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Mutational signatures of 1,2-dichloropropane and dichloromethane identified in mouse carcinogenicity assays [Meeting Abstract]

Lueong, S; Villar, S; Cahais, V; Heguy, A; Wanibuchi, H; Gi, M; Totsuka, Y; Herbert, R; Zavadil, J; Olivier, M
Introduction The analysis of somatic mutational signatures in a single tumour can reveal clues on the natural history of this tumour, including past exposures to carcinogens. Characterising the mutational signatures of potential carcinogens used in industry may thus help identify cancers that are due to occupational exposure. Here, we used experimental models to define the mutational signatures of dichloromethane (DCM) and 1,2- dichloropropane (DCP), two solvents suspected to cause cholangiocarcinomas in occupational settings. Material and methods Experimentally induced tumours and matching normal tissues from mice exposed to DCP (by gavage), DCM (by gavage or inhalation) or DCP +DCM (by gavage), and spontaneous tumours from vehicle/sham-exposed mice were analysed by whole-exome sequencing. Somatic mutation calling was performed to define exome-wide mutation patterns induced by DCP and DCM in these assays. Mutation data obtained in biliary tract cancers of workers in the printing industry who have been exposed to DCP and DCM as single agents or as mixtures, as well as with public somatic mutation data from biliary tract cancers were mined for the presence of the experimentally defined DCP and DCM mutational signatures. Results and discussions Liver tumours from DCP and DCM exposed mice had distinct somatic mutations patterns compared to spontaneous liver tumours from vehicle/sham-exposed mice. While mutations in DCP-exposed mice were dominated by C:G>T:A transitions, the most frequent types of mutations in DCM-exposed mice were T:A>A:T and T:A>C:G substitutions. An average of 10.3 somatic mutations was observed per Mb in tumours from DCM-exposed mice, approximately 3- fold higher than in DCP-exposed or sham-treated mice. The mutation patterns found in DCP-exposed mice, but not DCMexposed mice, presented some similarities with the mutational signature observed in cholangiocarcinomas of Japanese patients with occupational DCP/DCM exposure history. Conclusion These results show that the analysis of tumour genomes from mouse carcinogenicity assays can support the characterisation of mutational signatures of carcinogenic compounds relevant to human exposures
EMBASE:627975018
ISSN: 2059-7029
CID: 3932632

Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP containing the ancestral DUF1220 domain in pineoblastoma [Meeting Abstract]

Snuderl, M; Kannan, K; Pfaff, E; Wang, S; Stafford, J; Serrano, J; Heguy, A; Ray, K; Faustin, A; Aminova, O; Dolgalev, I; Stapleton, S; Zagzag, D; Chiriboga, L; Gardner, S; Wisoff, J; Golfinos, J; Capper, D; Hovestadt, V; Rosenblum, M; Placantonakis, D; LeBoeuf, S; Papagiannakopoulos, T; Chavez, L; Ahsan, S; Eberhart, C; Pfister, S; Jones, D; Karajannis, M
BACKGROUND: Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. METHODS: We analyzed pediatric and adult pineoblastoma samples (n=23) using integrated genomic studies, including genome-wide DNA methylation profiling, whole-exome or whole-genome sequencing, and whole-transcriptome analysis. RESULTS: Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower grade pineal tumors and normal pineal gland. Recurrent somatic mutations were found in genes involved in PKA-and NF-kappaB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expression of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain. Whole-transcriptome analysis showed that homozygous loss of DROSHA led to distinct changes in RNA expression profile. Disruption of the DROSHA locus in human neural stem cells using the CRISPR/Cas9 system, led to decrease of the DROSHA protein, and massive loss of miRNAs. CONCLUSION: We identified recurrent homozygous deletions of DROSHA in pineoblastoma, suggesting that different mechanisms disrupting miRNA processing are involved in the pathogenesis of familial versus sporadic pineoblastoma. Furthermore, a novel microduplication of PDE4DIP leading to upregulation of DUF1220 protein suggests DUF1220 as a novel oncogenic driver in pineoblastoma
EMBASE:623098707
ISSN: 1523-5866
CID: 3211282

