Publications by authors named "Douglas R Stewart"

77 Publications

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

JAMA Netw Open 2021 Feb 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
February 2021

Hematologic indices in individuals with pathogenic germline DICER1 variants.

Blood Adv 2021 Jan;5(1):216-223

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

Pathogenic germline variants in DICER1 underlie an autosomal dominant, pleiotropic tumor-predisposition disorder. Murine models with the loss of DICER1 in hematopoietic stem cell progenitors demonstrate hematologic aberrations that include reductions in red and white blood cell counts, hemoglobin volume, and impaired maturation resulting in dysplasia. We investigated whether hematologic abnormalities such as those observed in DICER1-deficient mice were observed in humans with a pathogenic germline variant in DICER1. A natural history study of individuals with germline pathogenic DICER1 variants and family controls conducted through the National Cancer Institute (NCI) evaluated enrollees at the National Institutes of Health Clinical Center during a comprehensive clinical outpatient visit that included collecting routine clinical laboratory studies. These were compared against normative laboratory values and compared between the DICER1 carriers and controls. There were no statistical differences in routine clinical hematology laboratory studies observed in DICER1 carriers and family controls. A review of the medical history of DICER1 carriers showed that none of the individuals in the NCI cohort developed myelodysplastic syndrome or leukemia. Query of the International Pleuropulmonary Blastoma/DICER1 Registry revealed 1 DICER1 carrier who developed a secondary leukemia after treatment of pleuropulmonary blastoma. We found limited evidence that the hematologic abnormalities observed in murine DICER1 models developed in our cohort of DICER1 carriers. In addition, no cases of myelodysplastic syndrome were observed in either the NCI cohort or the International Pleuropulmonary Blastoma/DICER1 Registry; 1 case of presumed secondary leukemia was reported. Abnormalities in hematologic indices should not be solely attributed to DICER1. This trial was registered at www.clinicaltrials.gov as #NCT01247597.
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http://dx.doi.org/10.1182/bloodadvances.2020002651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805337PMC
January 2021

Germline Cancer-Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report from the Children's Oncology Group.

J Natl Cancer Inst 2020 Dec 29. Epub 2020 Dec 29.

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, TX.

Background: Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy.

Methods: We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented through the Children's Oncology Group. We compared the prevalence of cancer-predisposition variants in 63 autosomal dominant cancer-predisposition genes in these patients with population controls (n = 9,963). All statistical tests were two-sided.

Results: We identified germline cancer-predisposition variants in 45 RMS patients (7.3%; all FOXO1 fusion-negative) across 15 autosomal dominant genes, which was statistically significantly enriched compared with controls (1.4%; p = 1.3 × 10-22). Specifically, 73.3% of the predisposition variants were found in predisposition syndrome genes previously associated with pediatric RMS risk, such as Li-Fraumeni syndrome (TP53) and neurofibromatosis type I (NF1). Notably, five patients had well-described oncogenic missense variants in HRAS (p.G12V and p. G12S) associated with Costello syndrome. Also, genetic etiology differed with histology, as germline variants were more frequent in embryonal versus alveolar RMS patients (10.0% vs. 3.0%, p = .02). While patients with a cancer-predisposition variant tended to be younger at diagnosis (p = 9.9 × 10-4), 40.0% of germline variants were identified in those >3 years of age, which is in contrast to current genetic testing recommendations based on early age at diagnosis.

Conclusions: These findings demonstrate that genetic risk of RMS results from germline predisposition variants associated with a wide spectrum of cancer-susceptibility syndromes. Germline genetic testing for children with RMS should be informed by RMS subtypes and not be limited to only young patients.
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http://dx.doi.org/10.1093/jnci/djaa204DOI Listing
December 2020

Lack of pathogenic germline DICER1 variants in males with testicular germ-cell tumors.

Cancer Genet 2020 10 24;248-249:49-56. Epub 2020 Oct 24.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA. Electronic address:

Background: Several studies have reported conflicting evidence on the inclusion of testicular germ cell tumors (TGCT) in the DICER1 tumor-predisposition phenotype. We evaluated the relationship between DICER1 and TGCT by reviewing scrotal ultrasounds of males with pathogenic germline variants in DICER1 and queried exome data from TGCT-affected men for DICER1 variants.

