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Publication Record


Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations.
Ahmed IA, Farooqi MS, Vander Lugt MT, Boklan J, Rose M, Friehling ED, Triplett B, Lieuw K, Saldana BD, Smith CM, Schwartz JR, Goyal RK
(2019) Biol Blood Marrow Transplant 25: 2186-2196
MeSH Terms: Allografts, Child, Preschool, Disease-Free Survival, Female, Genetic Diseases, Inborn, Germ-Line Mutation, Hematopoietic Stem Cell Transplantation, Humans, Infant, Intracellular Signaling Peptides and Proteins, Male, Myelodysplastic Syndromes, Retrospective Studies, Survival Rate, Syndrome, Tumor Suppressor Proteins
Show Abstract · Added September 19, 2019
Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.
Copyright © 2019 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.
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16 MeSH Terms
Pathogenic Germline Variants in 10,389 Adult Cancers.
Huang KL, Mashl RJ, Wu Y, Ritter DI, Wang J, Oh C, Paczkowska M, Reynolds S, Wyczalkowski MA, Oak N, Scott AD, Krassowski M, Cherniack AD, Houlahan KE, Jayasinghe R, Wang LB, Zhou DC, Liu D, Cao S, Kim YW, Koire A, McMichael JF, Hucthagowder V, Kim TB, Hahn A, Wang C, McLellan MD, Al-Mulla F, Johnson KJ, Cancer Genome Atlas Research Network, Lichtarge O, Boutros PC, Raphael B, Lazar AJ, Zhang W, Wendl MC, Govindan R, Jain S, Wheeler D, Kulkarni S, Dipersio JF, Reimand J, Meric-Bernstam F, Chen K, Shmulevich I, Plon SE, Chen F, Ding L
(2018) Cell 173: 355-370.e14
MeSH Terms: DNA Copy Number Variations, Databases, Genetic, Gene Deletion, Gene Frequency, Genetic Predisposition to Disease, Genotype, Germ Cells, Germ-Line Mutation, Humans, Loss of Heterozygosity, Mutation, Missense, Neoplasms, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-met, Proto-Oncogene Proteins c-ret, Tumor Suppressor Proteins
Show Abstract · Added October 30, 2019
We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.
Seow WJ, Matsuo K, Hsiung CA, Shiraishi K, Song M, Kim HN, Wong MP, Hong YC, Hosgood HD, Wang Z, Chang IS, Wang JC, Chatterjee N, Tucker M, Wei H, Mitsudomi T, Zheng W, Kim JH, Zhou B, Caporaso NE, Albanes D, Shin MH, Chung LP, An SJ, Wang P, Zheng H, Yatabe Y, Zhang XC, Kim YT, Shu XO, Kim YC, Bassig BA, Chang J, Ho JC, Ji BT, Kubo M, Daigo Y, Ito H, Momozawa Y, Ashikawa K, Kamatani Y, Honda T, Sakamoto H, Kunitoh H, Tsuta K, Watanabe SI, Nokihara H, Miyagi Y, Nakayama H, Matsumoto S, Tsuboi M, Goto K, Yin Z, Shi J, Takahashi A, Goto A, Minamiya Y, Shimizu K, Tanaka K, Wu T, Wei F, Wong JY, Matsuda F, Su J, Kim YH, Oh IJ, Song F, Lee VH, Su WC, Chen YM, Chang GC, Chen KY, Huang MS, Yang PC, Lin HC, Xiang YB, Seow A, Park JY, Kweon SS, Chen CJ, Li H, Gao YT, Wu C, Qian B, Lu D, Liu J, Jeon HS, Hsiao CF, Sung JS, Tsai YH, Jung YJ, Guo H, Hu Z, Wang WC, Chung CC, Lawrence C, Burdett L, Yeager M, Jacobs KB, Hutchinson A, Berndt SI, He X, Wu W, Wang J, Li Y, Choi JE, Park KH, Sung SW, Liu L, Kang CH, Hu L, Chen CH, Yang TY, Xu J, Guan P, Tan W, Wang CL, Sihoe AD, Chen Y, Choi YY, Hung JY, Kim JS, Yoon HI, Cai Q, Lin CC, Park IK, Xu P, Dong J, Kim C, He Q, Perng RP, Chen CY, Vermeulen R, Wu J, Lim WY, Chen KC, Chan JK, Chu M, Li YJ, Li J, Chen H, Yu CJ, Jin L, Lo YL, Chen YH, Fraumeni JF, Liu J, Yamaji T, Yang Y, Hicks B, Wyatt K, Li SA, Dai J, Ma H, Jin G, Song B, Wang Z, Cheng S, Li X, Ren Y, Cui P, Iwasaki M, Shimazu T, Tsugane S, Zhu J, Jiang G, Fei K, Wu G, Chien LH, Chen HL, Su YC, Tsai FY, Chen YS, Yu J, Stevens VL, Laird-Offringa IA, Marconett CN, Lin D, Chen K, Wu YL, Landi MT, Shen H, Rothman N, Kohno T, Chanock SJ, Lan Q
(2017) Hum Mol Genet 26: 454-465
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Antigens, Nuclear, Asian Continental Ancestry Group, Butyrophilins, Case-Control Studies, ErbB Receptors, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Germ-Line Mutation, HLA-DP beta-Chains, Humans, Lung Neoplasms, Male, Membrane Proteins, Nerve Tissue Proteins, Polymorphism, Single Nucleotide, Sex Characteristics, Smoking, Transcription Factors
Show Abstract · Added April 3, 2018
To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.
Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.
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23 MeSH Terms
Effects of Twelve Germline Missense Variations on DNA Lesion and G-Quadruplex Bypass Activities of Human DNA Polymerase REV1.
Yeom M, Kim IH, Kim JK, Kang K, Eoff RL, Guengerich FP, Choi JY
(2016) Chem Res Toxicol 29: 367-79
MeSH Terms: DNA, DNA Adducts, DNA Damage, G-Quadruplexes, Germ-Line Mutation, Humans, Models, Molecular, Mutation, Missense, Nuclear Proteins, Nucleotidyltransferases
Show Abstract · Added March 14, 2018
The Y-family DNA polymerase REV1 is involved in replicative bypass of damaged DNA and G-quadruplex (G4) DNA. In addition to a scaffolding role in the replicative bypass, REV1 acts in a catalytic role as a deoxycytidyl transferase opposite some replication stall sites, e.g., apurinic/apyrimidinic (AP) sites, N(2)-guanyl lesions, and G4 sites. We characterized the biochemical properties of 12 reported germline missense variants of human REV1, including the N373S variant associated with high risk of cervical cancer, using the recombinant REV1 (residues 330-833) proteins and DNA templates containing a G, AP site, N(2)-CH2(2-naphthyl)G (N(2)-NaphG), or G4. In steady-state kinetic analyses, the F427L, R434Q, M656V, D700N, R704Q, and P831L variants displayed 2- to 8-fold decreases in kcat/Km for dCTP insertion opposite all four templates, compared to that of wild-type, while the N373S, M407L, and N497S showed 2- to 3-fold increases with all four and the former three or two templates, respectively. The F427L, R434Q, M656V, and R704Q variants also had 2- to 3-fold lower binding affinities to DNA substrates containing G, an AP site, and/or N(2)-NaphG than wild-type. Distinctively, the N373S variant had a 3-fold higher binding affinity to G4 DNA than the wild-type, as well as a 2-fold higher catalytic activity opposite the first tetrad G, suggesting a facilitating effect of this variation on replication of G4 DNA sequences in certain human papillomavirus genomes. Our results suggest that the catalytic function of REV1 is moderately or slightly altered by at least nine genetic variations, and the G4 DNA processing function of REV1 is slightly enhanced by the N373S variation, which might provide the possibility that certain germline missense REV1 variations affect the individual susceptibility to carcinogenesis by modifying the capability of REV1 for replicative bypass past DNA lesions and G4 motifs derived from chemical and viral carcinogens.
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10 MeSH Terms
Heritable forms of pulmonary arterial hypertension.
