Publications by authors named "Sharon E Plon"

168 Publications

Genomic analysis and preclinical xenograft model development identify potential therapeutic targets for MYOD1-mutant soft-tissue sarcoma of childhood.

J Pathol 2021 Jun 4. Epub 2021 Jun 4.

Division of Pediatric Hematology and Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

The MYOD1 p.L122R somatic mutation was first discovered in a subset of clinically aggressive embryonal rhabdomyosarcomas and has since been described in both pediatric and adult spindle cell/sclerosing rhabdomyosarcomas. Relatively little is known about the clinical, molecular, and histopathological feature of these tumors in children. In order to further characterize the genomic and clinical features of pediatric MYOD1-mutant sarcomas, we evaluated a cohort of soft-tissue sarcoma patients treated at Texas Children's Hospital. Tumor DNA was subjected to next-generation panel sequencing and/or Sanger sequencing of the MYOD1 hotspot mutation. The MYOD1 p.L122R mutation was identified in six tumors, with a variant allele fraction greater than 0.8 in three cases, suggestive of loss of heterozygosity (LOH). One sclerosing rhabdomyosarcoma lacking the MYOD1 hotspot mutation was observed to have a MYOD1 copy number gain, also with evidence of LOH. Cancer gene panel sequencing revealed potentially targetable alterations in 6/7 (86%) patients with MYOD1 alterations, including four patients with an alteration in the PI3K-AKT pathway: two hotspot PIK3CA mutations and deletions in PTEN and TSC2. On histopathologic review, MYOD1-altered tumors exhibited spindle and/or round cells and varying degrees of hyaline sclerosis. At last follow-up, six patients had died of disease and the seventh progressed early and was subsequently lost to follow-up. Both pre- and post-therapy patient-derived xenograft (PDX) models were generated from one patient's tumor. These models were confirmed to harbor the MYOD1 and PIK3CA mutations seen in the primary tumor and were shown to be sensitive to PI3K/mTOR inhibition in vitro and in vivo. In conclusion, this study adds to recent reports describing the clinicopathologic and genomic features of MYOD1-altered soft-tissue sarcomas in children, including dismal prognosis and potential molecular targets for therapy. The novel pre-clinical models developed will facilitate further biological and pre-clinical study of this rare and aggressive tumor. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5736DOI Listing
June 2021

Pediatric Rhabdomyosarcoma: Epidemiology and Genetic Susceptibility.

J Clin Med 2021 May 9;10(9). Epub 2021 May 9.

Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet little is known about its etiology. Studies that examine either environmental exposures or germline genetic predisposition in RMS have begun to identify factors that contribute to this malignancy. Here, we summarize epidemiological reports of RMS incidence in terms of several factors, including age at diagnosis, biological sex, and geographic location. We then describe findings from association studies, which explore the role of parental exposures, birth and perinatal characteristics, and childhood exposures in RMS. Further, we discuss RMS predisposition syndromes and large-scale sequencing studies that have further identified RMS-associated genes. Finally, we propose future directions of study, which aim to advance our understanding of the origin of RMS and can provide knowledge for novel RMS therapies.
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http://dx.doi.org/10.3390/jcm10092028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125975PMC
May 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

Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Hum Mutat 2021 Mar 25;42(3):223-236. Epub 2020 Dec 25.

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

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.
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http://dx.doi.org/10.1002/humu.24152DOI Listing
March 2021

Male Sex and the Risk of Childhood Cancer: The Mediating Effect of Birth Defects.

JNCI Cancer Spectr 2020 Oct 11;4(5):pkaa052. Epub 2020 Jun 11.

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Background: There is a persistent, unexplained disparity in sex ratio among childhood cancer cases, whereby males are more likely to develop most cancers. This male predominance is also seen for most birth defects, which are strongly associated with risk of childhood cancer. We conducted mediation analysis to estimate whether the increased risk of cancer among males is partially explained by birth defect status.

Methods: We used a population-based birth cohort with linked data from birth certificates, birth defects registries, and cancer registries from Arkansas, Michigan, North Carolina, and Texas. We conducted counterfactual mediation analysis to estimate the natural direct and indirect effects of sex on cancer risk, modeling birth defect status as mediator. State; birth year; plurality; and maternal race and ethnicity, age, and education were considered confounders. We conducted separate analyses limited to cancers diagnosed younger than 1 year of age.