Methodology: Fifty-four male DICER1-carriers and family controls (n=41) enrolled in the National Cancer Institute (NCI) DICER1 Natural History Study were offered scrotal ultrasounds. These studies were examined by a single radiologist for abnormalities. In parallel, DICER1 variants from two large exome-sequenced TGCT cohorts were extracted. We used previously published AMG-AMP criteria to characterize rare DICER1 variants.

Results: There was no observed difference in frequency of testicular cystic structures in DICER1-carriers versus controls. DICER1 variation was not associated with TGCT in the NCI DICER1-carriers. In 1,264 exome-sequenced men with TGCT, none harbored ClinVar- or InterVar-determined pathogenic or likely pathogenic variants in DICER1. Three DICER1 variants of uncertain significance (one case and two controls) were predicted "damaging" based on a priori criteria.

Conclusion: Using two complementary approaches, we found no evidence of an association between pathogenic DICER1 variants and TGCT.
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http://dx.doi.org/10.1016/j.cancergen.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704203PMC
October 2020

A genotype-first approach to exploring Mendelian cardiovascular traits with clear external manifestations.

Genet Med 2021 Jan 29;23(1):94-102. Epub 2020 Sep 29.

Mindich Child Health and Development Institute, Icahn School of Medicine, New York, NY, USA.

Purpose: The purpose of this study is to use a genotype-first approach to explore highly penetrant, autosomal dominant cardiovascular diseases with external features, the RASopathies and Marfan syndrome (MFS), using biobank data.

Methods: This study uses exome sequencing and corresponding phenotypic data from Mount Sinai's BioMe (n = 32,344) and the United Kingdom Biobank (UKBB; n = 49,960). Variant curation identified pathogenic/likely pathogenic (P/LP) variants in RASopathy genes and FBN1.

Results: Twenty-one subjects harbored P/LP RASopathy variants; three (14%) were diagnosed, and another 46% had ≥1 classic Noonan syndrome (NS) feature. Major NS features (short stature [9.5% p = 7e-5] and heart anomalies [19%, p < 1e-5]) were less frequent than expected. Prevalence of hypothyroidism/autoimmune disorders was enriched compared with biobank populations (p = 0.007). For subjects with FBN1 P/LP variants, 14/41 (34%) had a MFS diagnosis or highly suggestive features. Five of 15 participants (33%) with echocardiographic data had aortic dilation, fewer than expected (p = 8e-6). Ectopia lentis affected only 15% (p < 1e-5).

Conclusions: Substantial fractions of individuals harboring P/LP variants with partial or full phenotypic matches to a RASopathy or MFS remain undiagnosed, some not meeting diagnostic criteria. Routine population genotyping would enable multidisciplinary care and avoid life-threatening events.
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http://dx.doi.org/10.1038/s41436-020-00973-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796917PMC
January 2021

Genome-wide association study of café-au-lait macule number in neurofibromatosis type 1.

Mol Genet Genomic Med 2020 10 31;8(10):e1400. Epub 2020 Aug 31.

Genometrics Section, Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA.

Background: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder that arises due to pathogenic variants in tumor suppressor NF1. NF1 has variable expressivity that may be due, at least in part, from heritable elements such as modifier genes; however, few genetic modifiers have been identified to date.

Methods: In this study, we performed a genome-wide association analysis of the number of café-au-lait macules (CALM) that are considered a tumor-like trait as a clinical phenotype modifying NF1.

Results: A borderline genome-wide significant association was identified in the discovery cohort (CALM1, N = 112) between CALM number and rs12190451 (and rs3799603, r  = 1.0; p = 7.4 × 10 ) in the intronic region of RPS6KA2. Although, this association was not replicated in the second cohort (CALM2, N = 59) and a meta-analysis did not show significantly associated variants in this region, a significant corroboration score (0.72) was obtained for the RPS6KA2 signal in the discovery cohort (CALM1) using Complementary Pairs Stability Selection for Genome-Wide Association Studies (ComPaSS-GWAS) analysis, suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error.

