Publications by authors named "Marie-Claude Gingras"

52 Publications

Transmission event of SARS-CoV-2 delta variant reveals multiple vaccine breakthrough infections.

BMC Med 2021 10 1;19(1):255. Epub 2021 Oct 1.

Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.

Background: This study aims to identify the causative strain of SARS-CoV-2 in a cluster of vaccine breakthroughs. Vaccine breakthrough by a highly transmissible SARS-CoV-2 strain is a risk to global public health.

Methods: Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) by qPCR (quantitative polymerase chain reaction) for Wuhan-Hu1 and alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant. GATK (genome analysis toolkit) variants were filtered with allele fraction ≥80 and min read depth 30x.

Results: Viral sequencing revealed an infection cluster of 6 vaccinated patients infected with the delta (B.1.617.2) SARS-CoV-2 variant. With no history of vaccine breakthrough, this suggests the delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152.

Conclusions: Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with previously described increased transmissibility over alpha variant and now, possible vaccine breakthrough.

Funding: Parts of this work was supported by the National Institute of Allergy and Infectious Diseases (1U19AI144297) and Baylor College of Medicine internal funding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-021-02103-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483940PMC
October 2021

Genetic testing in ambulatory cardiology clinics reveals high rate of findings with clinical management implications.

Genet Med 2021 Dec 6;23(12):2404-2414. Epub 2021 Aug 6.

Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Baylor College of Medicine, Houston, TX, USA.

Purpose: Cardiovascular disease (CVD) is the leading cause of death in adults in the United States, yet the benefits of genetic testing are not universally accepted.

Methods: We developed the "HeartCare" panel of genes associated with CVD, evaluating high-penetrance Mendelian conditions, coronary artery disease (CAD) polygenic risk, LPA gene polymorphisms, and specific pharmacogenetic (PGx) variants. We enrolled 709 individuals from cardiology clinics at Baylor College of Medicine, and samples were analyzed in a CAP/CLIA-certified laboratory. Results were returned to the ordering physician and uploaded to the electronic medical record.

Results: Notably, 32% of patients had a genetic finding with clinical management implications, even after excluding PGx results, including 9% who were molecularly diagnosed with a Mendelian condition. Among surveyed physicians, 84% reported medical management changes based on these results, including specialist referrals, cardiac tests, and medication changes. LPA polymorphisms and high polygenic risk of CAD were found in 20% and 9% of patients, respectively, leading to diet, lifestyle, and other changes. Warfarin and simvastatin pharmacogenetic variants were present in roughly half of the cohort.

Conclusion: Our results support the use of genetic information in routine cardiovascular health management and provide a roadmap for accompanying research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01294-8DOI Listing
December 2021

Sequencing of a central nervous system tumor demonstrates cancer transmission in an organ transplant.

Life Sci Alliance 2021 09 22;4(9). Epub 2021 Jul 22.

Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Four organ transplant recipients from an organ donor diagnosed with anaplastic pleomorphic xanthoastrocytoma developed fatal malignancies for which the origin could not be confirmed by standard methods. We identified the somatic mutational profiles of the neoplasms using next-generation sequencing technologies and tracked the relationship between the different samples. The data were consistent with the presence of an aggressive clonal entity in the donor and the subsequent proliferation of descendent tumors in each recipient. Deleterious mutations in , , , , and , and a chromosomal deletion spanning the genes, were shared between the recipients' lesions. In addition to demonstrating that DNA sequencing tracked a donor/recipient cancer transmission, this study established that the genetic profile of a donor tumor and its potential aggressive phenotype could have been determined before transplantation was considered. As the genetic correlates of tumor invasion and metastases become better known, adding genetic profiling by DNA sequencing to the data considered for transplant safety should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.26508/lsa.202000941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321656PMC
September 2021

Transmission event of SARS-CoV-2 Delta variant reveals multiple vaccine breakthrough infections.

medRxiv 2021 Jul 12. Epub 2021 Jul 12.

