David E C Cole

University of Toronto, Toronto, Ontario, Canada

Are you David E C Cole?

Claim your profile

Publications (212)1022.83 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To examine factors, in addition to bone mineral density (BMD), such as the common calcium-sensing receptor (CASR) gene polymorphisms, associated with vertebral fracture (VFx) risk in primary hyperparathyroidism (PHPT). . Design and Methods: Cross-sectional analysis of 266 Caucasian PHPT seen as outpatients. Calcium (sCa)-phosphate metabolism parameters were measured. BMD was assessed by dual-energy X-ray absorptiometry (DXA, expressed as Z-Score) at lumbar spine (Z-LS) and femoral neck (Z-FN), morphometric VFx by radiograph and CASR A986S/R990G genotypes by PCR amplification and genomic DNA sequencing. Results: Fractured patients (n=100, 37.6%) had lower sCa (10.8±0.7 mg/dL) and Z-LS BMD (-1.0±1.44), higher age (61±10 yrs) and prevalence (51%) of ≥1 S alleles of the CASR A986S single nucleotide polymorphism (SNP; AS/SS), than those not fractured (n =166, 11.2±1.0 mg/dL, -0.57±0.97, 58±13 yrs and 38% AS/SS, respectively, P<0.05 for all comparisons). Logistic regression, with VFx as dependent variable, showed independent risks associated with increased age (OR 1.03, 95% CI 1.01 - 1.06, P=0.006), decreased sCa (OR 1.86, 95% CI 1.28 - 2.7, P=0.001) and Z-LS BMD (OR 1.4, 95% CI 1.12 - 1.7, P=0.002) and presence of AS/SS (OR 1.8, 95% CI 1.1 - 2.9, P=0.05). The presence of two out of three (age ≥58 yr, sCa <10.8 and Z-LS BMD ≤ -1.0, and AS/SS genotype,) gave an overall OR of 4.2, 95% CI 2.25 - 7.85, P<0.0001). Conclusions: In PHPT, VFx is associated positively with age, negatively with sCa and spinal BMD, and presence of at least one copy of the CASR A986S SNP.
    European journal of endocrinology / European Federation of Endocrine Societies. 06/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Two single-nucleotide polymorphisms (SNPs) at the calcium-sensing receptor (CASR) gene were previously associated with kidney stones in patients with primary hyperparathyroidism (PHPT): rs1501899, likely associated with a decrease in CASR expression, and Arg990Gly, causing a gain of CASR function. To evaluate the interaction of these two SNPs in the stone risk, we tested the association of stones with the genotype at both SNPs in PHPT patients and the association of rs1501899 with CASR expression as messenger RNA (mRNA) in human kidney samples. Two hundred and ninety-six PHPT patients were genotyped at the rs1501899 and Arg990Gly SNPs. Minor allele frequency at tested SNPs was higher in PHPT stone formers relative to non-stone forming patients. PHPT patients carrying one or two copies of the minor allele at both rs1501899 and Arg990Gly (n = 16) had the maximal risk of stones (odds ratio, OR 8.3) and higher serum ionized calcium compared with homozygous patients for the wild-type allele at both SNPs. CASR expression as mRNA was measured by real time polymerase chain reaction (PCR) in normal kidney medulla samples from 109 subjects. CASR mRNA was significantly lower in medulla samples from homozygotes for the minor allele at rs1501899 than in subjects with other genotypes. We conclude that the simultaneous presence of the minor allele at rs1501899 and Arg990Gly may amplify the kidney stone risk in PHPT patients, despite their apparently opposite effects on CASR function in the kidney.
