Publications by authors named "Amanda Field"

26 Publications

  • Page 1 of 1

Expression of p53 is significantly associated with recurrence-free survival and overall survival in pleuropulmonary blastoma (PPB): a report from the International Pleuropulmonary Blastoma/DICER1 Registry.

Mod Pathol 2021 Jun 26;34(6):1104-1115. Epub 2021 Feb 26.

The Lauren V. Ackerman Laboratory of Surgical Pathology, Barnes-Jewish and St. Louis Children's Hospitals, Washington University Medical Center, St. Louis, MO, USA.

Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1-25%, 26-75%, and 76-100%. All type I PPBs showed 0-25% p53 expression compared to the higher p53 expression (>25%) in type III PPB (p < 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in >25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p < 0.0001). P53 expression was significantly associated with recurrence-free survival (p < 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.
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http://dx.doi.org/10.1038/s41379-021-00735-8DOI Listing
June 2021

A Genome-First Approach to Characterize DICER1 Pathogenic Variant Prevalence, Penetrance, and Phenotype.

JAMA Netw Open 2021 02 1;4(2):e210112. Epub 2021 Feb 1.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Importance: Genetic disorders are historically defined through phenotype-first approaches. However, risk estimates derived from phenotype-linked ascertainment may overestimate severity and penetrance. Pathogenic variants in DICER1 are associated with increased risks of rare and common neoplasms and thyroid disease in adults and children. This study explored how effectively a genome-first approach could characterize the clinical traits associated with germline DICER1 putative loss-of-function (pLOF) variants in an unselected clinical cohort.

Objective: To examine the prevalence, penetrance, and phenotypic characteristics of carriers of germline DICER1 pLOF variants via genome-first ascertainment.

Design, Setting, And Participants: This cohort study classifies DICER1 variants in germline exome sequence data from 92 296 participants of the Geisinger MyCode Community Health Initiative. Data for each MyCode participant were used from the start of the Geisinger electronic health record to February 1, 2018.

Main Outcomes And Measures: Prevalence of germline DICER1 variation; penetrance of malignant tumors and thyroid disease in carriers of germline DICER1 variation; structured, manual review of electronic health records; and DICER1 sequencing of available tumors from an associated cancer registry.

Results: A total of 92 296 adults (mean [SD] age, 59 [18] years; 98% white; 60% female) participated in the study. Germline DICER1 pLOF variants were observed in 1 in 3700 to 1 in 4600 participants, more than double the expected prevalence. Malignant tumors (primarily thyroid carcinoma) were observed in 4 of 25 participants (16%) with DICER1 pLOF variants, which is comparable (by 50 years of age) to the frequency of neoplasms in the largest registry- and clinic-based (phenotype-first) DICER1 studies published to date. DICER1 pLOF variants were significantly associated with risks of thyroidectomy (odds ratio [OR], 6.0; 95% CI, 2.2-16.3; P = .007) and thyroid cancer (OR, 9.2; 95% CI, 2.1-34.7; P = .02) compared with controls, but there was not a significant increase in the risk of goiter (OR, 1.8; 95% CI, 0.7-4.9). A female patient in her 80s who was a carrier of a germline DICER1 hotspot variant was apparently healthy on electronic health record review. The term DICER1 did not appear in any of the medical records of the 25 participants with a pLOF DICER1 variant, even in those affected with a known DICER1-associated tumor or thyroid phenotype.

Conclusions And Relevance: This cohort study was able to ascertain individuals with germline DICER1 variants based on a genome-first approach rather than through a previously established DICER1-related phenotype. Use of the genome-first approach may complement more traditional approaches to syndrome delineation and may be an efficient approach for risk estimation.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.0112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907958PMC
February 2021

Childhood Rhabdomyosarcoma of the Female Genital Tract: Association with Pathogenic DICER1 Variation, Clinicopathological Features, and Outcomes.

J Pediatr Adolesc Gynecol 2021 Jan 20. Epub 2021 Jan 20.

ResourcePath, Sterling, Virginia; Department of Pathology, Children's National Health System, Washington, DC; George Washington University School of Medicine and Health Sciences, Washington, DC.