Alkek Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.

Importance: Vaccine breakthrough by an emergent SARS-CoV-2 variant poses a great risk to global public health.

Objective: To determine the SARS-CoV-2 variant responsible for 6 cases of vaccine breakthrough.

Design: Nasopharyngeal swabs from suspected vaccine breakthrough cases were tested for SARS-CoV-2 by qPCR for Wuhan-Hu1 and Alpha variant. Positive samples were then sequenced by Swift Normalase Amplicon Panels to determine the causal variant.

Setting: Transmission event occurred at events surrounding a wedding outside of Houston, TX. Two patients from India, likely transmitted the Delta variant to other guests.

Participants: Following a positive SARS-CoV-2 qPCR test at a third-party site, six fully vaccinated patients were investigated. Three males and three females ranged from 53 to 69 years old. One patient suffered from diabetes while three others were classified as overweight. No significant other comorbidities were identified. None of the patients had a history of failed vaccination.

Key Points: Which SARS-CoV-2 variant is responsible for 6 cases of vaccine breakthrough, one interventional monoclonal antibody treatment, and one death? Viral sequencing revealed 6 vaccinated patients were infected with the Delta SARS-CoV-2 variant. With no histories of vaccine breakthrough, this suggests Delta variant may possess immune evasion in patients that received the Pfizer BNT162b2, Moderna mRNA-1273, and Covaxin BBV152. Delta variant may pose the highest risk out of any currently circulating SARS-CoV-2 variants, with increased transmissibility over Alpha variant and possible vaccine breakthrough.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.06.28.21258780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282118PMC
July 2021

Germline mutation in : a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.

HGG Adv 2021 Jan 20;2(1). Epub 2020 Nov 20.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

germline variation in was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic or inherited variants in , detail their phenotypes, and map all known variants to the domain structure of and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7%) than previously reported (3/15, 20%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7%) than previously reported (14/15, 93.3%) (p value = 0.076309). -related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xhgg.2020.100014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928427PMC
January 2021

DNA methylation patterns identify subgroups of pancreatic neuroendocrine tumors with clinical association.

Commun Biol 2021 02 3;4(1):155. Epub 2021 Feb 3.

University of Sydney, Sydney, New South Wales, 2006, Australia.

Here we report the DNA methylation profile of 84 sporadic pancreatic neuroendocrine tumors (PanNETs) with associated clinical and genomic information. We identified three subgroups of PanNETs, termed T1, T2 and T3, with distinct patterns of methylation. The T1 subgroup was enriched for functional tumors and ATRX, DAXX and MEN1 wild-type genotypes. The T2 subgroup contained tumors with mutations in ATRX, DAXX and MEN1 and recurrent patterns of chromosomal losses in half of the genome with no association between regions with recurrent loss and methylation levels. T2 tumors were larger and had lower methylation in the MGMT gene body, which showed positive correlation with gene expression. The T3 subgroup harboured mutations in MEN1 with recurrent loss of chromosome 11, was enriched for grade G1 tumors and showed histological parameters associated with better prognosis. Our results suggest a role for methylation in both driving tumorigenesis and potentially stratifying prognosis in PanNETs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42003-020-01469-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859232PMC
February 2021

NF-κB and STAT3 co-operation enhances high glucose induced aggressiveness of cholangiocarcinoma cells.

Life Sci 2020 Dec 7;262:118548. Epub 2020 Oct 7.

Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand; Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand.

Aims: The present report aimed to investigate the underlying genes and pathways of high glucose driving cholangiocarcinoma (CCA) aggressiveness.

Main Methods: We screened and compared the gene expression profiles obtained by RNA sequencing, of CCA cells cultured in high and normal glucose. Results from the transcriptomic analysis were confirmed in additional cell lines using in vitro migration-invasion assay, Western blotting and immunocytofluorescence.