Loss of Keap1 promotes KRAS-driven lung cancer and results in genotype-specific vulnerabilities. [Meeting Abstract]

Romero, Rodrigo; Sayin, Volkan I.; Shawn, Davidson M.; Bauer, Matthew; Singh, Simranjit X.; LeBoeuf, Sarah; Karakousi, Triantafyllia R.; Ellis, Donald C.; Bhutkar, Arjun; Sanchez-Rivera, Francisco; Subbaraj, Lakshmipriya; Martinez, Britney; Bronson, Roderick T.; Prigge, Justin R.; Schmidt, Edward E.; Thomas, Craig J.; Davies, Angela; Dolgalev, Igor; Heguy, Adriana; Allaj, Viola; Piorier, John T.; Moreira, Andre L.; Rudin, Charles M.; Pass, Harvey I.; Heiden, Matthew G. Vander; Jacks, Tyler; Papagiannakopoulos, Thales
ISI:000432307300068
ISSN: 0008-5472
CID: 3132562

Role of dysregulated cytokine signaling and bacterial triggers in the pathogenesis of Cutaneous T Cell Lymphoma

Fanok, Melania H; Sun, Amy; Fogli, Laura K; Narendran, Vijay; Eckstein, Miriam; Kannan, Kasthuri; Dolgalev, Igor; Lazaris, Charalampos; Heguy, Adriana; Laird, Mary E; Sundrud, Mark S; Liu, Cynthia; Kutok, Jeff; Lacruz, Rodrigo S; Latkowski, Jo-Ann; Aifantis, Iannis; Odum, Niels; Hymes, Kenneth B; Goel, Swati; Koralov, Sergei B
Cutaneous T cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome revealed a highly heterogeneous landscape of genetic perturbations and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway, previously implicated in CTCL pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of CTCL. Using this mouse model, we demonstrate that T cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.
PMCID:5912980
PMID: 29128259
ISSN: 1523-1747
CID: 2785082

Gut microbiota alterations in reactive arthritis in a Guatemalan cohort [Meeting Abstract]

Manasson, J; Shen, N; Ferrer, H G; Ubeda, C; Iraheta, I; Heguy, A; Von, Feldt J; Espinoza, L R; Kutzbach, A G; Segal, L N; Ogdie, A; Clemente, J C; Scher, J
Objective: To characterize the gut microbiota and host gene interactions in Reactive Arthritis (ReA) and postinfectious SpA. Methods: 32 patients with ReA and 32 controls with preceding Gastrointestinal (GI) and/or Genitourinary (GU) infections that did not develop arthritiswere prospectively recruited in Guatemala, a highly prevalent geographic region for this disease. Clinical variables, HLA status and 16S ribosomal RNA gene sequencing of intestinal microbiota were analysed. Results: Subjects with ReA showed no significant differences from controls in gut bacterial richness, alpha or beta diversity. However there was a higher abundance of Erwinia and Pseudomonas, and increased prevalence of typical enteropathogens associated with ReA. In Fact, at least one enteropathogen was present in 71.9% of ReA subjects vs 46.8% of controls (p<0.05). Subjects with ultrasound evidence of enthesitiswere enriched with Campylobacter,while subjects with Uveitis and radiographic sacroiliitis were enriched with Erwinia and unclassified Ruminococcaceae, respectively. Both were enriched in Dialister (log LDA>2). Host genetics, particularly HLA-A24 were associated with differences in gut microbiota diversity irrespective of disease status. We identified several co-occurring taxa that were also predictive of HLA-A24 status, including Ruminococcaceae-Rikenellaceae-Coriobacteriacea and Prevotellaceaeunclassified Sphingobacteriales-Elusimicrobiaceae. Conclusion: This is the first culture-independent study characterizing the gut microbial community of ReA. Although bacterial factors correlated with disease presence and clinical features of ReA, host genetics also appeared to be a major independent driver of intestinal community composition. Understanding of these gut microbiota host-genetic relationships may further clarify the pathogenesis of ReA and related Spondyloarthritis
EMBASE:622213869
ISSN: 1536-7355
CID: 3130272