Study Objective: Rhabdomyosarcomas (RMSs) of the female genital tract (FGT) have been recently shown to be associated with germline pathogenic variation in DICER1, which can underlie a tumor predisposition disorder. We sought to determine the incidence of a pathogenic variation in DICER1 in a cohort of RMSs of the FGT, as well as to evaluate the clinicopathological features and outcomes of the patients. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: We retrospectively reviewed medical records of the patients diagnosed with RMS of the FGT between 1990 and 2019. Molecular genetic sequencing of the tumor to detect an RNase IIIb domain hot spot mutation in DICER1 samples was performed in 7 patients. Individuals with a missense mutation in the tumor were also screened for a loss of function germline mutation in DICER1.

Results: Of 210 cases of pediatric RMS, 11 arose from the FGT. Molecular genetic sequencing of the tumor samples revealed a somatic missense mutation in the RNase IIIb domain of DICER1 in a total of 3 patients, 2 patients with embryonal RMS of the cervix/uterus, and 1 patient with ovarian embryonal RMS. As a result of genetic testing for the loss of function germline mutation in DICER1, a heterozygous pathogenic variant was also found in 2 of these patients.

Conclusion: Despite the limited number of patients, our findings suggest that it is important to be aware of the possible association between RMS of FGT and pathogenic germline DICER1 variants because the detection of this mutation in a patient or relatives can provide the opportunity for surveillance of related conditions that might improve long-term outcomes and survival.
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http://dx.doi.org/10.1016/j.jpag.2021.01.011DOI Listing
January 2021

Pleuropulmonary blastoma-like peritoneal sarcoma: a newly described malignancy associated with biallelic DICER1 pathogenic variation.

Mod Pathol 2020 10 15;33(10):1922-1929. Epub 2020 May 15.

International Pleuropulmonary Blastoma/DICER1 Registry, Children's Minnesota, Minneapolis, MN, USA.

Since the original description of pathogenic germline DICER1 variation underlying pleuropulmonary blastoma (PPB), the spectrum of extrapulmonary neoplasms known to be associated with DICER1 has continued to expand and now includes tumors of the ovary, thyroid, kidney, eye, and brain among other sites. This report documents our experience with another manifestation: a primitive sarcoma that resembles PPB and DICER1-associated sarcoma of the kidney. These tumors are distinguished by their unusual location in the peritoneal cavity, associated with visceral and/or parietal mesothelium. A total of seven cases were identified through pathology review in children presenting at a median age of 13 years (range 3-14 years). Primary sites of origin included the fallopian tube (four cases), serosal surface of the colon (one case), and pelvic sidewall (two cases). One case had pathologic features of type I PPB, another type Ir (regressed) PPB, and the remaining five had features of type II or III PPB with a mixed primitive sarcomatous pattern with or without cystic elements. All had a pathogenic DICER1 variation identified in germline and/or tumor DNA. PPB-like peritoneal tumors represent a newly described manifestation of DICER1 pathogenic variation whose pathologic features are also recapitulated in DICER1-related renal sarcoma, cervical embryonal rhabdomyosarcoma, and some Sertoli-Leydig cell tumors with heterologous elements. Tumors arising from the fallopian tube or elsewhere in the abdomen/pelvis, especially those with heterogeneous rhabdomyosarcomatous and/or cartilaginous differentiation, should prompt consideration of germline and tumor DICER1 testing.
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http://dx.doi.org/10.1038/s41379-020-0558-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529703PMC
October 2020

Structural renal abnormalities in the DICER1 syndrome: a family-based cohort study.

Pediatr Nephrol 2018 Dec 3;33(12):2281-2288. Epub 2018 Sep 3.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, 20850, USA.

Background: The DICER1 syndrome is a tumor-predisposition disorder caused by germline pathogenic variation in DICER1 and is associated with cystic nephroma and other renal neoplasms. Dicer1 mouse and rare human DICER1 syndrome case reports describe structural kidney and collecting system anomalies. We investigated renal function and the frequency of structural abnormalities of the kidney and collecting system in individuals with germline loss-of-function variants in DICER1.