Key Findings: Data indicated that high glucose increased the expression of interleukin-1β (IL-1β), an upstream regulator of nuclear factor-κB (NF-κB) pathway, through the nuclear localization of NF-κB. High glucose-induced NF-κB increased the migration and invasion of CCA cells and the expression of downstream NF-κB targeted genes associated with aggressiveness, including interleukin-6, a potent triggering signal of the signal transducer and activator of transcription 3 (STAT3) pathway. Such effects were reversed by inhibiting NF-κB nuclear translocation which additionally reduced the phosphorylation of STAT3 at Y705.

Significance: These results indicate that NF-κB is activated by high glucose and they suggest that NF-κB interaction with STAT3 enhances CCA aggressiveness. Therefore, targeting multiple pathways such as STAT3 and NF-κB might improve CCA treatment outcome especially in condition such as hyperglycemia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2020.118548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686287PMC
December 2020

Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.

Hum Mutat 2020 12 8;41(12):2094-2104. Epub 2020 Oct 8.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.24118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903881PMC
December 2020

Community-based recruitment and exome sequencing indicates high diagnostic yield in adults with intellectual disability.

Mol Genet Genomic Med 2020 10 7;8(10):e1439. Epub 2020 Aug 7.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.

Background: Establishing a genetic diagnosis for individuals with intellectual disability (ID) benefits patients and their families as it may inform the prognosis, lead to appropriate therapy, and facilitate access to medical and supportive services. Exome sequencing has been successfully applied in a diagnostic setting, but most clinical exome referrals are pediatric patients, with many adults with ID lacking a comprehensive genetic evaluation.

Methods: Our unique recruitment strategy involved partnering with service and education providers for individuals with ID. We performed exome sequencing and analysis, and clinical variant interpretation for each recruited family.

Results: All five families enrolled in the study opted-in for the return of genetic results. In three out of five families exome sequencing analysis identified pathogenic or likely pathogenic variants in KANSL1, TUSC3, and MED13L genes. Families discussed the results and any potential medical follow-up in an appointment with a board certified clinical geneticist.

Conclusion: Our study suggests high yield of exome sequencing as a diagnostic tool in adult patients with ID who have not undergone comprehensive sequencing-based genetic testing. Research studies including an option of return of results through a genetic clinic could help minimize the disparity in exome diagnostic testing between pediatric and adult patients with ID.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549560PMC
October 2020

Role of ESCRT component HD-PTP/ in cancer.

Biochem Soc Trans 2017 06;45(3):845-854

Department of Biochemistry, McGill University, Montréal, Québec, Canada H3G 1Y6

Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the ndosomal orting omplexes equired for ransport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/ was recently identified as a novel haplo-insufficient tumour suppressor and , in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/ in tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BST20160332DOI Listing
June 2017

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH-Mutant Molecular Profiles.

Cell Rep 2017 03;18(11):2780-2794

Departments of Genomic Medicine, Melanoma Medical Oncology, Bioinformatics and Computational Biology, Pathology, and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493145PMC
March 2017

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Haploinsufficiency of the ESCRT Component HD-PTP Predisposes to Cancer.

Cell Rep 2016 05 19;15(9):1893-900. Epub 2016 May 19.

Department of Biochemistry, McGill University, Montréal, QC H3G 1Y6, Canada; Goodman Cancer Research Center, McGill University, Montréal, QC H3A 1A3, Canada. Electronic address:

Endosomal sorting complexes required for transport (ESCRT) drive cell surface receptor degradation resulting in attenuation of oncogenic signaling and pointing to a tumor suppressor function. Here, we show that loss of function of an ESCRT protein (HD-PTP encoded by the PTPN23 gene, located on the tumor suppressor gene cluster 3p21.3) drives tumorigenesis in vivo. Indeed, Ptpn23(+/-) loss predisposes mice to sporadic lung adenoma, B cell lymphoma, and promotes Myc-driven lymphoma onset, dissemination, and aggressiveness. Ptpn23(+/-)-derived tumors exhibit an unaltered remaining allele and maintain 50% of HD-PTP expression. Consistent with the role of HD-PTP in attenuation of integrin recycling, cell migration, and invasion, hemizygous Ptpn23(+/-) loss increases integrin β1-dependent B cell lymphoma survival and dissemination. Finally, we reveal frequent PTPN23 deletion and downregulation in human tumors that correlates with poor survival. Altogether, we establish HD-PTP/PTPN23 as a prominent haploinsufficient tumor suppressor gene preventing tumor progression through control of integrin trafficking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2016.04.076DOI Listing
May 2016