    Journal of nephrology 05/2014; · 2.02 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Potential vitamin D-related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D-binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D-binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers. To test the hypothesis that GC single nucleotide polymorphisms encoding the D432E and T436K variants predict subsequent development of asthma in healthy children. A retrospective medical record review was performed to determine the development of asthma in 776 children in whom GC genotype, vitamin D-binding protein concentration, and circulating 25-hydroxyvitamin D had been determined at 6 to 36 months of age. Demographic and detailed current clinical data were collected and criteria for asthma were recorded. GC genotype was available for 463 subjects. After an initial analysis of all subject data, the analysis was limited to the predominant Hispanic population (72.1%) to minimize potential confounding effects of ethnicity. Asthma was diagnosed in 87 children (26%). Subjects with the GC genotype encoding the ET/ET (Gc1s/Gc1s) variant had lower odds of developing asthma, representing a protective effect compared with subjects with the DT/DT (Gc1f/Gc1f) variant. In the Hispanic population of inner-city New Haven, Connecticut, the ET/ET (Gc1s/Gc1s) genotype of vitamin D-binding protein might confer protection against the development of asthma compared with the wild-type genotype DT/DT (Gc1f/Gc1f).
    Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 04/2014; · 3.45 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disorder with three known subtypes: FHH1, FHH2, and FHH3. About 65% of FHH cases are FHH1, caused by inactivating mutations of the calcium-sensing receptor (CASR) gene. FHH3 was recently found to be caused by codon Arg15 (p.R15) mutations in the adaptor-related protein complex 2, sigma-2 subunit that interacts with the CaSR, and is encoded by the AP2S1 gene. Objective: To assess the prevalence of AP2S1 mutations, and describe the phenotype of FHH3, in an independent cohort of FHH subjects lacking CASR mutations. Patients and Methods: Thirty-nine patients presenting with some combination of hypercalcemia, hypermagnesemia, non-suppressed serum PTH levels, and reduced urinary calcium excretion were studied. Exon 2 of the AP2S1 gene was PCR amplified from patient genomic DNA and Sanger sequenced. The presence of p.R15 mutations was confirmed by restriction enzyme analysis. Results: Five of the 39 subjects had AP2S1 p.R15 mutations - a frequency of 13%. The three recurrent mutations reported previously were all found in our cohort (p.R15C in 2, p.R15L in 2, and p.R15H in one subject). The FHH3 phenotype did not differ materially from that of FHH1 due to CASR mutations. Conclusions: The results affirm that a significant number of patients suspected of having FHH but proven negative for CASR mutation have AP2S1 p.R15 mutations. Screening for AP2S1 p.R15 mutations in such cases should be considered, given the clinical benefits (avoiding unnecessary parathyroidectomy) that have already been demonstrated for CASR screening in FHH1.
    The Journal of Clinical Endocrinology and Metabolism 04/2014; · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background NSHPT is a life threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice. Objective To describe a case of NSHPT unresponsive to cinacalcet. Patient and Results A 23-day-old girl was admitted with hypercalcaemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9–52) and urinary Ca/Cr ratio: 0.5 mg/mg. First, calcitonin was given (10 IU/kg x 4/day) and then two days later, pamidronate (0.5 mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l, but thereafter rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation. Conclusion The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.
    Bone 01/2014; · 4.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Potential vitamin D–related influences on inflammatory diseases such as asthma are controversial, including the suggestion that vitamin D insufficiency is associated with increased asthma morbidity. Vitamin D–binding protein transports vitamin D metabolites in the circulation. Single nucleotide polymorphisms in the GC gene encoding vitamin D–binding protein are associated with circulating vitamin D metabolite levels in healthy infants and toddlers. Objective To test the hypothesis that GC single nucleotide polymorphisms encoding the D432E and T436K variants predict subsequent development of asthma in healthy children. Methods A retrospective medical record review was performed to determine the development of asthma in 776 children in whom GC genotype, vitamin D–binding protein concentration, and circulating 25-hydroxyvitamin D had been determined at 6 to 36 months of age. Demographic and detailed current clinical data were collected and criteria for asthma were recorded. Results GC genotype was available for 463 subjects. After an initial analysis of all subject data, the analysis was limited to the predominant Hispanic population (72.1%) to minimize potential confounding effects of ethnicity. Asthma was diagnosed in 87 children (26%). Subjects with the GC genotype encoding the ET/ET (Gc1s/Gc1s) variant had lower odds of developing asthma, representing a protective effect compared with subjects with the DT/DT (Gc1f/Gc1f) variant. Conclusion In the Hispanic population of inner-city New Haven, Connecticut, the ET/ET (Gc1s/Gc1s) genotype of vitamin D–binding protein might confer protection against the development of asthma compared with the wild-type genotype DT/DT (Gc1f/Gc1f).