Methods: In this family-based cohort study, prospectively ascertained germline DICER1-mutation carriers (DICER1-carriers) and unaffected family controls were evaluated at the National Institutes of Health Clinical Center with renal ultrasound and comprehensive laboratory testing. Two radiologists reviewed the imaging studies from all participants for structural abnormalities, cysts, and tumors.

Results: Eighty-nine DICER1-carriers and 61 family controls were studied. Renal cysts were detected in 1/33 DICER1-carrier children without history of cystic nephroma. Similar proportions of adult DICER1-carriers (8/48; 17%) and controls (11/50; 22%) had ultrasound-detected renal cysts (P = 0.504). 8/89 (9%) DICER1-carriers harbored ultrasound-detected structural abnormalities of varying severity within the collecting system or kidney, nephrolithiasis, or nephrocalcinosis. None of the family controls (0/61) had similar findings on ultrasound (P = 0.02). No meaningful differences in renal laboratory values between DICER1-carriers and unaffected family controls were observed.

Conclusions: Our report is the first to systematically characterize renal function and anatomy in a large prospective cohort of DICER1-carriers and DICER1-negative family controls. DICER1-carriers may be at increased risk of structural anomalies of the kidney or collecting system. The role for DICER1 in renal morphogenesis merits additional investigation.
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http://dx.doi.org/10.1007/s00467-018-4040-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203641PMC
December 2018

FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity.

J Am Soc Nephrol 2018 01 31;29(1):118-137. Epub 2017 Oct 31.

Departments of Medicine and

Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity. We also examined the individual effects of the selective FXR agonist obeticholic acid (OCA) and the TGR5 agonist INT-777 in diabetic mice. The FXR agonist OCA and the TGR5 agonist INT-777 modulated distinct renal signaling pathways involved in the pathogenesis and treatment of diabetic nephropathy. Treatment of diabetic DBA/2J and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. INT-767 exerted coordinated effects on multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1, sirtuin 3, estrogen-related receptor-, and Nrf-1; inhibition of endoplasmic reticulum stress; and inhibition of enhanced renal fatty acid and cholesterol metabolism. Additionally, in mice with diet-induced obesity, INT-767 prevented mitochondrial dysfunction and oxidative stress determined by fluorescence lifetime imaging of NADH and kidney fibrosis determined by second harmonic imaging microscopy. These results identify the renal signaling pathways regulated by FXR and TGR5, which may be promising targets for the treatment of nephropathy in diabetes and obesity.
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http://dx.doi.org/10.1681/ASN.2017020222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748904PMC
January 2018

DICER1-related Sertoli-Leydig cell tumor and gynandroblastoma: Clinical and genetic findings from the International Ovarian and Testicular Stromal Tumor Registry.

Gynecol Oncol 2017 12 14;147(3):521-527. Epub 2017 Oct 14.

International Ovarian and Testicular Stromal Tumor Registry, Children's Minnesota, Minneapolis, MN, United States; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States.

Background: Ovarian sex cord-stromal tumors (OSCST) include juvenile granulosa cell tumors (JGCT), Sertoli-Leydig cell tumor (SLCT) and gynandroblastoma (GAB) among others. These ovarian sex cord-stromal tumors as well as other tumors including pleuropulmonary blastoma (PPB) may be associated with DICER1 mutations. We sought to describe the clinical and genetic findings from the first 107 individuals enrolled in the International Ovarian and Testicular Stromal Tumor Registry.

Methods: Medical and family history were obtained for individuals consecutively enrolled in the International Ovarian and Testicular Stromal Tumor Registry. Pathology was centrally reviewed. DICER1 sequencing was performed on blood and tumor tissue.