Results: Our dataset included 10 181 074 children: 15 110 diagnosed with cancer, 539 567 diagnosed with birth defects, and 2124 co-occurring cases. Birth defect status mediated 38% of the association between sex and cancer overall. The proportion mediated varied by cancer type, including acute myeloid leukemia (93%), neuroblastoma (35%), and non-Hodgkin lymphoma (6%). Among children younger than 1 year of age at cancer diagnosis, the proportion mediated was substantially higher (82%).

Conclusions: Our results suggest that birth defects mediate a statistically significant proportion of the relationship between sex and childhood cancer. The proportion mediated varied by cancer type and diagnosis age. These findings improve our understanding of the causal pathway underlying male sex as a risk factor for childhood cancer.
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http://dx.doi.org/10.1093/jncics/pkaa052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583156PMC
October 2020

Clinical Genetics Lacks Standard Definitions and Protocols for the Collection and Use of Diversity Measures.

Am J Hum Genet 2020 07 6;107(1):72-82. Epub 2020 Jun 6.

Stanford Center for Biomedical Ethics, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Genetics, Stanford University, Stanford, CA 94305, USA.

Genetics researchers and clinical professionals rely on diversity measures such as race, ethnicity, and ancestry (REA) to stratify study participants and patients for a variety of applications in research and precision medicine. However, there are no comprehensive, widely accepted standards or guidelines for collecting and using such data in clinical genetics practice. Two NIH-funded research consortia, the Clinical Genome Resource (ClinGen) and Clinical Sequencing Evidence-generating Research (CSER), have partnered to address this issue and report how REA are currently collected, conceptualized, and used. Surveying clinical genetics professionals and researchers (n = 448), we found heterogeneity in the way REA are perceived, defined, and measured, with variation in the perceived importance of REA in both clinical and research settings. The majority of respondents (>55%) felt that REA are at least somewhat important for clinical variant interpretation, ordering genetic tests, and communicating results to patients. However, there was no consensus on the relevance of REA, including how each of these measures should be used in different scenarios and what information they can convey in the context of human genetics. A lack of common definitions and applications of REA across the precision medicine pipeline may contribute to inconsistencies in data collection, missing or inaccurate classifications, and misleading or inconclusive results. Thus, our findings support the need for standardization and harmonization of REA data collection and use in clinical genetics and precision health research.
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http://dx.doi.org/10.1016/j.ajhg.2020.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332657PMC
July 2020

Ancestry-specific predisposing germline variants in cancer.

Genome Med 2020 05 29;12(1):51. Epub 2020 May 29.

Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Background: Distinct prevalence of inherited genetic predisposition may partially explain the difference of cancer risks across ancestries. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis of diverse populations.

Methods: We conducted analyses using germline and somatic sequencing data generated by The Cancer Genome Atlas. Collapsing pathogenic and likely pathogenic variants to cancer predisposition genes (CPG), we analyzed the association between CPGs and cancer types within ancestral groups. We also identified the predisposition-associated two-hit events and gene expression effects in tumors.

Results: Genetic ancestry analysis classified the cohort of 9899 cancer cases into individuals of primarily European (N = 8184, 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N = 48, 0.5%), Native/Latin American (N = 41, 0.4%), and admixed (N = 11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) previously identified in Europeans, along with a known association of BRCA2 in ovarian serous cystadenocarcinoma (OR = 8.5 [95% CI, 1.5-47.4]; FDR = 0.045). In the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR = 12.8 [95% CI, 1.8-90.8]; FDR = 0.038). Rare variant burden analysis further identified 7 suggestive associations in African ancestry individuals previously described in European ancestry, including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Most predisposing variants were found exclusively in one ancestry in the TCGA and gnomAD datasets. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic-specific expression and low gene expression of their respective affected genes, and FH splice-site variant carriers showed mis-splicing of FH.

Conclusions: While several CPGs are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Studies using larger cohorts of diverse ancestries are required to pinpoint ancestry-specific genetic predisposition and inform genetic screening strategies.
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http://dx.doi.org/10.1186/s13073-020-00744-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260738PMC
May 2020

Cancer diagnostic profile in children with structural birth defects: An assessment in 15,000 childhood cancer cases.

