Publications by authors named "Fengqi Chang"

16 Publications

  • Page 1 of 1

Development and Clinical Validation of a Large Fusion Gene Panel for Pediatric Cancers.

J Mol Diagn 2019 09 27;21(5):873-883. Epub 2019 Jun 27.

Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address:

Gene fusions are one of the most common genomic alterations in pediatric cancer. Many fusions encode oncogenic drivers and play important roles in cancer diagnosis, risk stratification, and treatment selection. We report the development and clinical validation of a large custom-designed RNA sequencing panel, CHOP Fusion panel, using anchored multiplex PCR technology. The panel interrogates 106 cancer genes known to be involved in nearly 600 different fusions reported in hematological malignancies and solid tumors. The panel works well with different types of samples, including formalin-fixed, paraffin-embedded samples. The panel demonstrated excellent analytic accuracy, with 100% sensitivity and specificity on 60 pediatric tumor validation samples. In addition to identifying all known fusions in the validation samples, three unrecognized, yet clinically significant, fusions were also detected. A total of 276 clinical cases were analyzed after the validation, and 51 different fusions were identified in 104 cases. Of these fusions, 16 were not previously reported at the time of discovery. These fusions provided genomic information useful for clinical management. Our experience demonstrates that CHOP Fusion panel can detect the vast majority of known and certain novel clinically relevant fusion genes in pediatric cancers accurately, efficiently, and cost-effectively; and the panel provides an excellent tool for new fusion gene discovery.
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http://dx.doi.org/10.1016/j.jmoldx.2019.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734859PMC
September 2019

Clinical utility of custom-designed NGS panel testing in pediatric tumors.

Genome Med 2019 05 28;11(1):32. Epub 2019 May 28.

Department of Pathology and Laboratory Medicine, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.

Background: Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers.

Methods: Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed.

Results: NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration.

Conclusions: Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.
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http://dx.doi.org/10.1186/s13073-019-0644-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537185PMC
May 2019

Overgrowth Syndromes Caused by Somatic Variants in the Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Pathway.

J Mol Diagn 2017 07 11;19(4):487-497. Epub 2017 May 11.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Somatic variants have been well described in tumorigenesis; however, they are only recently appreciated in other human disorders, such as mosaic overgrowth syndromes. Although overgrowth is a manifestation in many genetic syndromes, not all overgrowth syndromes are inherited. Mosaic somatic variants have been lately described in several overgrowth disorders, such as Proteus syndrome, CLOVES (congenital, lipomatous, overgrowth, vascular malformations, epidermal nevi, and spinal/skeletal anomalies and/or scoliosis) syndrome, and megalencephalyepolymicrogyria-polydactyly-hydrocephalus syndrome. These syndromes are caused by somatic variants in the genes associated with the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway, resulting in a spectrum of overgrowth syndromes with overlapping features that could be difficult to distinguish based on phenotypic presentations alone. In addition, Sanger sequencing is ineffective for the detection of a causal variant because of the mosaic nature of these variants, whereas targeted next-generation sequencing technology offers a deeper sequencing coverage and allows the detection of low-level mosaicism. Recent studies have shown that the causal variants are only present in the affected tissues in most cases, and can be enriched by in vitro tissue culture. In this review, we describe several mosaic somatic overgrowth syndromes caused by variants in genes of the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin signaling pathway, their phenotypic and molecular spectrum, and the clinical utility of next-generation sequencing technology in the diagnosis of these disorders.
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http://dx.doi.org/10.1016/j.jmoldx.2017.04.001DOI Listing
July 2017

Molecular Diagnosis of Mosaic Overgrowth Syndromes Using a Custom-Designed Next-Generation Sequencing Panel.