Results: Of the 107 participants, 49 had SLCT, 25 had JGCT and 5 had GAB. Nearly all (36/37) SLCTs and 4/4 GAB tested had a DICER1 mutation in an RNase IIIb domain hotspot; approximately half of these individuals had a predisposing germline DICER1 mutation. Metachronous SLCTs were seen in 3 individuals with germline DICER1 mutations. Other DICER1-associated conditions were seen in 19% of patients with SLCT or GAB. Three children of women with SLCT were diagnosed with PPB based on genetic testing and clinical screening during the course of this study. All were diagnosed with PPB in its earliest and most curable form (Type I), were treated with surgery alone, and are alive without evidence of disease.

Conclusions: Recognition of the distinct genetic basis for a group of these tumors improves precise classification in difficult cases and promotes mutation-based screening and early detection.
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http://dx.doi.org/10.1016/j.ygyno.2017.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5716477PMC
December 2017

The prevalence of DICER1 pathogenic variation in population databases.

Int J Cancer 2017 11 21;141(10):2030-2036. Epub 2017 Aug 21.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.

The DICER1 syndrome is associated with a variety of rare benign and malignant tumors, including pleuropulmonary blastoma (PPB), cystic nephroma (CN) and Sertoli-Leydig cell tumor (SLCT). The prevalence and penetrance of pathogenic DICER1 variation in the general population is unknown. We examined three publicly-available germline whole exome sequence datasets: Exome Aggregation Consortium (ExAC), 1,000 Genomes (1,000 G) and the Exome Sequencing Project (ESP). To avoid over-estimation of pathogenic DICER1 variation from cancer-associated exomes, we excluded The Cancer Genome Atlas (TCGA) variants from ExAC. All datasets were annotated with snpEff and ANNOVAR and variants were classified into four categories: likely benign (LB), unknown significance (VUS), likely pathogenic (LP), or pathogenic (P). The prevalence of DICER1 P/LP variants was 1:870 to 1:2,529 in ExAC-nonTCGA (53,105 exomes) estimated by metaSVM and REVEL/CADD, respectively. A more stringent prevalence calculation considering only loss-of-function and previously-published pathogenic variants detected in ExAC-nonTCGA, yielded a prevalence of 1:10,600. Despite the rarity of most DICER1 syndrome tumors, pathogenic DICER1 variation is more common than expected. If confirmed, these findings may inform future sequencing-based newborn screening programs for PPB, CN and SLCT, in which early detection improves prognosis.
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http://dx.doi.org/10.1002/ijc.30907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749397PMC
November 2017

Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study.

J Clin Endocrinol Metab 2017 05;102(5):1614-1622

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland 20850.

Context: The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown.

Objective: To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome.

Design: Family-based cohort study.

Setting: National Institutes of Health (NIH) Clinical Center (CC).

Participants: The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families.

Interventions: Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC.

Main Outcome Measures: The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing.

Results: By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations.

Conclusions: We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.
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http://dx.doi.org/10.1210/jc.2016-2954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443331PMC
May 2017

Activation of Ftz-F1-Responsive Genes through Ftz/Ftz-F1 Dependent Enhancers.

PLoS One 2016 10;11(10):e0163128. Epub 2016 Oct 10.

Department of Entomology and Program in Molecular & Cell Biology, University of Maryland, College Park, Maryland, 20742, United States of America.

The orphan nuclear receptor Ftz-F1 is expressed in all somatic nuclei in Drosophila embryos, but mutations result in a pair-rule phenotype. This was explained by the interaction of Ftz-F1 with the homeodomain protein Ftz that is expressed in stripes in the primordia of segments missing in either ftz-f1 or ftz mutants. Ftz-F1 and Ftz were shown to physically interact and coordinately activate the expression of ftz itself and engrailed by synergistic binding to composite Ftz-F1/Ftz binding sites. However, attempts to identify additional target genes on the basis of Ftz-F1/ Ftz binding alone has met with only limited success. To discern rules for Ftz-F1 target site selection in vivo and to identify additional target genes, a microarray analysis was performed comparing wildtype and ftz-f1 mutant embryos. Ftz-F1-responsive genes most highly regulated included engrailed and nine additional genes expressed in patterns dependent on both ftz and ftz-f1. Candidate enhancers for these genes were identified by combining BDTNP Ftz ChIP-chip data with a computational search for Ftz-F1 binding sites. Of eight enhancer reporter genes tested in transgenic embryos, six generated expression patterns similar to the corresponding endogenous gene and expression was lost in ftz mutants. These studies identified a new set of Ftz-F1 targets, all of which are co-regulated by Ftz. Comparative analysis of enhancers containing Ftz/Ftz-F1 binding sites that were or were not bona fide targets in vivo suggested that GAF negatively regulates enhancers that contain Ftz/Ftz-F1 binding sites but are not actually utilized. These targets include other regulatory factors as well as genes involved directly in morphogenesis, providing insight into how pair-rule genes establish the body pattern.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0163128PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056698PMC
April 2017