Cancer 2020 08 29;126(15):3483-3492. Epub 2020 May 29.

Department of Medicine, Baylor College of Medicine, Houston, Texas.

Background: Birth defects are established risk factors for childhood cancer. Nonetheless, cancer epidemiology in children with birth defects is not well characterized.

Methods: Using data from population-based registries in 4 US states, this study compared children with cancer but no birth defects (n = 13,111) with children with cancer and 1 or more nonsyndromic birth defects (n = 1616). The objective was to evaluate cancer diagnostic characteristics, including tumor type, age at diagnosis, and stage at diagnosis.

Results: Compared with the general population of children with cancer, children with birth defects were diagnosed with more embryonal tumors (26.6% vs 18.7%; q < 0.001), including neuroblastoma (12.5% vs 8.2%; q < 0.001) and hepatoblastoma (5.0% vs 1.3%; q < 0.001), but fewer hematologic malignancies, including acute lymphoblastic leukemia (12.4% vs 24.4%; q < 0.001). In age-stratified analyses, differences in tumor type were evident among children younger than 1 year and children 1 to 4 years old, but they were attenuated among children 5 years of age or older. The age at diagnosis was younger in children with birth defects for most cancers, including leukemia, lymphoma, astrocytoma, medulloblastoma, ependymoma, embryonal tumors, and germ cell tumors (all q < 0.05).

Conclusions: The results indicate possible etiologic heterogeneity in children with birth defects, have implications for future surveillance efforts, and raise the possibility of differential cancer ascertainment in children with birth defects.

Lay Summary: Scientific studies suggest that children with birth defects are at increased risk for cancer. However, these studies have not been able to determine whether important tumor characteristics, such as the type of tumor diagnosed, the age at which the tumor is diagnosed, and the degree to which the tumor has spread at the time of diagnosis, are different for children with birth defects and children without birth defects. This study attempts to answer these important questions. By doing so, it may help scientists and physicians to understand the causes of cancer in children with birth defects and diagnose cancer at earlier stages when it is more treatable.
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http://dx.doi.org/10.1002/cncr.32982DOI Listing
August 2020

A brief history of human disease genetics.

Nature 2020 01 8;577(7789):179-189. Epub 2020 Jan 8.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.
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http://dx.doi.org/10.1038/s41586-019-1879-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405896PMC
January 2020

ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants.

Blood Adv 2019 10;3(20):2962-2979

Department of Scientific Affairs, American Society of Hematology, Washington, DC.

Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously classified as benign/likely benign, pathogenic/likely pathogenic, variant of unknown significance (VUS), or conflicting interpretations (CONF) in ClinVar. The application of RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the benefit of gene-specific criteria and sharing internal laboratory data.
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http://dx.doi.org/10.1182/bloodadvances.2019000644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849945PMC
October 2019

A case for expert curation: an overview of cancer curation in the Clinical Genome Resource (ClinGen).

Cold Spring Harb Mol Case Stud 2019 10 23;5(5). Epub 2019 Oct 23.

Baylor College of Medicine, Houston, Texas 77030, USA.

We describe the Clinical Genome Resource (ClinGen) cancer-related curation activities and the importance of curation to the evolving state of variant interpretation in a clinical context for both pediatric and adult cancer patients. We highlight specific examples from the and Variant Curation Expert Panels (VCEPs) of the FDA-recognized process by which ClinGen VCEPs specify the American College of Medical Genetics and Genomics/Association of Molecular Pathology evidence code to develop variant classifications. We also review gene curations performed within the Hereditary Cancer Clinical Domain. We describe the parallel efforts for curation of somatic cancer variants from the Somatic Cancer Working Group. The ClinGen Germline/Somatic Committee is working to improve incorporation of both hereditary and somatic variant data to aid clinical interpretation. These ClinGen efforts rely on broad data sharing and detailed phenotypic and molecular information from published case studies to provide expert-curated variant interpretation to the cancer community.
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http://dx.doi.org/10.1101/mcs.a004739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824250PMC
October 2019

Germline mutation in a child with hypermutated medulloblastoma and features of constitutional mismatch repair deficiency.

Cold Spring Harb Mol Case Stud 2019 10 23;5(5). Epub 2019 Oct 23.