Atrx inactivation drives disease-defining phenotypes in glioma cells of origin through global epigenomic remodeling

Danussi, Carla; Bose, Promita; Parthasarathy, Prasanna T; Silberman, Pedro C; Van Arnam, John S; Vitucci, Mark; Tang, Oliver Y; Heguy, Adriana; Wang, Yuxiang; Chan, Timothy A; Riggins, Gregory J; Sulman, Erik P; Lang, Frederick; Creighton, Chad J; Deneen, Benjamin; Miller, C Ryan; Picketts, David J; Kannan, Kasthuri; Huse, Jason T
Mutational inactivation of the SWI/SNF chromatin regulator ATRX occurs frequently in gliomas, the most common primary brain tumors. Whether and how ATRX deficiency promotes oncogenesis by epigenomic dysregulation remains unclear, despite its recent implication in both genomic instability and telomere dysfunction. Here we report that Atrx loss recapitulates characteristic disease phenotypes and molecular features in putative glioma cells of origin, inducing cellular motility although also shifting differentiation state and potential toward an astrocytic rather than neuronal histiogenic profile. Moreover, Atrx deficiency drives widespread shifts in chromatin accessibility, histone composition, and transcription in a distribution almost entirely restricted to genomic sites normally bound by the protein. Finally, direct gene targets of Atrx that mediate specific Atrx-deficient phenotypes in vitro exhibit similarly selective misexpression in ATRX-mutant human gliomas. These findings demonstrate that ATRX deficiency and its epigenomic sequelae are sufficient to induce disease-defining oncogenic phenotypes in appropriate cellular and molecular contexts.
PMCID:5849741
PMID: 29535300
ISSN: 2041-1723
CID: 2992712

Microglandular Adenosis with Somatic TP53 Mutation is a Clonally-Advanced Lesion with a Molecular Signature Significantly Overlapping with That of Its Corresponding Metaplastic Carcinoma [Meeting Abstract]

Schwartz, Christopher J.; Yoon, Esther; Dolgalev, Igor; de Miera, Eleazar Vega-Saenz; Heguy, Adriana; Osman, Iman; Darvishian, Farbod
ISI:000429308600292
ISSN: 0893-3952
CID: 3049112

Microglandular adenosis with somatic TP53 mutation is a clonally-advanced lesion with a molecular signature significantly overlapping with that of its corresponding metaplastic carcinoma [Meeting Abstract]

Schwartz, C J; Yoon, E; Dolgalev, I; Vega-Saenz, De Miera E; Heguy, A; Osman, I; Darvishian, F
Background: Microglandular adenosis (MGA) is a rare borderline lesion of the breast characterized by an infiltrative collection of small glands that characteristically lack a myoepithelial cell layer. MGA is associated with invasive carcinoma in 20-30% of cases, and has been proposed as a non-obligate precursor to basal-like breast cancers. Somatic TP53 mutation of MGA and its associated carcinoma has been previously reported. We identified a case of triple negative metaplastic carcinoma with mesenchymal differentiation with morphologic and immunohistochemical evidence of progression from MGA to atypical MGA (AMGA), carcinoma in situ (CIS) and invasive carcinoma. We performed laser microdissection and whole exome sequencing of each four components (MGA, AMGA, CIS and cancer) with a matched benign sample to characterize the mutational landscape of these foci. Design: We selected a case of a metaplastic carcinoma with mesenchymal differentiation in juxtaposition to foci of MGA, AMGA and CIS. Immunohistochemically, all four foci were negative for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (her2) and positive for S-100. The distinct morphologic components and a matched control lymph node were separately microdissected from formalin-fixed paraffin embedded blocks. DNA extraction was performed and subjected to whole-exome sequencing on Illumina HiSeq platform. The results were demultiplexed and converted to FASTQ format using Illumina bcl2fastq software. Singlenucleotide and small indel somatic variants were called with MuTect2. Copy number profiles were calculated using Control-FREEC. Clonal populations were identified and quantified using PyClone. Results: Sequencing data resulted in mean coverage of 96-134X of targeted exome regions. Our results found a recurrent stop-gain R213* TP53 mutation in MGA, atypical MGA, CIS and metaplastic carcinoma. In addition, through variant allele frequency analysis, we identified two putative clonal clusters shared by all foci indicating a common molecular signature that is preserved in the morphologic spectrum of MGA-AMGA-CIS-metaplastic carcinoma. Conclusions: MGA is a molecularly advanced lesion with somatic mutation of TP53. We postulate that TP53 is an early event in the progression of MGA through AMGA, CIS and its associated metaplastic carcinoma. We report significant genetic overlap between MGA and its associated cancer
EMBASE:621624072
ISSN: 1530-0307
CID: 3046332

