A5*7 are a few functionally-relevant variants of these genes which this study provides data for, in the Nigerian population. Blood samples were processed for genomic DNA from 178 unrelated subjects spread across Nigerian ethnicities and screened for these polymorphism through the Sequenom iPLEX MassARRAY platform. Results obtained were further validated with Sanger sequencing of a few samples and thereafter, the genotype data were statistically processed. All alleles were in Hardy-Weinberg equilibrium and CYP2C8*2 occurred at a frequency (95% CI) of 0.194 (0.154, 0.239), while CYP3A5*3, CYP3A5*6 and CYP3A5*7 were found at frequencies (95% CI) of 0.160 (0.124, 0.202), 0.096 (0.067, 0.131) and 0.126 (0.094, 0.166), respectively. However, CYP2C8*3 was not detected in the population. The study observed a 60% prevalence of carriers of at least a CYP3A5 polymorphism in the population, suggesting the probable existence of huge variability in CYP3A5 activity which may prove significant in the administration of drugs with narrow therapeutic windows and whose metabolism is largely mediated by CYP3A5.

PMID: 28427759 [PubMed - as supplied by publisher]

Learning from biomedical linked data to suggest valid pharmacogenes.

J Biomed Semantics. 2017 Apr 20;8(1):16

Authors: Dalleau K, Marzougui Y, Da Silva S, Ringot P, Ndiaye NC, Coulet A

Abstract
BACKGROUND: A standard task in pharmacogenomics research is identifying genes that may be involved in drug response variability, i.e., pharmacogenes. Because genomic experiments tended to generate many false positives, computational approaches based on the use of background knowledge have been proposed. Until now, only molecular networks or the biomedical literature were used, whereas many other resources are available.
METHOD: We propose here to consume a diverse and larger set of resources using linked data related either to genes, drugs or diseases. One of the advantages of linked data is that they are built on a standard framework that facilitates the joint use of various sources, and thus facilitates considering features of various origins. We propose a selection and linkage of data sources relevant to pharmacogenomics, including for example DisGeNET and Clinvar. We use machine learning to identify and prioritize pharmacogenes that are the most probably valid, considering the selected linked data. This identification relies on the classification of gene-drug pairs as either pharmacogenomically associated or not and was experimented with two machine learning methods -random forest and graph kernel-, which results are compared in this article.
RESULTS: We assembled a set of linked data relative to pharmacogenomics, of 2,610,793 triples, coming from six distinct resources. Learning from these data, random forest enables identifying valid pharmacogenes with a F-measure of 0.73, on a 10 folds cross-validation, whereas graph kernel achieves a F-measure of 0.81. A list of top candidates proposed by both approaches is provided and their obtention is discussed.

PMID: 28427468 [PubMed - in process]

Polymorphisms of genes related to metotrexate response and toxicity in high-grade osteosarcoma.

Expert Opin Drug Metab Toxicol. 2017 01;13(1):123

Authors: Serra M, Hattinger CM

PMID: 27852114 [PubMed - indexed for MEDLINE]

Comparative genomics of Burkholderia multivorans, a ubiquitous pathogen with a highly conserved genomic structure.

PLoS One. 2017;12(4):e0176191

Authors: Peeters C, Cooper VS, Hatcher PJ, Verheyde B, Carlier A, Vandamme P

Abstract
The natural environment serves as a reservoir of opportunistic pathogens. A well-established method for studying the epidemiology of such opportunists is multilocus sequence typing, which in many cases has defined strains predisposed to causing infection. Burkholderia multivorans is an important pathogen in people with cystic fibrosis (CF) and its epidemiology suggests that strains are acquired from non-human sources such as the natural environment. This raises the central question of whether the isolation source (CF or environment) or the multilocus sequence type (ST) of B. multivorans better predicts their genomic content and functionality. We identified four pairs of B. multivorans isolates, representing distinct STs and consisting of one CF and one environmental isolate each. All genomes were sequenced using the PacBio SMRT sequencing technology, which resulted in eight high-quality B. multivorans genome assemblies. The present study demonstrated that the genomic structure of the examined B. multivorans STs is highly conserved and that the B. multivorans genomic lineages are defined by their ST. Orthologous protein families were not uniformly distributed among chromosomes, with core orthologs being enriched on the primary chromosome and ST-specific orthologs being enriched on the second and third chromosome. The ST-specific orthologs were enriched in genes involved in defense mechanisms and secondary metabolism, corroborating the strain-specificity of these virulence characteristics. Finally, the same B. multivorans genomic lineages occur in both CF and environmental samples and on different continents, demonstrating their ubiquity and evolutionary persistence.