DICER1 Mutations and Differentiated Thyroid Carcinoma: Evidence of a Direct Association.

J Clin Endocrinol Metab 2016 Jan 10;101(1):1-5. Epub 2015 Nov 10.

Division of Endocrinology (M.M.R.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229; PRIMA Pediatrics (P.J.), Cumberland, Rhode Island 02864; Division of Cancer and Blood Disorders (K.A.P.S., A.K.H.), Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404; International Ovarian and Testicular Stromal Tumor Registry (K.A.P.S., A.K.H., D.A.H.), Minneapolis, Minnesota 55404; Waukesha County Medical Examiner's Office (A.S.), Waukesha, Wisconsin 53188; Division of Endocrinology and Diabetes (A.J.B.), Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104; Department of Pathology (A.L.F., D.A.H.), Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington, DC 20010; and Division of Oncology (J.G.), Cincinnati Children's Hospital Medical Center and University of Cincinnati, Cincinnati, Ohio 45229.

Context: DICER1 germline mutation carriers have an increased predisposition to cancer, such as pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT), and a high prevalence of multinodular goiter (MNG). Although differentiated thyroid carcinoma (DTC) has been reported in some DICER1 mutation carriers with PPB treated with chemotherapy, the association of DTC with DICER1 mutations is not well established.

Case Description: We report a family with DICER1 mutation and familial DTC without a history of chemotherapy. A 12-year-old female (patient A) and her 14-year-old sister (patient B) presented with MNG. Family history was notable for a maternal history of DTC and bilateral ovarian SLCT. Both sisters underwent total thyroidectomy. Pathological examination showed nodular hyperplasia and focal papillary thyroid carcinoma within hyperplastic nodules. Subsequently, patient A developed virilization secondary to a unilateral ovarian SLCT. During her evaluation, an incidental cystic nephroma was also found. Three other siblings had MNG on surveillance ultrasound examination; two had thyroidectomies, and one had two microscopic foci of papillary carcinoma. Patient A, her mother, and four affected siblings had a germline heterozygous pathogenic DICER1 mutation c.5441C>T in exon 25, resulting in an amino acid change from p.Ser1814Leu of DICER1. Somatic DICER1 RNase IIIb missense mutations were identified in thyroid nodules from three of the four siblings.

Conclusions: This family provides novel insight into an emerging phenotype for DICER1 syndrome, with evidence that germline DICER1 mutations are associated with an increased risk of developing familial DTC, even in the absence of prior treatment with chemotherapy.
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http://dx.doi.org/10.1210/jc.2015-2169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4701837PMC
January 2016

Temporal order of RNase IIIb and loss-of-function mutations during development determines phenotype in pleuropulmonary blastoma / syndrome: a unique variant of the two-hit tumor suppression model.

F1000Res 2015 10;4:214. Epub 2015 Jul 10.

Division of Pathology, Children's Research Institute, Children's National Medical Center and the George Washington University School of Medicine & Health Sciences, Washington, DC, 20010, USA.