    Annals of Allergy, Asthma & Immunology. 01/2014;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacogenetics investigates the influence of genetic variants on physiological phenotypes related to drug response and disease, while pharmacogenomics takes a genome-wide approach to advancing this knowledge. Both play an important role in identifying responders and nonresponders to medication, avoiding adverse drug reactions, and optimizing drug dose for the individual. G protein-coupled receptors (GPCRs) are the primary target of therapeutic drugs and have been the focus of these studies. With the advance of genomic technologies, there has been a substantial increase in the inventory of naturally occurring rare and common GPCR variants. These variants include single-nucleotide polymorphisms and insertion or deletions that have potential to alter GPCR expression of function. In vivo and in vitro studies have determined functional roles for many GPCR variants, but genetic association studies that define the physiological impact of the majority of these common variants are still limited. Despite the breadth of pharmacogenetic data available, GPCR variants have not been included in drug labeling and are only occasionally considered in optimizing clinical use of GPCR-targeted agents. In this chapter, pharmacogenetic and genomic studies on GPCR variants are reviewed with respect to a subset of GPCR systems, including the adrenergic, calcium sensing, cysteinyl leukotriene, cannabinoid CB1 and CB2 receptors, and the de-orphanized receptors such as GPR55. The nature of the disruption to receptor function is discussed with respect to regulation of gene expression, expression on the cell surface (affected by receptor trafficking, dimerization, desensitization/downregulation), or perturbation of receptor function (altered ligand binding, G protein coupling, constitutive activity). The large body of experimental data generated on structure and function relationships and receptor-ligand interactions are being harnessed for the in silico functional prediction of naturally occurring GPCR variants. We provide information on online resources dedicated to GPCRs and present applications of publically available computational tools for pharmacogenetic studies of GPCRs. As the breadth of GPCR pharmacogenomic data becomes clearer, the opportunity for routine assessment of GPCR variants to predict disease risk, drug response, and potential adverse drug effects will become possible.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1175:189-242. · 1.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common pharmacogenetic variants.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1175:153-187. · 1.29 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The identification and characterization of the genes encoding G protein-coupled receptors (GPCRs) and the proteins necessary for the processes of ligand binding, GPCR activation, inactivation, and receptor trafficking to the membrane are discussed in the context of human genetic disease. In addition to functional GPCR variants, the identification of genetic disruptions affecting proteins necessary to GPCR functions have provided insights into the function of these pathways. Gsα and Gβ subunit polymorphisms have been found to result in complex phenotypes. Disruptions in accessory proteins that normally modify or organize heterotrimeric G-protein coupling may also result in disease states. These include the contribution of variants of the regulator of G protein signaling (RGS) protein to hypertension; the role variants of the activator of G protein signaling (AGS) proteins to phenotypes (such as the type III AGS8 variant to hypoxia); the contribution of G protein-coupled receptor kinase (GRK) proteins, such as GRK4, in disorders such as hypertension. The role of accessory proteins in GPCR structure and function is discussed in the context of genetic disorders associated with disruption of the genes that encode them. An understanding of the pharmacogenomics of GPCR and accessory protein signaling provides the basis for examining both GPCR pharmacogenetics and the genetics of monogenic disorders that result from disruption of given receptor systems.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1175:121-152. · 1.29 Impact Factor
  • Geoffrey N Hendy, David E C Cole
    The Journal of Clinical Endocrinology and Metabolism 12/2013; 98(12):4666-9. · 6.31 Impact Factor
  • Source