Conclusion: rs12190451 is located in a melanocyte-specific enhancer and may influence RPS6KA2 expression in melanocytes-warranting further functional studies.
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http://dx.doi.org/10.1002/mgg3.1400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549607PMC
October 2020

Comparative clinical and genomic analysis of neurofibromatosis type 2-associated cranial and spinal meningiomas.

Sci Rep 2020 07 28;10(1):12563. Epub 2020 Jul 28.

Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

Neurofibromatosis type 2 (NF2) is an autosomal dominant Mendelian tumor predisposition disorder caused by germline pathogenic variants in the tumor suppressor NF2. Meningiomas are the second most common neoplasm in NF2, often occurring in multiple intracranial and spinal locations within the same patient. In this prospective longitudinal study, we assessed volumes and growth rates of ten spinal and ten cranial benign meningiomas in seven NF2 patients that concluded with surgical resection and performed whole-exome sequencing and copy-number variant (CNV) analysis of the tumors. Our comparison of the volume and the growth rate of NF2-associated spinal and cranial meningiomas point to the differences in timing of tumor initiation and/or to the differences in tumor progression (e.g., non-linear, saltatory growth) at these two anatomical locations. Genomic investigation of these tumors revealed that somatic inactivation of NF2 is the principal and perhaps the only driver of tumor initiation; and that tumor progression likely occurs via accumulation of CNVs, rather than point mutations. Results of this study contribute to a better understanding of NF2-associated meningiomas clinical behavior and their genetic underpinnings.
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http://dx.doi.org/10.1038/s41598-020-69074-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387487PMC
July 2020

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

Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG).

Genet Med 2020 Jul 23;22(7):1142-1148. Epub 2020 Apr 23.

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

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http://dx.doi.org/10.1038/s41436-020-0783-8DOI Listing
July 2020

Gynecologic and reproductive health in patients with pathogenic germline variants in DICER1.

Gynecol Oncol 2020 03 15;156(3):647-653. Epub 2020 Jan 15.

Office of the Clinical Director, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892, USA.

Objective: Germline pathogenic variation in DICER1 underlies a tumor-predisposition disorder with increased risk for cervical embryonal rhabdomyosarcoma and ovarian sex-cord stromal tumors, particularly Sertoli-Leydig cell tumors. The gynecologic and reproductive health of these females has not yet been described.

Methods: All female subjects recruited from November 2011 to July 2018 participating in an epidemiologic study of families with pathogenic DICER1 germline variation were included in this cross-sectional analysis. Participant evaluation included obstetric-gynecologic history, physical examination, hormone testing, pelvic ultrasound and record review.

Results: Of 64 females aged 2-72 years, fifteen underwent treatment for pleuropulmonary blastoma as children and three were treated for cervical embryonal rhabdomyosarcoma. Of nine patients reporting a history of ovarian tumors, all presented with virilization or amenorrhea; eight occurred in adolescence. Post-pubertal females with no history of ovarian tumors experienced normal pubertal development, reported regular menstrual cycles, were fertile and underwent natural menopause at median age of 52 years. Thirty-two of 33 women who tried to conceive successfully delivered liveborn children. Of these 32, 10 experienced pregnancy-related thyroid enlargement resulting in thyroidectomy within one year of pregnancy; nine others had undergone pre-pregnancy thyroidectomy.

Conclusion: In these DICER1-carrier females, DICER1-related gynecological tumors occurred during childhood or adolescence in some after which women generally experienced healthy reproductive lives. Individual education and screening for these tumors is warranted. The high rate of DICER1-related multinodular goiter resulting in pre- and post-pregnancy thyroidectomy underscores the importance of thyroid monitoring during pregnancy to ensure maternal and fetal wellbeing.
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http://dx.doi.org/10.1016/j.ygyno.2019.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462333PMC
March 2020

Advancing RAS/RASopathy therapies: An NCI-sponsored intramural and extramural collaboration for the study of RASopathies.