J Mol Diagn 2017 07 11;19(4):613-624. Epub 2017 May 11.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas. Electronic address:

Recent studies have discovered a group of overgrowth syndromes, such as congenital lipomatous overgrowth with vascular, epidermal, and skeletal anomalies (CLOVES) syndrome, Proteus syndrome, and megalencephaly-capillary malformation-polymicrogyria (MCAP) syndrome, are caused by somatic activating variants in genes involved in the phosphatidylinositol 3-kinase/AKT/mechanistic target of rapamycin pathway. Because of the low-abundance nature of these variants, Sanger sequencing often yields negative results. We have developed and validated a next-generation sequencing (NGS) panel that targets all known variants associated with these syndromes. Fifty cases, including two prenatal cases, were tested using the panel. A pathogenic variant in the PIK3CA, PIK3R2, or AKT1 gene was identified in 28 of the 50 cases with the variant allele frequencies ranging from 1.0% to 49.2%. These variants were only present in the affected tissues in most of the cases, demonstrating a causal role in the development of these diseases. In vitro cell culture showed significant enrichment of the cells harboring variant alleles, suggesting that these variants render growth advantages to mutant cells. Phenotype-genotype correlation analysis showed PIK3CA mutation hotspots at residues E542, E545, and H1047 are often associated with CLOVES syndrome, whereas PIK3CA G914R is preferentially related to MCAP. We thus demonstrate that NGS technology is highly sensitive for detecting low-level mosaicism and can facilitate clinical diagnosis of mosaic overgrowth syndromes in both prenatal and postnatal settings.
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http://dx.doi.org/10.1016/j.jmoldx.2017.04.006DOI Listing
July 2017

The Genomic Era of Clinical Oncology: Integrated Genomic Analysis for Precision Cancer Care.

Cytogenet Genome Res 2016 22;150(3-4):162-175. Epub 2016 Dec 22.

Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Genomic alterations are important biological markers for cancer diagnosis and prognosis, disease classification, risk stratification, and treatment selection. Chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) technologies are superb new tools for evaluating cancer genomes. These state-of-the-art technologies offer high-throughput, highly accurate, targeted and whole-genome evaluation of genomic alterations in tumor tissues. The application of CMA and NGS technologies in cancer research has generated a wealth of useful information about the landscape of genomic alterations in cancer and their implications in cancer care. As the knowledge base in cancer genomics and genome biology grows, the focus of research is now shifting toward the clinical applications of these technologies to improve patient care. Although not yet standard of care in cancer, there is an increasing interest among the cancer genomics communities in applying these new technologies to cancer diagnosis in the Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. Many clinical laboratories have already started adopting these technologies for cancer genomic analysis. We anticipate that CMA and NGS will soon become the major diagnostic means for cancer genomic analysis to meet the increasing demands of precision cancer care.
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http://dx.doi.org/10.1159/000454655DOI Listing
April 2017

Levels and Profiles of Polybrominated Diphenyl Ethers in Breast Milk During Different Nursing Durations.

Bull Environ Contam Toxicol 2016 Oct 23;97(4):510-6. Epub 2016 Aug 23.

Hebei Provincial Center for Disease Control and Prevention, Shijiazhuang, 050021, People's Republic of China.

Eight PBDE congeners, BDE-28, 47, 99, 100, 153, 154, 183 and 209, were measured using gas chromatography coupled to mass spectrometry. The concentrations of Σ8PBDEs ranged from 0.04 to 19.93 ng g(-1) lipid weight (lw), with median and mean value of 1.21 and 2.72 ng g(-1) lw. PBDE congeners were detected in approximately 90 % of samples with BDE-209 as the dominant one. No significant correlations were found between the mothers' age, body mass index and PBDEs concentrations. We estimated the infant's dietary intake of the studied PBDEs via human milk during different nursing durations, and found that babies younger than 1 month might take a relatively higher body burden of PBDEs. The median levels of Σ8PBDEs were 0.74, 2.80, 2.43 and 0.90 ng g(-1) lw in colostrum, milk sampled at 1, 3 and 6 months after birth, respectively. High consumption of animal-origin food after birth may lead to the elevated ΣPBDEs concentrations in breast milk. A rational nutrition deployment is essential for postpartum mother.
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http://dx.doi.org/10.1007/s00128-016-1908-2DOI Listing
October 2016

Occurrence of deoxynivalenol in wheat, Hebei Province, China.

Food Chem 2016 Apr 11;197 Pt B:1271-4. Epub 2015 Nov 11.