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D insufficiency, as measured by 25-hydroxyvitamin D (25[OH]D) levels, has been associated with important health outcomes. The majority of vitamin D in circulation is bound to vitamin D-binding protein (DBP) and albumin, and recent genetic studies have demonstrated that serum DBP is a major determinant of 25(OH)D concentrations in adults. The impact of circulating DBP levels on vitamin D's biologic action, is unclear, but is of particular relevance to vitamin D epidemiology, since a lack of control for DBP levels could strongly influence the association of vitamin D with disease. Serum parathyroid hormone (PTH) levels can act as a biological readout of 25(OH)D activity. We therefore assessed the relationship between serum total and free 25(OH)D and PTH with and without adjusting for DBP, in 2,073 subjects of European descent. Total 25(OH)D levels correlated positively (r = 0.19, P = 1.8 × 10(-17) ) with DBP, whereas the free 25(OH)D correlated negatively (r = - 0.14, P = 5.0 × 10(-12) ). Total and free 25(OH)D levels correlated negatively with PTH (r = - 0.29, P= 1.3 × 10(-39) ; r = - 0.26, P= 1.9 × 10(-33) , respectively). Including age, BMI, sex, estimated glomerular filtration rate, calcium and season of blood draw as covariates, total 25(OH)D levels were significantly associated with lnPTH levels (linear term: β= -0.010, P <0.0001, squared term: β= 0.00004, P <0.0001) and this association was not changed by adjusting for DBP. These findings provide evidence that in a largely vitamin D-sufficient cohort, the biological effect of vitamin D on PTH levels is mainly independent of DBP concentration. Accordingly, this study may provide useful information for studies investigating the relationship between vitamin D, DBP and disease.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2013; · 6.04 Impact Factor
  • Geoffrey N Hendy, Lucie Canaff, David E C Cole
    [Show abstract] [Hide abstract]
    ABSTRACT: The calcium-sensing receptor (CaSR) is a G protein-coupled receptor encoded by a single copy gene. The human CASR gene spans ∼103-kb and has eight exons. Promoters P1 and P2 drive transcription of exons 1A and 1B, respectively, encoding alternative 5'-UTRs that splice to exon 2 encoding the common part of the 5'-UTR. Exons 2-7 encode the CaSR protein of 1078 amino acids. Functional elements responsive to 1,25-dihydroxyvitamin D, proinflammatory cytokines, and glial cells missing-2 are present in the CASR promoters. Evolutionarily, the exon structure, first seen in aquatic vertebrates, is well-conserved with a single linkage disequilibrium haplotype block for protein coding exons 2-7. Structural features of the human CaSR protein are: an N-terminal signal peptide (19 amino acids (aa)); an extracellular domain (∼600 aa) having a bi-lobed Venus Flytrap (VFT) domain with several Ca(2+)-binding sites; and a nine-cysteines domain that transduces the activation signal to the 7-transmembrane domain (250 aa) and the C-terminal tail (216 aa).
    Best practice & research. Clinical endocrinology & metabolism. 06/2013; 27(3):285-301.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The vitamin D binding protein (DBP) is the major plasma carrier for vitamin D and its metabolites, but it is also an actin scavenger, and is the precursor to the immunomodulatory protein, Gc-MAF. Two missense variants of the DBP gene - rs7041 encoding Asp432Glu and rs4588 encoding Thr436Lys - change the amino acid sequence and alter the protein function. They are common enough to generate population-wide constitutive differences in vitamin D status, based on assay of the serum metabolite, 25-hydroxyvitamin D (25OHD). Whether these variants also influence the role of vitamin D in an immunologic milieu is not known. However, the issue is relevant, given the immunomodulatory effects of DBP and the role of protracted innate immune-related inflammation in response to tissue injury or repeated infection. Indeed, DBP and vitamin D may jointly or independently contribute to a variety of adverse health outcomes unrelated to classical notions of their function in bone and mineral metabolism. This review summarizes the reports to date of associations between DBP variants, and various chronic and infectious diseases. The available information leads us to conclude that DBP variants are a significant and common genetic factor in some common disorders, and therefore, are worthy of closer attention. In view of the heightened interest in vitamin D as a public health target, well-designed studies that look simultaneously at vitamin D and its carrier in relation to genotypes and adverse health outcome should be encouraged.