Am J Med Genet A 2020 04 8;182(4):866-876. Epub 2020 Jan 8.

Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.

RASopathies caused by germline pathogenic variants in genes that encode RAS pathway proteins. These disorders include neurofibromatosis type 1 (NF1), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), and Costello syndrome (CS), and others. RASopathies are characterized by heterogenous manifestations, including congenital heart disease, failure to thrive, and increased risk of cancers. Previous work led by the NCI Pediatric Oncology Branch has altered the natural course of one of the key manifestations of the RASopathy NF1. Through the conduct of a longitudinal cohort study and early phase clinical trials, the MEK inhibitor selumetinib was identified as the first active therapy for the NF1-related peripheral nerve sheath tumors called plexiform neurofibromas (PNs). As a result, selumetinib was granted breakthrough therapy designation by the FDA for the treatment of PN. Other RASopathy manifestations may also benefit from RAS targeted therapies. The overall goal of Advancing RAS/RASopathy Therapies (ART), a new NCI initiative, is to develop effective therapies and prevention strategies for the clinical manifestations of the non-NF1 RASopathies and for tumors characterized by somatic RAS mutations. This report reflects discussions from a February 2019 initiation meeting for this project, which had broad international collaboration from basic and clinical researchers and patient advocates.
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http://dx.doi.org/10.1002/ajmg.a.61485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456498PMC
April 2020

Stomaching Multigene Panel Testing: What to Do About CDH1?

J Natl Cancer Inst 2020 04;112(4):325-326

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

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http://dx.doi.org/10.1093/jnci/djz230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156934PMC
April 2020

Dental abnormalities in individuals with pathogenic germline variation in DICER1.

Am J Med Genet A 2019 09 16;179(9):1820-1825. Epub 2019 Jul 16.

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

Pathogenic germline variation in the microRNA processing gene DICER1 gives rise to an autosomal dominant, tumor-predisposition disorder. Conditional deletion of Dicer1 in murine dental epithelium shows that it controls tooth patterning, size, number, and shape. The human dental phenotype of people with germline pathogenic variation in DICER1 is unknown. DICER1-carriers (n = 57) and family controls (n = 55) were evaluated at the NIH Clinical Center dental clinic as part of a comprehensive medical evaluation. Digital panoramic radiographs, bite-wing radiographs, and oral photographs were collected. A single observer, blind to DICER1 status, reviewed the dental records and determined the presence or absence of 11 dental characteristics as described in the clinic notes, radiographs, or oral photographs. Subjective phenotypes were reviewed on radiographs by two examiners (blind to DICER1 status) for the presence or absence of the dental characteristics to reduce inconsistencies. By simple association, bulbous crown, periodontitis, and taurodontism were all significant (p < .05). Logistic regression with chi-square maximum likelihood estimates showed that bulbous crown and periodontitis remained significant. Recognition of these phenotypes may aid identification of individuals and families at risk for DICER1-associated neoplasms. These findings may also guide dental care for individuals with germline DICER1 pathogenic variation.
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http://dx.doi.org/10.1002/ajmg.a.61292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692906PMC
September 2019

Presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation.

Mod Pathol 2019 12 11;32(12):1744-1750. Epub 2019 Jul 11.

Division of Pathology and Center for Cancer and Immunology Research, Children's National Health System, Washington, DC, USA.

We report two malignant sacrococcygeal tumors in infants that were associated with pathogenic DICER1 variation. These tumors were composed of primitive neuroepithelium, embryonal rhabdomyosarcoma, and cartilage and initially diagnosed as immature teratomas. One child developed intracranial metastasis and died. The second child underwent surgery and chemotherapy and achieved complete remission. This child subsequently developed five additional DICER1-associated neoplasms by age nine. Genetic analysis revealed that both tumors harbored biallelic pathogenic DICER1 variation. We believe these cases represent another novel subtype of DICER1-associated tumor. This new entity, which we propose to call DICER1-associated presacral malignant teratoid neoplasm, may be difficult initially to distinguish from immature teratoma, but recognizing it as an entity can prompt appropriate classification as an aggressive malignancy and facilitate appropriate genetic counseling, DICER1 germline variant testing, screening, and education.
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http://dx.doi.org/10.1038/s41379-019-0319-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881536PMC
December 2019

Response to: Concern regarding classification of germlineTP53 variants as likely pathogenic.