Department of Pediatrics, Division of Hematology-Oncology, Baylor College of Medicine, Houston, Texas 77030, USA.

Ultra-hypermutation (>100 mutations/Mb) is rare in childhood cancer genomes and has been primarily reported in patients with constitutional mismatch repair deficiency (CMMRD) caused by biallelic germline mismatch repair (MMR) gene mutations. We report a 5-yr-old child with classic clinical features of CMMRD and an ultra-hypermutated medulloblastoma with retained MMR protein expression and absence of germline MMR mutations. Mutational signature analysis of tumor panel sequencing data revealed a canonical DNA polymerase-deficiency-associated signature, prompting further genetic testing that uncovered a germline p.A456P missense variant, which has previously been reported as a recurrent somatic driver mutation in cancers. This represents the earliest known onset of malignancy in a patient with a germline mutation in the POLE proofreading polymerase. The clinical features in this child, virtually indistinguishable from those of CMMRD, suggest that polymerase-proofreading deficiency should be considered in the differential diagnosis of CMMRD patients with retained MMR function.
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http://dx.doi.org/10.1101/mcs.a004499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824253PMC
October 2019

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors.

Proc Natl Acad Sci U S A 2019 10 7;116(43):21715-21726. Epub 2019 Oct 7.

Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030;

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.
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http://dx.doi.org/10.1073/pnas.1912858116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815170PMC
October 2019

Mutations in ANAPC1, Encoding a Scaffold Subunit of the Anaphase-Promoting Complex, Cause Rothmund-Thomson Syndrome Type 1.

Am J Hum Genet 2019 09 11;105(3):625-630. Epub 2019 Jul 11.

Centre Hospitalier Universitaire Sainte-Justine Research Center, University of Montreal, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T 1C5, Canada. Electronic address:

Rothmund-Thomson syndrome (RTS) is an autosomal-recessive disorder characterized by poikiloderma, sparse hair, short stature, and skeletal anomalies. Type 2 RTS, which is defined by the presence of bi-allelic mutations in RECQL4, is characterized by increased cancer susceptibility and skeletal anomalies, whereas the genetic basis of RTS type 1, which is associated with juvenile cataracts, is unknown. We studied ten individuals, from seven families, who had RTS type 1 and identified a deep intronic splicing mutation of the ANAPC1 gene, a component of the anaphase-promoting complex/cyclosome (APC/C), in all affected individuals, either in the homozygous state or in trans with another mutation. Fibroblast studies showed that the intronic mutation causes the activation of a 95 bp pseudoexon, leading to mRNAs with premature termination codons and nonsense-mediated decay, decreased ANAPC1 protein levels, and prolongation of interphase. Interestingly, mice that were heterozygous for a knockout mutation have an increased incidence of cataracts. Our results demonstrate that deficiency in the APC/C is a cause of RTS type 1 and suggest a possible link between the APC/C and RECQL4 helicase because both proteins are involved in DNA repair and replication.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731352PMC
September 2019

Association Between Birth Defects and Cancer Risk Among Children and Adolescents in a Population-Based Assessment of 10 Million Live Births.

JAMA Oncol 2019 Aug;5(8):1150-1158

Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

Importance: Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes.

Objectives: To identify specific birth defect-childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects.

Design, Setting, And Participants: This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019.

Exposures: Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries.

Main Outcomes And Measures: Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk.

Results: Compared with children without any birth defects, children with chromosomal anomalies were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.3-6.4) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjusted P < .05) after accounting for multiple comparisons. Cancers most frequently associated with nonchromosomal defects were hepatoblastoma and neuroblastoma.

Conclusions And Relevance: Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.
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http://dx.doi.org/10.1001/jamaoncol.2019.1215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587148PMC
August 2019

Responsibility, culpability, and parental views on genomic testing for seriously ill children.

Genet Med 2019 12 12;21(12):2791-2797. Epub 2019 Jun 12.

Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX, USA.

Purpose: We describe parental perceptions of and experiences with genomic sequencing (GS) in the care of seriously ill children. Understanding parents' perspectives is vital for clinicians caring for children, given the uptake of genomic technologies into clinical practice.