    Critical Reviews in Clinical Laboratory Sciences 02/2013; · 3.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Genotypic counts of paired relatives discordant for a complex late-onset disease are often used to test for genetic association. The power of the various statistical test options, when data on covariates are unavailable, has been the focus of recent research. Comparison of the Cochran-Armitage, Bhapkar, and McNemar tests indicates that none is superior to the others in all cases. Using an alternative approach, we found that the theoretical genotypic frequencies of the discordant pairs depend only on the penetrance odds ratios, after conditioning. These odds ratios can be estimated by maximizing a product binomial likelihood and provide insight into the mode of inheritance. We identified cases where exact maximum likelihood (ML) estimates can be explicitly obtained. This approach led us to two tests for association which depend on likelihood ratio (LR) or score statistics. We quantified the power of these tests analytically and examined their performance through simulation. We explored the utility of these tests with an example from the literature-the association between complement factor H (CFH) polymorphisms and age-related macular degeneration. The LR and Score tests serve as simple and effective ways of interpreting paired case-control data sets.
    Annals of Human Genetics 01/2013; · 2.22 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Hyperparathyroidism Jaw-Tumour Syndrome (HPT-JT) is characterized by primary hyperparathyroidism (PHPT), maxillary/mandible ossifying fibromas and by parathyroid carcinoma in 15% of cases. Inactivating mutations of the tumour suppressor CDC73/HRPT2 gene have been found in HPT-JT patients and also as genetic determinants of sporadic parathyroid carcinoma/atypical adenomas and, rarely, typical adenomas, in familial PHPT. Here we report the genetic and molecular analysis of the CDC73/HRPT2 gene in three patients affected by PHPT due to atypical and typical parathyroid adenomas, in one case belonging to familial PHPT. Flag-tagged WT and mutant CDC73/HRPT2 proteins were transiently transfected in HEK293 cells and functional assays were performed in order to investigate the effect of the variants on the whole protein expression, nuclear localization and cell overgrowth induction. We identified four CDC73/HRPT2 gene mutations, three germline (c.679_680delAG, p.Val85_Val86del and p.Glu81_Pro84del), one somatic (p.Arg77Pro). In three cases the mutation was located within the Nucleolar Localisation Signals (NoLS). The three NoLS variants led to instability either of the corresponding mutated protein or mRNA or both. When transfected in HEK293 cells, NoLS mutated proteins mislocalized with a predeliction for cytoplasmic or nucleo-cytoplasmic localization and, finally, they resulted in overgrowth, consistent with a dominant negative interfering effect in the presence of the endogenous protein.
    PLoS ONE 01/2013; 8(12):e82292. · 3.53 Impact Factor
  • Geoffrey N Hendy, David E C Cole
    [Show abstract] [Hide abstract]
    ABSTRACT: Primary hyperparathyroidism (PHPT) occurs sporadically, but occasionally it may be a feature of a familial condition, such as multiple endocrine neoplasia type 1 (MEN1), MEN2A, or the HPT-jaw tumor syndrome (HPT-JT), and familial hypocalciuric hypercalcemia/neonatal severe hyperparathyroidism (FHH/NSHPT). PHPT may also occur as familial isolated hyperparathyroidism (FIHP), and has been observed as a consequence of mutations in the CDKN1B gene (MEN4). Tumorigenesis in these conditions may be the result of protooncogene activation (e.g. RET in MEN2) or two-hit losses of a tumor suppressor (e.g. MEN1, HPT-JT). In patients with MEN1, HPT-JT or FHH/NSHPT, the hyperparathyroidism manifests at a younger age and affects both sexes equally. In MEN1, mutations of the MEN1 gene also cause enteropancreatic and anterior pituitary tumors. In MEN2, activating mutations in the RET protooncogene also cause medullary thyroid carcinoma and pheochromocytoma. In HPT-JT, mutations of CDC73/HRPT2 are associated with parathyroid carcinoma, but tumors of the kidneys and uterus are additional features. In some FIHP families, a CASR mutation may be identified. In parathyroid carcinoma, even if sporadic, molecular diagnostics for CDC73/HRPT2 should be considered, as it should be for younger patients. Further exploration of these hereditary syndromes may shed light on the molecular mechanisms giving rise to nonhereditary PHPT.