Hum Mutat 2019 06 18;40(6):832-833. Epub 2019 Apr 18.

Oncogenetics Unit, Oncology Center, Sírio-Libanês Hospital, São Paulo, Brazil.

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http://dx.doi.org/10.1002/humu.23749DOI Listing
June 2019

Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1-associated atypical neurofibromas.

Neuro Oncol 2019 08;21(8):981-992

Clinical Genetics Branch, DCEG, NCI, National Institutes of Health (NIH), Rockville, Maryland, USA.

Background: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation.

Methods: In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs.

Results: We identified a low number of mutations (median 1, range 0-5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3, and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only.

Conclusions: The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction and cell-cycle and pluripotency self-renewal genes.
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http://dx.doi.org/10.1093/neuonc/noz028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682216PMC
August 2019

Neoplasm Risk Among Individuals With a Pathogenic Germline Variant in DICER1.

J Clin Oncol 2019 03 4;37(8):668-676. Epub 2019 Feb 4.

2 Children's Hospitals and Clinics of Minnesota, Minneapolis, MN.

Purpose: DICER1 syndrome is an autosomal-dominant, pleiotropic tumor-predisposition disorder caused by pathogenic germline variants in DICER1. We sought to quantify risk, hazard rates, and the probability of neoplasm incidence accounting for competing risks ("cumulative incidence") of neoplasms (benign and malignant) and standardized incidence ratios for malignant tumors in individuals with DICER1 pathogenic variation.

Patients And Methods: We combined data from three large cohorts of patients who carry germline pathogenic variation in DICER1. To reduce ascertainment bias, we distinguished probands from nonprobands. Neoplasm diagnoses were confirmed by review of pathology reports and/or central review of surgical pathology materials. Standardized cancer incidence ratios were determined relative to the SEER program, which does not capture all DICER1-associated neoplasms. For all malignancies and benign tumors ("neoplasms," excluding type Ir pleuropulmonary blastoma and thyroid nodules), we used the Kaplan-Meier method and nonparametric cumulative incidence curves to estimate neoplasm-free survival.

Results: We calculated the age at first neoplasm diagnosis (systematically ascertained cancers plus DICER1-associated neoplasms pleuropulmonary blastoma, cystic nephroma, and nasal chondromesenchymal hamartoma) in 102 female and male nonproband DICER1 carriers. By age 10 years, 5.3% (95% CI, 0.6% to 9.7%) of nonproband DICER1 carriers had developed a neoplasm (females, 4.0%; males, 6.6%). By age 50 years, 19.3% (95% CI, 8.4% to 29.0%) of nonprobands had developed a neoplasm (females, 26.5%; males, 10.2%). After age 10 years, female risk was elevated compared with male risk. Standardized cancer incidence ratio analysis of 102 nonproband DICER1 carriers, which represented 3,344 person-years of observation, showed significant cancer excesses overall, particularly of gynecologic and thyroid cancers.

Conclusion: This work provides the first quantitative analysis of site-specific neoplasm risk and excess malignancy risk in 102 systematically characterized nonproband DICER1 carriers. Our findings inform DICER1 syndrome phenotype, natural history, and genetic counseling.
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http://dx.doi.org/10.1200/JCO.2018.78.4678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553836PMC
March 2019

Association of Inherited Pathogenic Variants in Checkpoint Kinase 2 (CHEK2) With Susceptibility to Testicular Germ Cell Tumors.

JAMA Oncol 2019 Apr;5(4):514-522

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Importance: Approximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs.

Objective: To systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls.

Design, Setting, And Participants: A case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018.