Austin ED, Loyd JE
(2013) Semin Respir Crit Care Med 34: 568-80
MeSH Terms: Activin Receptors, Type II, Antigens, CD, Bone Morphogenetic Protein Receptors, Type II, Caveolin 1, Endoglin, Familial Primary Pulmonary Hypertension, Female, Gene-Environment Interaction, Genetic Counseling, Genetic Testing, Germ-Line Mutation, Humans, Hypertension, Pulmonary, Male, Nerve Tissue Proteins, Penetrance, Potassium Channels, Tandem Pore Domain, Pregnancy, Preimplantation Diagnosis, Receptors, Cell Surface, Sex Distribution, TGF-beta Superfamily Proteins
Show Abstract · Added March 20, 2014
Tremendous progress has been made in understanding the genetics of heritable pulmonary arterial hypertension (HPAH) since its description in the 1950s. Germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of HPAH, and in a small proportion of cases of idiopathic pulmonary arterial hypertension (IPAH). Recent advancements in gene sequencing methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH (CAV1, KCNK3). HPAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, and female predominance. These characteristics suggest that genetic and nongenetic factors modify disease expression, highlighting areas of active investigation. The reduced penetrance makes genetic counseling complex, as the majority of carriers of PAH-related mutations will never be diagnosed with the disease. This issue is increasingly important, as clinical testing for BMPR2 and other mutations is now available for the evaluation of patients and their at-risk kin. The possibilities to avoid mutation transmission, such as the rapidly advancing field of preimplantation genetic testing, highlight the need for all clinicians to understand the genetic features of PAH risk.
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
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22 MeSH Terms
Two co-existing germline mutations P53 V157D and PMS2 R20Q promote tumorigenesis in a familial cancer syndrome.
Wang Z, Sun Y, Gao B, Lu Y, Fang R, Gao Y, Xiao T, Liu XY, Pao W, Zhao Y, Chen H, Ji H
(2014) Cancer Lett 342: 36-42
MeSH Terms: Adenocarcinoma, Adenosine Triphosphatases, Adult, Animals, Animals, Genetically Modified, Base Sequence, Carcinogenesis, Cell Line, DNA Mutational Analysis, DNA Repair Enzymes, DNA-Binding Proteins, Drosophila, Female, Genetic Association Studies, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Lung Neoplasms, Male, Mice, Middle Aged, Mismatch Repair Endonuclease PMS2, Mutation, Missense, Neoplastic Syndromes, Hereditary, Pedigree, Radiography, Tumor Suppressor Protein p53, Young Adult
Show Abstract · Added September 3, 2013
Germline mutations are responsible for familial cancer syndromes which account for approximately 5-10% of all types of cancers. These mutations mainly occur at tumor suppressor genes or genome stability genes, such as DNA repair genes. Here we have identified a cancer predisposition family, in which eight members were inflicted with a wide spectrum of cancer including one diagnosed with lung cancer at 22years old. Sequencing analysis of tumor samples as well as histologically normal specimens identified two germline mutations co-existing in the familial cancer syndrome, the mutation of tumor suppressor gene P53 V157D and mismatch repair gene PMS2 R20Q. We further demonstrate that P53 V157D and/or PMS2 R20Q mutant promotes lung cancer cell proliferation. These two mutants are capable of promoting colony formation in soft agar as well as tumor formation in transgenic drosophila system. Collectively, these data have uncovered the important role of co-existing germline P53 and PMS2 mutations in the familial cancer syndrome development.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
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28 MeSH Terms
Cancer pharmacogenomics: strategies and challenges.
Wheeler HE, Maitland ML, Dolan ME, Cox NJ, Ratain MJ
(2013) Nat Rev Genet 14: 23-34
MeSH Terms: Antineoplastic Agents, Clinical Trials as Topic, Genome-Wide Association Study, Germ-Line Mutation, Humans, Neoplasms, Pharmacogenetics, Reproducibility of Results, Research Design, Signal Transduction
Show Abstract · Added February 22, 2016
Genetic variation influences the response of an individual to drug treatments. Understanding this variation has the potential to make therapy safer and more effective by determining selection and dosing of drugs for an individual patient. In the context of cancer, tumours may have specific disease-defining mutations, but a patient's germline genetic variation will also affect drug response (both efficacy and toxicity), and here we focus on how to study this variation. Advances in sequencing technologies, statistical genetics analysis methods and clinical trial designs have shown promise for the discovery of variants associated with drug response. We discuss the application of germline genetics analysis methods to cancer pharmacogenomics with a focus on the special considerations for study design.
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10 MeSH Terms
Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission.