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

An open access pilot freely sharing cancer genomic data from participants in Texas.

Sci Data 2016 Feb 16;3:160010. Epub 2016 Feb 16.

Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Genomic data sharing in cancer has been restricted to aggregate or controlled-access initiatives to protect the privacy of research participants. By limiting access to these data, it has been argued that the autonomy of individuals who decide to participate in data sharing efforts has been superseded and the utility of the data as research and educational tools reduced. In a pilot Open Access (OA) project from the CPRIT-funded Texas Cancer Research Biobank, many Texas cancer patients were willing to openly share genomic data from tumor and normal matched pair specimens. For the first time, genetic data from 7 human cancer cases with matched normal are freely available without requirement for data use agreements nor any major restriction except that end users cannot attempt to re-identify the participants (http://txcrb.org/open.html).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/sdata.2016.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755126PMC
February 2016

Functional annotation of rare gene aberration drivers of pancreatic cancer.

Nat Commun 2016 Jan 25;7:10500. Epub 2016 Jan 25.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.

As we enter the era of precision medicine, characterization of cancer genomes will directly influence therapeutic decisions in the clinic. Here we describe a platform enabling functionalization of rare gene mutations through their high-throughput construction, molecular barcoding and delivery to cancer models for in vivo tumour driver screens. We apply these technologies to identify oncogenic drivers of pancreatic ductal adenocarcinoma (PDAC). This approach reveals oncogenic activity for rare gene aberrations in genes including NAD Kinase (NADK), which regulates NADP(H) homeostasis and cellular redox state. We further validate mutant NADK, whose expression provides gain-of-function enzymatic activity leading to a reduction in cellular reactive oxygen species and tumorigenesis, and show that depletion of wild-type NADK in PDAC cell lines attenuates cancer cell growth in vitro and in vivo. These data indicate that annotating rare aberrations can reveal important cancer signalling pathways representing additional therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms10500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737758PMC
January 2016

Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation.

Cell Rep 2016 Feb 21;14(4):907-919. Epub 2016 Jan 21.

Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2015.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4982376PMC
February 2016

Mitochondrial Phosphoenolpyruvate Carboxykinase Regulates Metabolic Adaptation and Enables Glucose-Independent Tumor Growth.

Mol Cell 2015 Oct;60(2):195-207

Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada; Department of Physiology, McGill University, Montreal, QC H3G 1Y6, Canada. Electronic address:

Cancer cells adapt metabolically to proliferate under nutrient limitation. Here we used combined transcriptional-metabolomic network analysis to identify metabolic pathways that support glucose-independent tumor cell proliferation. We found that glucose deprivation stimulated re-wiring of the tricarboxylic acid (TCA) cycle and early steps of gluconeogenesis to promote glucose-independent cell proliferation. Glucose limitation promoted the production of phosphoenolpyruvate (PEP) from glutamine via the activity of mitochondrial PEP-carboxykinase (PCK2). Under these conditions, glutamine-derived PEP was used to fuel biosynthetic pathways normally sustained by glucose, including serine and purine biosynthesis. PCK2 expression was required to maintain tumor cell proliferation under limited-glucose conditions in vitro and tumor growth in vivo. Elevated PCK2 expression is observed in several human tumor types and enriched in tumor tissue from non-small-cell lung cancer (NSCLC) patients. Our results define a role for PCK2 in cancer cell metabolic reprogramming that promotes glucose-independent cell growth and metabolic stress resistance in human tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2015.08.013DOI Listing
October 2015

Interplay of Endosomal pH and Ligand Occupancy in Integrin α5β1 Ubiquitination, Endocytic Sorting, and Cell Migration.