Pleuropulmonary blastoma (PPB) is the most frequent pediatric lung tumor and often the first indication of a pleiotropic cancer predisposition,   syndrome, comprising a range of other individually rare, benign and malignant tumors of childhood and early adulthood. The genetics of  -associated tumorigenesis are unusual in that tumors typically bear neomorphic missense mutations at one of five specific "hotspot" codons within the RNase IIIb domain of  , combined with complete loss of function (LOF) in the other allele. We analyzed a cohort of 124 PPB children for predisposing   mutations and sought correlations with clinical phenotypes. Over 70% have inherited or   germline LOF mutations, most of which truncate the   open reading frame. We identified a minority of patients who have no germline mutation, but are instead mosaic for predisposing   mutations. Mosaicism for RNase IIIb domain hotspot mutations defines a special category of   syndrome patients, clinically distinguished from those with germline or mosaic LOF mutations by earlier onsets and numerous discrete foci of neoplastic disease involving multiple syndromic organ sites. A final category of PBB patients lack predisposing germline or mosaic mutations and have sporadic (rather than syndromic) disease limited to a single PPB tumor bearing tumor-specific RNase IIIb and LOF mutations. We propose that acquisition of a neomorphic RNase IIIb domain mutation is the rate limiting event in  -associated tumorigenesis, and that distinct clinical phenotypes associated with mutational categories reflect the temporal order in which LOF and RNase IIIb domain mutations are acquired during development.
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http://dx.doi.org/10.12688/f1000research.6746.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712775PMC
July 2015

-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions.

Pathol Case Rev 2014 Mar;19(2):90-100

International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN ; International Ovarian and Testicular Stromal Tumor Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN ; Division of Pathology, Children's National Medical Center and Center for Genetic Medicine Research, Children's Research Institute, Washington DC ; Department of Integrative Systems Biology, George Washington University School of Medicine & Health Sciences, Washington DC.

Germline mutations in are associated with increased risk for a wide variety of neoplastic conditions, including pleuropulmonary blastoma (PPB), cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, botryoid embryonal rhabdomyosarcoma of the uterine cervix, ciliary body medulloepithelioma, pineoblastoma, pituitary blastoma and nodular thyroid hyperplasia or thyroid carcinoma. These tumors may be seen in isolation or in constellation with other characteristic tumor types in individuals or family members. Here we describe the medical history of a child with a heterozygous, loss of function germline mutation and multiple tumors associated with the syndrome.. Although germline mutations in are rare, tumors of these types will be seen by practicing pathologists and should prompt consideration of an underlying mutation.
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http://dx.doi.org/10.1097/PCR.0000000000000027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4209484PMC
March 2014

Nasal chondromesenchymal hamartomas arise secondary to germline and somatic mutations of DICER1 in the pleuropulmonary blastoma tumor predisposition disorder.

Hum Genet 2014 Nov 14;133(11):1443-50. Epub 2014 Aug 14.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA,

Nasal chondromesenchymal hamartoma (NCMH) is a rare nasal tumor that typically presents in young children. We previously reported on NCMH occurrence in children with pleuropulmonary blastoma (PPB), a rare pulmonary dysembryonic sarcoma that is the hallmark neoplasm in the PPB-associated DICER1 tumor predisposition disorder. Original pathologic materials from individuals with a PPB, PPB-associated tumor and/or a DICER1 mutation were centrally reviewed by the International PPB Registry. Paraffin-embedded NCMH tumor tissue was available in three cases. Laser-capture microdissection was used to isolate mesenchymal spindle cells and cartilage in one case for Sanger sequencing of DICER1. Nine patients (5F/4M) had PPB and NCMH. NCMH was diagnosed at a median age of 10 years (range 6-21 years). NCMH developed 4.5-13 years after PPB. Presenting NCMH symptoms included chronic sinusitis and nasal congestion. Five patients had bilateral tumors. Local NCMH recurrences required several surgical resections in two patients, but all nine patients were alive at 0-16 years of follow-up. Pathogenic germline DICER1 mutations were found in 6/8 NCMH patients tested. In 2 of the patients with germline DICER1 mutations, somatic DICER1 missense mutations were also identified in their NCMH (E1813D; n = 2). Three additional PPB patients developed other nasal lesions seen in the general population (a Schneiderian papilloma, chronic sinusitis with cysts, and allergic nasal polyps with eosinophils). Two of these patients had germline DICER1 mutations. Pathogenic germline and somatic mutations of DICER1 in NCMH establishes that the genetic etiology of NCMH is similar to PPB, despite the disparate biological potential of these neoplasms.
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http://dx.doi.org/10.1007/s00439-014-1474-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185226PMC
November 2014

DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.