Methods: Longitudinal, semistructured interviews were conducted with parents of pediatric cancer patients who underwent exome sequencing (ES) as a part of the BASIC3 study. Interviews were conducted at baseline, one to eight months after results disclosure, and approximately one year after disclosure. Using thematic qualitative analysis, parent interviews were coded with both inductive and deductive approaches.

Results: Before receiving genomic information, parents indicated that they saw ES as something responsible parents would agree to if their child had cancer. Some parents talked about the possibility of sequencing affecting feelings of culpability for their child's cancer, worrying that they passed on a cancer-causing gene or made parenting decisions that caused the disease. However, after receiving their child's ES results many reported feeling relieved of guilt and worry, and felt they had fulfilled parental duties by agreeing to ES for their child.

Conclusion: These results reveal a layer of meaning that parents associate with GS that may inform clinicians' approach to care.
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http://dx.doi.org/10.1038/s41436-019-0570-6DOI Listing
December 2019

Genetic Predisposition to Childhood Cancer in the Genomic Era.

Annu Rev Genomics Hum Genet 2019 08 13;20:241-263. Epub 2019 May 13.

Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA; email:

Developments over the past five years have significantly advanced our ability to use genome-scale analyses-including high-density genotyping, transcriptome sequencing, exome sequencing, and genome sequencing-to identify the genetic basis of childhood cancer. This article reviews several key results from an expanding number of genomic studies of pediatric cancer: () Histopathologic subtypes of cancers can be associated with a high incidence of germline predisposition, () neurodevelopmental disorders or highly penetrant cancer predisposition syndromes can result from specific patterns of variation in genes encoding the SMARC family of chromatin remodelers, () genome-wide association studies with relatively small pediatric cancer cohorts have successfully identified single-nucleotide polymorphisms with large effect sizes and provided insight into population differences in cancer risk, and () multiple exome or genome analyses of unselected childhood cancer cohorts have yielded a 7-10% incidence of pathogenic variants in cancer predisposition genes. This work supports the increasing use of genomic sequencing in the care of pediatric cancer patients and at-risk family members.
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http://dx.doi.org/10.1146/annurev-genom-083118-015415DOI Listing
August 2019

Severe therapy-related toxicities after treatment for Hodgkin lymphoma due to a pathogenic TERT variant and shortened telomeres.

Pediatr Blood Cancer 2019 08 2;66(8):e27779. Epub 2019 May 2.

Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.

Telomere biology disorders predispose affected individuals to specific malignancies and organ fibrosis in tissues sensitive to telomere length (TL) shortening, especially after exposure to chemotherapy and radiation. We report a case of a 17-year-old female with Hodgkin lymphoma who developed severe chemotherapy-related toxicities. She was subsequently found to have peripheral blood lymphocyte TL < 1st percentile and a pathogenic variant in TERT inherited from her father. This case demonstrates that early genetic evaluation of patients who experience greater than expected therapy-related toxicities may be warranted to help guide further decisions regarding therapy, imaging modalities, and lifelong cancer prevention surveillance.
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http://dx.doi.org/10.1002/pbc.27779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880543PMC
August 2019

Characterization of pediatric hepatocellular carcinoma reveals genomic heterogeneity and diverse signaling pathway activation.

Pediatr Blood Cancer 2019 07 11;66(7):e27745. Epub 2019 Apr 11.

Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.

Background: Pediatric hepatocellular carcinoma (HCC) is a rare liver tumor in children with a poor prognosis. Comprehensive molecular profiling to understand the underlying genomic drivers of this tumor has not been completed, and it is unclear whether nonfibrolamellar pediatric HCC is more genomically similar to hepatoblastoma or adult HCC.

Procedure: To characterize the molecular landscape of these tumors, we analyzed a cohort of 15 pediatric non-FL-HCCs by sequencing a panel of cancer-associated genes and conducting copy-number and gene-expression analyses.

Results: We detected multiple types of molecular alterations in Wnt signaling genes, including APC inversion, AMER1 somatic mutation, and most commonly CTNNB1 intragenic deletions. There were multiple alterations to the telomerase pathway via TERT activation or ATRX mutation. Therapeutically targetable activating mutations in MAPK/ERK signaling pathway genes, including MAPK1 and BRAF, were detected in 20% of tumors. TP53 mutations occurred far less frequently in our pediatric HCC cohort than reported in adult cohorts. Tumors arising in children with underlying liver disease were found to be molecularly distinct from the remainder and lacking detectable oncogenic drivers, as compared with those arising in patients without a history of underlying liver disease; the majority of both types were positive for glypican-3, another potential therapeutic target.