Main Outcomes And Measures: Gene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls.

Results: Among 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009).

Conclusions And Relevance: This multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.
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http://dx.doi.org/10.1001/jamaoncol.2018.6477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459214PMC
April 2019

The prevalence of germline DICER1 pathogenic variation in cancer populations.

Mol Genet Genomic Med 2019 03 22;7(3):e555. Epub 2019 Jan 22.

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

Background: The DICER1 syndrome is an autosomal dominant tumor-predisposition disorder associated with pleuropulmonary blastoma, a rare pediatric lung cancer. Somatic missense variation in "hotspot" codons in the RNaseIIIb domain (E1705, D1709, G1809, D1810, E1813) is observed in DICER1-associated tumors. Previously, we found the prevalence of germline pathogenic DICER1 variation in the general population is 1:10,600. In this study, we investigated the prevalence of pathogenic DICER1 germline variation in The Cancer Genome Atlas (TCGA; 32 adult cancer types; 9,173 exomes) and the Therapeutically Applicable Research to Generate Effective Treatment (TARGET; two pediatric cancer types; 175 exomes) cohorts.

Methods: All datasets were annotated and binned into four categories: pathogenic, likely pathogenic, variant of unknown significance, or likely benign.

Results: The prevalence of DICER1 pathogenic variants was 1:4,600 in TCGA. A single participant with a uterine corpus endometrial carcinoma harbored two pathogenic germline DICER1 (hotspot and splice-donor) variants, and a single participant with a rectal adenocarcinoma harbored a germline DICER1 stop-gained variant. In the smaller TARGET dataset, we observed no pathogenic germline variants.

Conclusion: This is the largest comprehensive analysis of DICER1 pathogenic variation in adult and pediatric cancer populations using publicly available data. The observation of germline DICER1 variation with uterine corpus endometrial carcinoma merits additional investigation.
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http://dx.doi.org/10.1002/mgg3.555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418698PMC
March 2019

Prevalence of pathogenic/likely pathogenic variants in the 24 cancer genes of the ACMG Secondary Findings v2.0 list in a large cancer cohort and ethnicity-matched controls.

Genome Med 2018 12 24;10(1):99. Epub 2018 Dec 24.

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

Background: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982).

Methods: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS).

Results: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers.

Conclusion: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.
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http://dx.doi.org/10.1186/s13073-018-0607-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305568PMC
December 2018

Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis.

Hum Mutat 2019 01 19;40(1):97-105. Epub 2018 Nov 19.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland.

Reports of variable cancer penetrance in Li-Fraumeni syndrome (LFS) have raised questions regarding the prevalence of pathogenic germline TP53 variants. We previously reported higher-than-expected population prevalence estimates in sequencing databases composed of individuals unselected for cancer history. This study aimed to expand and further evaluate the prevalence of pathogenic and likely pathogenic germline TP53 variants in the gnomAD dataset (version r2.0.2, n = 138,632). Variants were selected and classified based on our previously published algorithm and compared with alternative estimates based on three different classification databases: ClinVar, HGMD, and the UMD_TP53 database. Conservative prevalence estimates of pathogenic and likely pathogenic TP53 variants were within the range of one carrier in 3,555-5,476 individuals. Less stringent classification increased the approximate prevalence to one carrier in every 400-865 individuals, mainly due to the inclusion of the controvertible p.N235S, p.V31I, and p.R290H variants. This study shows a higher-than-expected population prevalence of pathogenic and likely pathogenic germline TP53 variants even with the most conservative estimates. However, these estimates may not necessarily reflect the prevalence of the classical LFS phenotype, which is based upon family history of cancer. Comprehensive approaches are needed to better understand the interplay of germline TP53 variant classification, prevalence estimates, cancer penetrance, and LFS-associated phenotype.
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http://dx.doi.org/10.1002/humu.23673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296902PMC
January 2019

DICER1 Syndrome: Characterization of the Ocular Phenotype in a Family-Based Cohort Study.

Ophthalmology 2019 02 17;126(2):296-304. Epub 2018 Oct 17.