PMID: 28430818 [PubMed - in process]

Understanding the Entanglement: Neutrophil Extracellular Traps (NETs) in Cystic Fibrosis.

Front Cell Infect Microbiol. 2017;7:104

Authors: Martínez-Alemán SR, Campos-García L, Palma-Nicolas JP, Hernández-Bello R, González GM, Sánchez-González A

Abstract
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene that codes for the CF trans-membrane conductance regulator. These mutations result in abnormal secretions viscous airways of the lungs, favoring pulmonary infection and inflammation in the middle of neutrophil recruitment. Recently it was described that neutrophils can contribute with disease pathology by extruding large amounts of nuclear material through a mechanism of cell death known as Neutrophil Extracellular Traps (NETs) into the airways of patients with CF. Additionally, NETs production can contribute to airway colonization with bacteria, since they are the microorganisms most frequently found in these patients. In this review, we will discuss the implication of individual or mixed bacterial infections that most often colonize the lung of patients with CF, and the NETs role on the disease.

PMID: 28428948 [PubMed - in process]

CFTR-dependent defect in alternatively-activated macrophages in cystic fibrosis.

J Cyst Fibros. 2017 Apr 17;:

Authors: Tarique AA, Sly PD, Holt PG, Bosco A, Ware RS, Logan J, Bell SC, Wainwright CE, Fantino E

Abstract
BACKGROUND: The role of the macrophages in cystic fibrosis (CF) lung disease has been poorly studied. We hypothesized that alternatively activated M2 macrophages are abnormal in CF lung disease.
METHODS: Blood samples were collected from adults (n=13) children (n=27) with CF on admission for acute pulmonary exacerbation and when clinically stable. Monocytes were differentiated into macrophages and polarized into classical (M1) and alternatively-activated (M2) phenotypes, function determined ex-vivo and compared with healthy controls.
RESULTS: In the absence of functional cystic fibrosis trans-membrane conductance regulator (CFTR), either naturally in patients with CF or induced with CFTR inhibitors, monocyte-derived macrophages do not respond to IL-13/IL-4, fail to polarize into M2s associated with a post-transcriptional failure to produce and express IL-13Rα1 on the macrophage surface Polarization to the M1 phenotype was unaffected.
CONCLUSIONS: CFTR-dependent imbalance of macrophage phenotypes and functions could contribute to the exaggerated inflammatory response seen in CF lung disease.

PMID: 28428011 [PubMed - as supplied by publisher]

Curcumin/poly(2-methyl-2-oxazoline-b-tetrahydrofuran-b-2-methyl-2-oxazoline) formulation: An improved penetration and biological effect of curcumin in F508del-CFTR cell lines.

Eur J Pharm Biopharm. 2017 Apr 17;:

Authors: Gonçalves C, Gomez JP, Même W, Rasolonjatovo B, Gosset D, Nedellec S, Hulin P, Huin C, Le Gall T, Montier T, Lehn P, Pichon C, Guégan P, Cheradame H, Midoux P