Conclusion: Our study revealed pediatric HCC to be a molecularly heterogeneous group of tumors. Those non-FL-HCC tumors arising in the absence of underlying liver disease harbor genetic alterations affecting multiple cancer pathways, most notably Wnt signaling, and share some characteristics with adult HCC.
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http://dx.doi.org/10.1002/pbc.27745DOI Listing
July 2019

Correction: Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment, and health-care costs from a multisite study.

Genet Med 2019 May;21(5):1261-1262

Knight Diagnostic Laboratories, Oregon Health Science University, Portland, OR, USA.

The originally published version of this Article contained errors in Fig. 2. The numbers below the black arrowheads were incorrect; please see incorrect Figure in associated Correction. These errors have now been corrected in the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-019-0440-2DOI Listing
May 2019

BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.

PLoS Genet 2018 12 26;14(12):e1007752. Epub 2018 Dec 26.

University of California Santa Cruz Genomics Institute, University of California, Santa Cruz, California, United States of America.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.
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http://dx.doi.org/10.1371/journal.pgen.1007752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324924PMC
December 2018

Agents of empathy: How medical interpreters bridge sociocultural gaps in genomic sequencing disclosures with Spanish-speaking families.

Patient Educ Couns 2019 05 10;102(5):895-901. Epub 2018 Dec 10.

Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, USA. Electronic address:

Objectives: To describe how linguistic tools used by interpreters during return of genomic sequencing results may have impacted communication with Spanish-speaking families, and to discuss the implications for the role of medical interpreters.

Methods: Using discourse analysis, we identified and categorized the various ways hospital-based interpreters adapted clinicians' language in 37 audio-recorded sessions in which Spanish-speaking parents participating in a clinical trial received their child's genomic sequencing results from English-speaking clinicians.

Results: We found that interpreters adapted clinicians' statements using five empathic linguistic tools: contextualization, encouragement, checking comprehension, endearment, and softening. Interpreters used an average of four linguistic tools per session, with contextualization and encouragement being the most frequently used.

Conclusions: Interpreters used empathic linguistic tools to alter clinicians' statements when communicating genomic information to Spanish-speaking families. Our findings demonstrate the critical role of interpreters as cultural mediators and facilitators of understanding for Spanish-speaking families.

Practice Implications: This study expands upon the definition of clinical empathy in interpreter-mediated sessions. Our findings suggest that revisions of standards of medical interpretation practice may be warranted regarding interpreters' ability to adapt clinicians' language in a culturally sensitive manner during interpretation.
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http://dx.doi.org/10.1016/j.pec.2018.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197396PMC
May 2019

Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework.

Genet Med 2019 07 7;21(7):1507-1516. Epub 2018 Dec 7.

Mayo Clinic, Rochester, MN, USA.

Purpose: Gene-disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework.

Methods: Forty-two gene-disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene-disease relationship was curated independently by two trained biocurators. Evidence was reviewed with experts and assigned a final clinical validity classification.

Results: Of all gene-disease pairs evaluated, 14/42 (33.3%) were Definitive, 1/42 (2.4%) were Strong, 6/42 (14.3%) were Moderate, 18/42 (42.9%) were Limited, and 3/42 (7.1%) were either No Reported Evidence, Disputed, or Refuted. Of panels in the National Institutes of Health Genetic Testing Registry, 4/26 (~15.4%) contain genes with Limited clinical evidence.

Conclusion: Clinicians and laboratory diagnosticians should note that <60% of the genes on clinically available panels have Strong or Definitive evidence of association with hereditary colon cancer or polyposis, and >40% have only Moderate, Limited, Disputed, or Refuted evidence. Continuing to expand the structured assessment of the clinical relevance of genes listed on hereditary cancer testing panels will help clinicians and diagnostic laboratories focus the communication of genetic testing results on clinically significant genes.
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http://dx.doi.org/10.1038/s41436-018-0373-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579719PMC
July 2019

Clinical validity assessment of genes frequently tested on hereditary breast and ovarian cancer susceptibility sequencing panels.