Prognostic role of elevated mir-24-3p in breast cancer and its association with the metastatic process

Khodadadi-Jamayran, Alireza; Akgol-Oksuz, Betul; Afanasyeva, Yelena; Heguy, Adriana; Thompson, Marae; Ray, Karina; Giro-Perafita, Ariadna; Sánchez, Irma; Wu, Xifeng; Tripathy, Debu; Zeleniuch-Jacquotte, Anne; Tsirigos, Aristotelis; Esteva, Francisco J
MicroRNAs have been shown to play important roles in breast cancer progression and can serve as biomarkers. To assess the prognostic role of a panel of miRNAs in breast cancer, we collected plasma prospectively at the time of initial diagnosis from 1,780 patients with stage I-III breast cancer prior to definitive treatment. We identified plasma from 115 patients who subsequently developed distant metastases and 115 patients without metastatic disease. Both groups were matched by: age at blood collection, year of blood collection, breast cancer subtype, and stage. The median follow up was 3.4 years (range, 1-9 years). We extracted RNA from plasma and analyzed the expression of 800 miRNAs using Nanostring technology. We then assessed the expression of miRNAs in primary and metastatic breast cancer samples from The Cancer Genome Atlas (TCGA). We found that, miR-24-3p was upregulated in patients with metastases, both in plasma and in breast cancer tissues. Patients whose primary tumors expressed high levels of miR-24-3p had a significantly lower survival rate compared to patients with low mir-24-3p levels in the TCGA cohort (n=1,024). RNA-Seq data of the samples with the highest miR-24-3p expression versus those with the lowest miR-24-3p in the TCGA cohort identified a specific gene expression signature for those tumors with high miR-24-3p. Possible target genes for miR-24-3p were predicted based on gene expression and binding site, and their effects on cancer pathways were evaluated. Cancer, breast cancer and proteoglycans were the top three pathways affected by miR-24-3p overexpression.
PMCID:5849180
PMID: 29560116
ISSN: 1949-2553
CID: 3000882

The Ancient Origins of Neural Substrates for Land Walking

Jung, Heekyung; Baek, Myungin; D'Elia, Kristen P; Boisvert, Catherine; Currie, Peter D; Tay, Boon-Hui; Venkatesh, Byrappa; Brown, Stuart M; Heguy, Adriana; Schoppik, David; Dasen, Jeremy S
Walking is the predominant locomotor behavior expressed by land-dwelling vertebrates, but it is unknown when the neural circuits that are essential for limb control first appeared. Certain fish species display walking-like behaviors, raising the possibility that the underlying circuitry originated in primitive marine vertebrates. We show that the neural substrates of bipedalism are present in the little skate Leucoraja erinacea, whose common ancestor with tetrapods existed ∼420 million years ago. Leucoraja exhibits core features of tetrapod locomotor gaits, including left-right alternation and reciprocal extension-flexion of the pelvic fins. Leucoraja also deploys a remarkably conserved Hox transcription factor-dependent program that is essential for selective innervation of fin/limb muscle. This network encodes peripheral connectivity modules that are distinct from those used in axial muscle-based swimming and has apparently been diminished in most modern fish. These findings indicate that the circuits that are essential for walking evolved through adaptation of a genetic regulatory network shared by all vertebrates with paired appendages. VIDEO ABSTRACT.
PMCID:5808577
PMID: 29425489
ISSN: 1097-4172
CID: 2948352