Cell Rep 2015 Oct 8;13(3):599-609. Epub 2015 Oct 8.

Department of Biochemistry, Goodman Cancer Research Centre, McGill University, Montreal, Canada, H3G 1Y6. Electronic address:

Membrane trafficking of integrins plays a pivotal role in cell proliferation and migration. How endocytosed integrins are targeted either for recycling or lysosomal delivery is not fully understood. Here, we show that fibronectin (FN) binding to α5β1 integrin triggers ubiquitination and internalization of the receptor complex. Acidification facilitates FN dissociation from integrin α5β1 in vitro and in early endosomes, promoting receptor complex deubiquitination by the USP9x and recycling to the cell surface. Depending on residual ligand occupancy of receptors, some α5β1 integrins remain ubiquitinated and are captured by ESCRT-0/I, containing histidine domain-containing protein tyrosine phosphatase (HD-PTP) and ubiquitin-associated protein 1 (UBAP1), and are directed for lysosomal proteolysis, limiting receptor downstream signaling and cell migration. Thus, HD-PTP or UBAP1 depletion confers a pro-invasive phenotype. Thus, pH-dependent FN-integrin dissociation and deubiquitination of the activated integrin α5β1 are required for receptor resensitization and cell migration, representing potential targets to modulate tumor invasiveness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2015.09.024DOI Listing
October 2015

FLCN and AMPK Confer Resistance to Hyperosmotic Stress via Remodeling of Glycogen Stores.

PLoS Genet 2015 Oct 6;11(10):e1005520. Epub 2015 Oct 6.

Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.

Mechanisms of adaptation to environmental changes in osmolarity are fundamental for cellular and organismal survival. Here we identify a novel osmotic stress resistance pathway in Caenorhabditis elegans (C. elegans), which is dependent on the metabolic master regulator 5'-AMP-activated protein kinase (AMPK) and its negative regulator Folliculin (FLCN). FLCN-1 is the nematode ortholog of the tumor suppressor FLCN, responsible for the Birt-Hogg-Dubé (BHD) tumor syndrome. We show that flcn-1 mutants exhibit increased resistance to hyperosmotic stress via constitutive AMPK-dependent accumulation of glycogen reserves. Upon hyperosmotic stress exposure, glycogen stores are rapidly degraded, leading to a significant accumulation of the organic osmolyte glycerol through transcriptional upregulation of glycerol-3-phosphate dehydrogenase enzymes (gpdh-1 and gpdh-2). Importantly, the hyperosmotic stress resistance in flcn-1 mutant and wild-type animals is strongly suppressed by loss of AMPK, glycogen synthase, glycogen phosphorylase, or simultaneous loss of gpdh-1 and gpdh-2 enzymes. Our studies show for the first time that animals normally exhibit AMPK-dependent glycogen stores, which can be utilized for rapid adaptation to either energy stress or hyperosmotic stress. Importantly, we show that glycogen accumulates in kidneys from mice lacking FLCN and in renal tumors from a BHD patient. Our findings suggest a dual role for glycogen, acting as a reservoir for energy supply and osmolyte production, and both processes might be supporting tumorigenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1005520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4595296PMC
October 2015

Genomic profiling guides the choice of molecular targeted therapy of pancreatic cancer.

Cancer Lett 2015 Jul 15;363(1):1-6. Epub 2015 Apr 15.