Genet Med 2019 07 3;21(7):1497-1506. Epub 2018 Dec 3.

Mayo Clinic, Rochester, MN, USA.

Purpose: Several genes on hereditary breast and ovarian cancer susceptibility test panels have not been systematically examined for strength of association with disease. We employed the Clinical Genome Resource (ClinGen) clinical validity framework to assess the strength of evidence between selected genes and breast or ovarian cancer.

Methods: Thirty-one genes offered on cancer panel testing were selected for evaluation. The strength of gene-disease relationship was systematically evaluated and a clinical validity classification of either Definitive, Strong, Moderate, Limited, Refuted, Disputed, or No Reported Evidence was assigned.

Results: Definitive clinical validity classifications were made for 10/31 and 10/32 gene-disease pairs for breast and ovarian cancer respectively. Two genes had a Moderate classification whereas, 6/31 and 6/32 genes had Limited classifications for breast and ovarian cancer respectively. Contradictory evidence resulted in Disputed or Refuted assertions for 9/31 genes for breast and 4/32 genes for ovarian cancer. No Reported Evidence of disease association was asserted for 5/31 genes for breast and 11/32 for ovarian cancer.

Conclusion: Evaluation of gene-disease association using the ClinGen clinical validity framework revealed a wide range of classifications. This information should aid laboratories in tailoring appropriate gene panels and assist health-care providers in interpreting results from panel testing.
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http://dx.doi.org/10.1038/s41436-018-0361-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6579711PMC
July 2019

Exome sequencing disclosures in pediatric cancer care: Patterns of communication among oncologists, genetic counselors, and parents.

Patient Educ Couns 2019 04 12;102(4):680-686. Epub 2018 Nov 12.

Department of Medicine, Baylor College of Medicine, 6620 Main St., Houston, TX 77030, United States; Department of Communication, Texas A&M University, TAMU 4234, College Station, TX 77843, United States; Center for Innovation in Healthcare Quality, Effectiveness, & Safety, Michael E. DeBakey Veterans Affairs Medical Center, 2450 Holcombe Blvd., Suite 01Y, Houston, TX 77021, United States. Electronic address:

Objective: To examine communication patterns and behaviors during disclosure of exome sequencing (ES) results to parents of pediatric cancer patients, and describe common themes in parental communication.

Methods: Using mixed methods, we analyzed transcripts of sessions where parents of pediatric cancer patients received ES results from an oncologist and genetic counselor. Seventy-six transcripts were analyzed for frequency of clinician information-giving, partnering-supportive talk, and active parent participation. A subset of 40 transcripts were analyzed using thematic content analysis.

Results: Disclosures consisted mostly of clinician talk (84% of total talk), which was focused on providing information (62% of clinicians' utterances) with occasional partnering-supportive talk (7% of clinicians' utterances). Most parents assumed a passive, listening role (16% of total talk). Themes in parental communication included expressing relief and the significance of an answer, concern about sharing results and responsibility for inheritance, and seeking clarification of health implications of results.

Conclusion: Our finding of low levels of active parent participation during ES disclosures highlights the need to improve patient/parent engagement and understanding in a genetic setting.

Practice Implications: Clinician communication strategies that could encourage parent participation and understanding include checking for parent understanding, partnership-building, and tailoring ES discussions to address parent concerns and preferences.
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http://dx.doi.org/10.1016/j.pec.2018.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440863PMC
April 2019

Current Controversies in Prenatal Diagnosis 2: NIPT results suggesting maternal cancer should always be disclosed.

Prenat Diagn 2019 04 10;39(5):339-343. Epub 2018 Dec 10.

National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

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http://dx.doi.org/10.1002/pd.5379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714972PMC
April 2019

ClinGen Variant Curation Expert Panel experiences and standardized processes for disease and gene-level specification of the ACMG/AMP guidelines for sequence variant interpretation.

Hum Mutat 2018 11;39(11):1614-1622

Department of Genetics, University of North Carolina, Chapel Hill, North Carolina.

Genome-scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high-quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health, is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen variant curation expert panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.
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http://dx.doi.org/10.1002/humu.23645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225902PMC
November 2018