Mod Pathol 2014 Sep 31;27(9):1267-80. Epub 2014 Jan 31.

1] Division of Pathology, and Children's National Medical Center, George Washington University School of Medicine & Health Sciences, Washington, DC, USA [2] Center for Genetic Medicine Research, Children's Research Institute, Minneapolis, MN, USA [3] International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN, USA [4] Integrative Systems Biology, George Washington University School of Medicine & Health Sciences, Washington, DC, USA.

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.
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http://dx.doi.org/10.1038/modpathol.2013.242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117822PMC
September 2014

Intrinsically thermochromic fluorans.

Chem Commun (Camb) 2012 Jan 24;48(5):750-2. Epub 2011 Nov 24.

St Mary Cray Research, Sun Chemical Ltd, St Mary Cray, Orpington, Kent BR5 3PP, UK.

A Suzuki coupling strategy has been employed to access a series of novel fluorans substituted with a phenolic moiety. These fluorans display good thermochromism in methyl stearate and obviate the need for traditional complex formulations containing acidic colour developers.
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http://dx.doi.org/10.1039/c1cc15854fDOI Listing
January 2012

Understanding gene-environment interactions.

Genet Test Mol Biomarkers 2011 Jun;15(6):371-2

Genetic Alliance, 4301 Connecticut Avenue NW, Washington, DC 20008, USA.

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http://dx.doi.org/10.1089/gtmb.2011.1520DOI Listing
June 2011

Recommendations of the European society of human genetics on genetic testing for common disorders.

Genet Test Mol Biomarkers 2011 May;15(5):291-2

Genetic Alliance, 4301 Connecticut Avenue NW, Washington, DC 20008, USA.

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http://dx.doi.org/10.1089/gtmb.2011.1519DOI Listing
May 2011

From bench to practice to population health impact: barriers to realizing the public health and clinical promise of basic scientific discovery.

Genet Test Mol Biomarkers 2011 Apr;15(4):191-2

Genetic Alliance, Washington, District of Columbia 20008, USA.

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http://dx.doi.org/10.1089/gtmb.2011.1518DOI Listing
April 2011

"Insufficient evidence" isn't sufficient anymore.

Genet Test Mol Biomarkers 2011 Mar;15(3):115-6

Genetic Alliance, Washington, District of Columbia 20008, USA.

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http://dx.doi.org/10.1089/gtmb.2011.1517DOI Listing
March 2011

Answering the hard questions: the Genetic Testing Registry and its request for information.

Genet Test Mol Biomarkers 2011 Jan-Feb;15(1-2):1-2

Genetic Alliance, Washington, District of Columbia 20008, USA.

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http://dx.doi.org/10.1089/gtmb.2010.1516DOI Listing
July 2011

Direct-to-consumer marketing of genetic tests: access does not reflect clinical utility.

Genet Test Mol Biomarkers 2010 Dec;14(6):731-2

Genetic Alliance , Washington, District of Columbia 20008, USA.

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http://dx.doi.org/10.1089/gtmb.2010.1514DOI Listing
December 2010

The big brown eyes of Samuel Pepys.

Arch Ophthalmol 2002 Jul;120(7):969-75

Royal Victoria Hospital, Belfast, Northern Ireland.

Samuel Pepys (1633-1703) is known for writing the finest diary in the English language. He was a man of remarkable accomplishments who transformed the English Navy, was president of the Royal Society, and was a member of the British Parliament. He survived the Great Plague and imprisonment in the Tower of London. During the years when he was writing the diary, Pepys began to experience great pain in his eyes when reading and writing and from photophobia, which caused him to give up writing the diary. Pepys also had an ultimately unjustifiable fear of blindness.
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http://dx.doi.org/10.1001/archopht.120.7.969DOI Listing
July 2002