The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, TX 77030, USA; Department of Medicine, Department of Surgery, The University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1262A, Oklahoma City, OK 73104, USA. Electronic address:

Pancreatic cancer has the worst five-year survival rate of all malignancies due to its aggressive progression and resistance to therapy. Current therapies are limited to gemcitabine-based chemotherapeutics, surgery, and radiation. The current trend toward "personalized genomic medicine" has the potential to improve the treatment options for pancreatic cancer. Gene identification and genetic alterations like single nucleotide polymorphisms and mutations will allow physicians to predict the efficacy and toxicity of drugs, which could help diagnose pancreatic cancer, guide neoadjuvant or adjuvant treatment, and evaluate patients' prognosis. This article reviews the multifaceted roles of genomics and pharmacogenomics in pancreatic cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canlet.2015.04.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451193PMC
July 2015

Trans-ancestry mutational landscape of hepatocellular carcinoma genomes.

Nat Genet 2014 Dec 2;46(12):1267-73. Epub 2014 Nov 2.

Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ng.3126DOI Listing
December 2014

Folliculin regulates ampk-dependent autophagy and metabolic stress survival.

PLoS Genet 2014 Apr 24;10(4):e1004273. Epub 2014 Apr 24.

Goodman Cancer Research Center, McGill University, Montréal, Québec, Canada; Department of Biochemistry, McGill University, Montréal, Québec, Canada.

Dysregulation of AMPK signaling has been implicated in many human diseases, which emphasizes the importance of characterizing AMPK regulators. The tumor suppressor FLCN, responsible for the Birt-Hogg Dubé renal neoplasia syndrome (BHD), is an AMPK-binding partner but the genetic and functional links between FLCN and AMPK have not been established. Strikingly, the majority of naturally occurring FLCN mutations predisposing to BHD are predicted to produce truncated proteins unable to bind AMPK, pointing to the critical role of this interaction in the tumor suppression mechanism. Here, we demonstrate that FLCN is an evolutionarily conserved negative regulator of AMPK. Using Caenorhabditis elegans and mammalian cells, we show that loss of FLCN results in constitutive activation of AMPK which induces autophagy, inhibits apoptosis, improves cellular bioenergetics, and confers resistance to energy-depleting stresses including oxidative stress, heat, anoxia, and serum deprivation. We further show that AMPK activation conferred by FLCN loss is independent of the cellular energy state suggesting that FLCN controls the AMPK energy sensing ability. Together, our data suggest that FLCN is an evolutionarily conserved regulator of AMPK signaling that may act as a tumor suppressor by negatively regulating AMPK function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1004273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998892PMC
April 2014

The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation.

J Clin Invest 2014 Jun 24;124(6):2640-50. Epub 2014 Apr 24.

The Warburg effect is a tumorigenic metabolic adaptation process characterized by augmented aerobic glycolysis, which enhances cellular bioenergetics. In normal cells, energy homeostasis is controlled by AMPK; however, its role in cancer is not understood, as both AMPK-dependent tumor-promoting and -inhibiting functions were reported. Upon stress, energy levels are maintained by increased mitochondrial biogenesis and glycolysis, controlled by transcriptional coactivator PGC-1α and HIF, respectively. In normoxia, AMPK induces PGC-1α, but how HIF is activated is unclear. Germline mutations in the gene encoding the tumor suppressor folliculin (FLCN) lead to Birt-Hogg-Dubé (BHD) syndrome, which is associated with an increased cancer risk. FLCN was identified as an AMPK binding partner, and we evaluated its role with respect to AMPK-dependent energy functions. We revealed that loss of FLCN constitutively activates AMPK, resulting in PGC-1α-mediated mitochondrial biogenesis and increased ROS production. ROS induced HIF transcriptional activity and drove Warburg metabolic reprogramming, coupling AMPK-dependent mitochondrial biogenesis to HIF-dependent metabolic changes. This reprogramming stimulated cellular bioenergetics and conferred a HIF-dependent tumorigenic advantage in FLCN-negative cancer cells. Moreover, this pathway is conserved in a BHD-derived tumor. These results indicate that FLCN inhibits tumorigenesis by preventing AMPK-dependent HIF activation and the subsequent Warburg metabolic transformation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI71749DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038567PMC
June 2014

FLCN: A new regulator of AMPK-dependent Warburg metabolic reprogramming.