    Frontiers of hormone research 01/2013; 41:149-65. · 1.24 Impact Factor
  • D.E.C. Cole, G.N. Hendy
    Bone 12/2012; 51(6):S26. · 4.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: To determine if molecular and immunohistochemical (IHC) features of the HRPT2/CDC73 gene and its product, parafibromin, predict the natural history of parathyroid malignancy, particularly atypical adenoma, as seen in a single-centre patient cohort. METHODS: Matched tumor and non-tumor tissues were obtained from 46 patients with parathyroid carcinoma (CA) (n = 15), atypical adenoma (AA) (n = 14) and typical adenoma (TA) (n = 17), as defined by standardized histopathological criteria. Exons and exon-intron boundaries of the CDC73 gene were sequenced to identify germline or somatic mutations. IHC staining for parafibromin was performed and scored as positive if nuclear staining was at least partially IHC-positive. RESULTS: Mutations of CDC73 were observed in 9/15 (60 %) CA, 2/14 (14 %) AA, and 1/17 (6 %) TA tumors. A recurrent two basepair mutation in exon 7 -- c.679_680delAG -- accounted for half of all identified mutations. Absence of parafibromin nuclear staining was noted in 8/12 (67 %) CA, 2/13 (15 %) AA, and 3/17 (18 %) TA tumors. Median follow up times were 88 months for CA, 76 months for AA, and 104 months for TA patients. One patient, a member of a previously reported multiplex family with a germline CDC73 mutation was found to have a second adenoma after removal of an atypical adenoma. CONCLUSIONS: Molecular screening and IHC are both useful tools in the differential diagnosis of parathyroid tumors, but both have limited sensitivity and specificity. CDC73 mutations and negative immunostaining were common in atypical adenomas, but no local recurrence was observed in any case with successful surgical removal after follow-up periods of 27 to 210 months.
    Cellular oncology (Dordrecht). 09/2012;

Publication Stats

5k Citations
1,022.83 Total Impact Points

Institutions

  • 1995–2014
    • University of Toronto
      • • Department of Laboratory Medicine and Pathobiology
      • • Department of Medicine
      • • Mount Sinai Hospital
      • • Laboratory Medicine Program
      Toronto, Ontario, Canada
  • 2013
    • Public Health Agency of Canada
      Ottawa, Ontario, Canada
  • 1992–2013
    • McGill University
      • • Department of Medicine
      • • Hormones and Cancer Research Unit
      • • Department of Human Genetics
      Montréal, Quebec, Canada
  • 2012
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy
  • 2011–2012
    • Yale University
      • Department of Pediatrics
      New Haven, Connecticut, United States
  • 2000–2012
    • SickKids
      • Division of Clinical and Metabolic Genetics
      Toronto, Ontario, Canada
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 1999–2012
    • Sunnybrook Health Sciences Centre
      • • Division of Medical Oncology and Hematology
      • • Department of Medicine
      • • Division of Rheumatology
      Toronto, Ontario, Canada
  • 2004–2011
    • IRCCS Ospedale Casa Sollievo della Sofferenza
      • Department of Endocrinology
      Giovanni Rotondo, Apulia, Italy
  • 2009
    • McMaster University
      • Department of Pathology and Molecular Medicine
      Hamilton, Ontario, Canada
    • University of Milan
      • Department of Medical Sciences
      Milano, Lombardy, Italy
  • 2006–2009
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
    • Texas Tech University Health Sciences Center
      • School of Pharmacy
      Lubbock, TX, United States
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 2004–2009
    • Dalhousie University
      • Department of Mathematics and Statistics
      Halifax, Nova Scotia, Canada
  • 1998–2009
    • Women's College Hospital
      Toronto, Ontario, Canada
  • 2003–2008
    • Université de Moncton
      Moncton, New Brunswick, Canada
  • 1999–2005
    • UHN: Toronto General Hospital
      Toronto, Ontario, Canada
  • 2002
    • University Health Network
      Toronto, Ontario, Canada
  • 2001
    • Mount Sinai Hospital, Toronto
      Toronto, Ontario, Canada
  • 1997
    • Brigham and Women's Hospital
      • Department of Medicine
      Boston, MA, United States
  • 1995–1996
    • Toronto Western Hospital
      Toronto, Ontario, Canada