Abstract
Neutral amphiphilic triblock ABA copolymers are of great interest to solubilize hydrophobic drugs. We reported that a triblock ABA copolymer consisting of methyl-2-oxazoline (MeOx) and tetrahydrofuran (THF) (MeOx6-THF19-MeOx6) (TBCP2) can solubilize curcumin (Cur) a very hydrophobic molecule exhibiting multiple therapeutic effects but whose insolubility and low stability in water is a major drawback for clinical applications. Here, we provide evidences by flow cytometry and confocal microscopy that Cur penetration in normal and ΔF508-CFTR human airway epithelial cell lines is facilitated by TBCP2. When used on ΔF508-CFTR cell lines, the Cur/TBCP2 formulation promotes the restoration of the expression of the CFTR protein in the plasma membrane. Furthermore, patch-clamp and MQAE fluorescence experiments show that this effect is associated with a correction of a Cl(-) selective current at the membrane surface of F508del-CFTR cells. The results show the great potential of the neutral amphiphilic triblock copolymer MeOx6-THF19-MeOx6 as carrier for curcumin in a Cystic Fibrosis context. We anticipate that other MeOxn-THFm-MeOxn copolymers could have similar behaviours for other highly insoluble therapeutic drugs or cosmetic active ingredients.

PMID: 28427956 [PubMed - as supplied by publisher]

Autosomal dominant gain of function STAT1 mutation and severe bronchiectasis.

Respir Med. 2017 May;126:39-45

Authors: Breuer O, Daum H, Cohen-Cymberknoh M, Unger S, Shoseyov D, Stepensky P, Keller B, Warnatz K, Kerem E

Abstract
BACKGROUND: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown.
OBJECTIVE: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis.
METHODS: A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping.
RESULTS: The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen.
CONCLUSIONS: Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease.

PMID: 28427548 [PubMed - in process]

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.

Nat Commun. 2017 Apr 20;8:14944

Authors: Brown D, Smeets D, Székely B, Larsimont D, Szász AM, Adnet PY, Rothé F, Rouas G, Nagy ZI, Faragó Z, Tőkés AM, Dank M, Szentmártoni G, Udvarhelyi N, Zoppoli G, Pusztai L, Piccart M, Kulka J, Lambrechts D, Sotiriou C, Desmedt C

Abstract
Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination.

PMID: 28429735 [PubMed - in process]

Clonal evolution in myelodysplastic syndromes.

Nat Commun. 2017 Apr 21;8:15099

Authors: da Silva-Coelho P, Kroeze LI, Yoshida K, Koorenhof-Scheele TN, Knops R, van de Locht LT, de Graaf AO, Massop M, Sandmann S, Dugas M, Stevens-Kroef MJ, Cermak J, Shiraishi Y, Chiba K, Tanaka H, Miyano S, de Witte T, Blijlevens NMA, Muus P, Huls G, van der Reijden BA, Ogawa S, Jansen JH

Abstract
Cancer development is a dynamic process during which the successive accumulation of mutations results in cells with increasingly malignant characteristics. Here, we show the clonal evolution pattern in myelodysplastic syndrome (MDS) patients receiving supportive care, with or without lenalidomide (follow-up 2.5-11 years). Whole-exome and targeted deep sequencing at multiple time points during the disease course reveals that both linear and branched evolutionary patterns occur with and without disease-modifying treatment. The application of disease-modifying therapy may create an evolutionary bottleneck after which more complex MDS, but also unrelated clones of haematopoietic cells, may emerge. In addition, subclones that acquired an additional mutation associated with treatment resistance (TP53) or disease progression (NRAS, KRAS) may be detected months before clinical changes become apparent. Monitoring the genetic landscape during the disease may help to guide treatment decisions.

PMID: 28429724 [PubMed - in process]

Detection of 1p36 deletion by clinical exome-first diagnostic approach.

Hum Genome Var. 2016;3:16006

Authors: Watanabe M, Hayabuchi Y, Ono A, Naruto T, Horikawa H, Kohmoto T, Masuda K, Nakagawa R, Ito H, Kagami S, Imoto I

Abstract
Although chromosome 1p36 deletion syndrome is considered clinically recognizable based on characteristic features, the clinical manifestations of patients during infancy are often not consistent with those observed later in life. We report a 4-month-old girl who showed multiple congenital anomalies and developmental delay, but no clinical signs of syndromic disease caused by a terminal deletion in 1p36.32-p36.33 that was first identified by targeted-exome sequencing for molecular diagnosis.

PMID: 28428889 [PubMed - in process]