Mol Cell Oncol 2014 Apr-Jun;1(2):e961819. Epub 2014 Oct 30.

Goodman Cancer Research Center; McGill University; Montréal, QC Canada; Department of Biochemistry; McGill University; Montréal, QC Canada.

Tumor cells manage their energy to support aberrant proliferation by reprogramming their cellular metabolism, for example through the Warburg effect. Although AMPK is a major regulator of energy homeostasis, its role in cancer metabolic adaptation is unclear. We recently identified the tumor suppressor folliculin as a new regulator of AMPK-dependent metabolic transformation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4161/23723548.2014.961819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905253PMC
June 2016

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Nature 2012 Nov 24;491(7424):399-405. Epub 2012 Oct 24.

The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature11547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530898PMC
November 2012

PDX-1 is a therapeutic target for pancreatic cancer, insulinoma and islet neoplasia using a novel RNA interference platform.

PLoS One 2012 8;7(8):e40452. Epub 2012 Aug 8.

Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California, United States of America.

Pancreatic and duodenal homeobox-1 (PDX-1) is a transcription factor that regulates insulin expression and islet maintenance in the adult pancreas. Our recent studies demonstrate that PDX-1 is an oncogene for pancreatic cancer and is overexpressed in pancreatic cancer. The purpose of this study was to demonstrate that PDX-1 is a therapeutic target for both hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Immunohistochemistry of human pancreatic and islet neoplasia specimens revealed marked PDX-1 overexpression, suggesting PDX-1 as a "drugable" target within these diseases. To do so, a novel RNA interference effector platform, bifunctional shRNA(PDX-1), was developed and studied in mouse and human cell lines as well as in mouse models of pancreatic cancer, insulinoma and islet neoplasia. Systemic delivery of bi-shRNA(humanPDX-1) lipoplexes resulted in marked reduction of tumor volume and improved survival in a human pancreatic cancer xenograft mouse model. bi-shRNA(mousePDX-1) lipoplexes prevented death from hyperinsulinemia and hypoglycemia in an insulinoma mouse model. shRNA(mousePDX-1) lipoplexes reversed hyperinsulinemia and hypoglycemia in an immune-competent mouse model of islet neoplasia. PDX-1 was overexpressed in pancreatic neuroendocrine tumors and nesidioblastosis. These data demonstrate that PDX-1 RNAi therapy controls hormonal symptoms and tumor volume in mouse models of pancreatic cancer, insulinoma and islet neoplasia, therefore, PDX-1 is a potential therapeutic target for these pancreatic diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040452PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414490PMC
February 2013

Mutations in KAT6B, encoding a histone acetyltransferase, cause Genitopatellar syndrome.

Am J Hum Genet 2012 Feb 19;90(2):282-9. Epub 2012 Jan 19.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Genitopatellar syndrome (GPS) is a skeletal dysplasia with cerebral and genital anomalies for which the molecular basis has not yet been determined. By exome sequencing, we found de novo heterozygous truncating mutations in KAT6B (lysine acetyltransferase 6B, formerly known as MYST4 and MORF) in three subjects; then by Sanger sequencing of KAT6B, we found similar mutations in three additional subjects. The mutant transcripts do not undergo nonsense-mediated decay in cells from subjects with GPS. In addition, human pathological analyses and mouse expression studies point to systemic roles of KAT6B in controlling organismal growth and development. Myst4 (the mouse orthologous gene) is expressed in mouse tissues corresponding to those affected by GPS. Phenotypic differences and similarities between GPS, the Say-Barber-Biesecker variant of Ohdo syndrome (caused by different mutations of KAT6B), and Rubinstein-Taybi syndrome (caused by mutations in other histone acetyltransferases) are discussed. Together, the data support an epigenetic dysregulation of the limb, brain, and genital developmental programs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2011.11.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276659PMC
February 2012
-->