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

Purpose: To characterize the ocular phenotype of DICER1 syndrome.

Design: Prospective, single-center, case-control study.

Participants: One hundred three patients with an identified germline pathogenic DICER1 variant (DICER1 carriers) and 69 family control participants underwent clinical and ophthalmic examination at the National Institutes of Health between 2011 and 2016.

Methods: All participants were evaluated with a comprehensive ophthalmic examination, including best-corrected visual acuity, slit-lamp biomicroscopy, and a dilated fundus examination. A subset of patients returned for a more detailed evaluation including spectral-domain OCT, color fundus photography, fundus autofluorescence imaging, visual field testing, full-field electroretinography, and genetic testing for inherited retinal degenerative diseases.

Main Outcome Measures: Visual acuity and examination findings.

Results: Most DICER1 carriers (97%) maintained a visual acuity of 20/40 or better in both eyes. Twenty-three DICER1 carriers (22%) showed ocular abnormalities compared with 4 family controls (6%; P = 0.005). These abnormalities included retinal pigment abnormalities (n = 6 [5.8%]), increased cup-to-disc ratio (n = 5 [4.9%]), optic nerve abnormalities (n = 2 [1.9%]), epiretinal membrane (n = 2 [1.9%]), and drusen (n = 2 [1.9%]). Overall, we observed a significant difference (P = 0.03) in the rate of retinal abnormalities in DICER1 carriers (n = 11 [11%]) versus controls (n = 1 [1.5%]). One patient demonstrated an unexpected diagnosis of retinitis pigmentosa with a novel variant of unknown significance in PRPF31, and 1 showed optic nerve elevation in the setting of increased intracranial pressure (ICP) of unclear cause. Three patients (3%) demonstrated DICER1-related ciliary body medulloepithelioma (CBME), 2 of which were identified during routine examination, a higher rate than that reported previously.

Conclusions: Ophthalmologists should be aware of the ophthalmic manifestations of DICER1 syndrome, and individuals and families should be counseled on the potential signs and symptoms. We recommend that children with a germline pathogenic variant in DICER1, especially those younger than 10 years, undergo annual dilated ophthalmic examination, looking for evidence of CBME, signs of increased ICP, and perhaps changes in the retinal pigment epithelium.
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http://dx.doi.org/10.1016/j.ophtha.2018.09.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348055PMC
February 2019

Response to Hannah-Shmouni and Stratakis.

Genet Med 2019 05 4;21(5):1256. Epub 2018 Oct 4.

Department of Neurology, New York University School of Medicine, New York, NY, USA.

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http://dx.doi.org/10.1038/s41436-018-0313-0DOI Listing
May 2019

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

Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Genet Med 2018 07 26;20(7):671-682. Epub 2018 Apr 26.

Department of Neurology, New York University School of Medicine, New York, New York, USA.

Disclaimer: This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a heterozygous loss-of-function variant in the tumor suppressor gene NF1; it affects ~1/1,900-1/3,500 people worldwide. The disorder is associated with an 8-15-year reduction in average life expectancy in both men and women, primarily due to malignant neoplasms and cardiovascular causes.

Methods: A work group of experts sought to determine the prevalence, morbidity and mortality, and available treatments of common and emerging NF1-related clinical problems in adults. Work-group members identified peer-reviewed publications from PubMed. Publications derived from populations and multi-institution cohorts were prioritized. Recommendations for management arose by consensus from this literature and the collective expertise of the authors.

Results: Malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses are common problems in patients with NF1.

Conclusion: Patient education and sensitization to worrisome signs and symptoms such as progressive severe pain (MPNST), changes in tumor volume (MPNST), new, unexplained neurologic symptoms (MPNST, brain tumors), and diaphoresis/palpitations (pheochromocytoma) are important. Although many issues in adults with NF1 can be managed by an internist or family physician, we strongly encourage evaluation by, and care coordination with, a specialized NF1 clinic.
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http://dx.doi.org/10.1038/gim.2018.28DOI Listing
July 2018