Freyer C, Cree LM, Mourier A, Stewart JB, Koolmeister C, Milenkovic D, Wai T, Floros VI, Hagström E, Chatzidaki EE, Wiesner RJ, Samuels DC, Larsson NG, Chinnery PF
(2012) Nat Genet 44: 1282-5
MeSH Terms: Animals, DNA Polymerase gamma, DNA, Mitochondrial, DNA-Directed DNA Polymerase, Female, Fertility, Genetic Heterogeneity, Genome, Mitochondrial, Germ-Line Mutation, Mice, Mice, Inbred C57BL, Oocytes, RNA, RNA, Mitochondrial, RNA, Transfer, Met
Show Abstract · Added December 12, 2013
A genetic bottleneck explains the marked changes in mitochondrial DNA (mtDNA) heteroplasmy that are observed during the transmission of pathogenic mutations, but the precise timing of these changes remains controversial, and it is not clear whether selection has a role. These issues are important for the genetic counseling of prospective mothers and for the development of treatments aimed at disease prevention. By studying mice transmitting a heteroplasmic single-base-pair deletion in the mitochondrial tRNA(Met) gene, we show that the extent of mammalian mtDNA heteroplasmy is principally determined prenatally within the developing female germline. Although we saw no evidence of mtDNA selection prenatally, skewed heteroplasmy levels were observed in the offspring of the next generation, consistent with purifying selection. High percentages of mtDNA genomes with the tRNA(Met) mutation were linked to a compensatory increase in overall mitochondrial RNA levels, ameliorating the biochemical phenotype and explaining why fecundity is not compromised.
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15 MeSH Terms
Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia.
Yang JJ, Cheng C, Devidas M, Cao X, Campana D, Yang W, Fan Y, Neale G, Cox N, Scheet P, Borowitz MJ, Winick NJ, Martin PL, Bowman WP, Camitta B, Reaman GH, Carroll WL, Willman CL, Hunger SP, Evans WE, Pui CH, Loh M, Relling MV
(2012) Blood 120: 4197-204
MeSH Terms: Alleles, Antineoplastic Combined Chemotherapy Protocols, Biotransformation, DNA, Neoplasm, Genome-Wide Association Study, Genotype, Germ-Line Mutation, Glycogen Phosphorylase, Humans, Neoplasm Proteins, Neoplasm, Residual, Polymorphism, Single Nucleotide, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Recurrence, Remission Induction, Risk
Show Abstract · Added February 22, 2016
With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 × 10(-9)). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111).
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17 MeSH Terms
Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer.
Breyer JP, Avritt TG, McReynolds KM, Dupont WD, Smith JR
(2012) Cancer Epidemiol Biomarkers Prev 21: 1348-53
MeSH Terms: Adult, Aged, Case-Control Studies, Genetic Predisposition to Disease, Genotype, Germ-Line Mutation, Homeodomain Proteins, Humans, Male, Middle Aged, Prostatic Neoplasms, Risk Assessment
Show Abstract · Added March 7, 2014
BACKGROUND - A recent study of familial and early onset prostate cancer reported a recurrent rare germline mutation of HOXB13 among men of European descent. The gene resides within the 17q21 hereditary prostate cancer linkage interval.
METHODS - We evaluated the G84E germline mutation (rs138213197) of HOXB13 in a case-control study of familial prostate cancer at Vanderbilt University (Nashville, TN) to independently evaluate the association of the mutation with familial prostate cancer. We genotyped 928 familial prostate cancer probands and 930 control probands without a personal or family history of prostate cancer.
RESULTS - Our study confirmed the association between the G84E mutation of HOXB13 and risk of prostate cancer among subjects of European descent. We observed the mutation in 16 familial cases and in two controls, each as heterozygotes. The odds ratio (OR) for prostate cancer was 7.9 [95% confidence interval, (CI) 1.8-34.5, P = 0.0062] among carriers of the mutation. The carrier rate was 1.9% among all familial case probands and 2.7% among probands of pedigrees with ≥3 affected. In a separate case series of 268 probands of European descent with no additional family history of prostate cancer, the carrier rate was 1.5%.
CONCLUSIONS - The germline mutation G84E of HOXB13 is a rare but recurrent mutation associated with elevated risk of prostate cancer in men of European descent, with an effect size that is greater than observed for previously validated risk variants of genome wide association studies.
IMPACT - This study independently confirms the association of a germline HOXB13 mutation with familial prostate cancer.
©2012 AACR.
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12 MeSH Terms