Hebei Provincial Center for Disease Control and Prevention, Shijiazhuang 050021, PR China. Electronic address:

Analysis of deoxynivalenol (DON) and its metabolites 3-acetyl and 15-acetyldeoxynivalenol (3-ADON and 15-ADON) in wheat flour samples by liquid chromatography-tandem mass spectrometry (LC/MS/MS) during 2011-2013 was conducted. [(13)C15]-DON was used as the internal standard to accomplish as accurate as possible quantitation. Of all wheat samples (n=672), 91.5% were positive for DON, at levels ranging from 2.4 to 1130 μg/kg, with a median value of 154 μg/kg. The DON derivatives (3-Ac-DON, 15-Ac-DON) were far less frequently found and at lower levels than DON. The probable daily intakes (PDI) of DON (0.49 in 2011; 0.86 in 2012; 0.56 in 2013, expressed as μg/kg body weight/day) were all within the PDI of 1.0 μg/kg of bw/day for DON set by Scientific Committee for Food (SCF) in 2002. Still, persistent monitoring of DON is important.
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http://dx.doi.org/10.1016/j.foodchem.2015.11.047DOI Listing
April 2016

Survey of 11 mycotoxins in wheat flour in Hebei province, China.

Food Addit Contam Part B Surveill 2015 24;8(4):250-4. Epub 2015 Aug 24.

a Institute of Physical and Chemical Inspection, Hebei Provincial Center for Disease Control and Prevention , Shijiazhuang , PR China.

A survey of 11 mycotoxins in 348 wheat flour samples marketed in Hebei province of China were analysed by liquid chromatography-tandem mass spectrometry, was carried out. The selected mycotoxins consisted of four aflatoxins (AFs: AFB1, AFB2, AFG1 and AFG2) and seven Fusarium toxins, i.e. deoxynivalenol (DON), nivalenol, 3-acetyldeoxynivalenol and 15-acetyldeoxynivalenol, zearalenone, Fusarenon-X and deoxynivalenol-3-glucoside. Results indicated that most of the wheat samples analysed were contaminated with mycotoxins. Wheat was most susceptible to DON (91.4% contamination), with a mean level of 240 μg kg(-1). On average the probable daily intake (PDI, expressed as µg kg(-1) body weight day(-1)) of mycotoxins was within the provisional maximum tolerable daily intake (PMTDI, 2.0 µg kg(-1) of body weight day(-1)) as set by the Joint FAO/WHO Expert Committee on Food Additives. Nevertheless, exposure assessment revealed that the maximum PDI of mycotoxins was 4.06 µg kg(-1) body weight day(-1), which was twice the PMTDI value. Thus, consistent monitoring is recommended, as to keep the contamination level under control.
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http://dx.doi.org/10.1080/19393210.2015.1074291DOI Listing
August 2016

2-acetyl-4-tetrahydroxybutylimidazole and 4-methylimidazole in caramel colours, vinegar and beverages in China.

Food Addit Contam Part B Surveill 2015 8;8(3):163-8. Epub 2015 May 8.

a Hebei Provincial Center for Disease Control and Prevention , Shijiazhuang , China.

A survey of 2-acetyl-4-tetrahydroxybutylimidazole (THI) and 4-methylimidazole (4-MeI) concentrations in caramel colours, vinegar and beverages from the Chinese market were performed by ultrahigh-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). In total, 117 samples, 78 caramel colour samples, 23 vinegar samples and 16 beverage samples, were investigated. The results indicated that 4-MeI was found in all samples. THI was found in a part of the samples and also the level range was lower compared to 4-MeI. In caramel colour samples, the concentration level range of THI was 1.0-74.3 mg/kg and of 4-MeI was 1.5-1291.8 mg/kg. In vinegar samples, the concentration level range of THI was 13.3-119.2 µg/L and for 4-MeI 111.2-2077.8 µg/L. In beverage samples, THI was only found in two samples and the concentration level range of 4-MeI was 10.8-307.1 µg/L. THI and 4-MeI levels in vinegar and beverages were rather low compared with those in caramel colour samples. These observations can be helpful for evaluating individual exposure to THI and 4-MeI from caramel colours, vinegar and beverages in China.
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http://dx.doi.org/10.1080/19393210.2015.1027286DOI Listing
May 2016

Prenatal diagnosis of CLOVES syndrome confirmed by detection of a mosaic PIK3CA mutation in cultured amniocytes.

Am J Med Genet A 2014 Oct 14;164A(10):2633-7. Epub 2014 Jul 14.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.

Congenital lipomatous asymmetric overgrowth of the trunk, lymphatic, capillary, venous, and combined-type vascular malformations, epidermal nevi, skeletal and spinal anomalies (CLOVES) syndrome, a segmental overgrowth syndrome, is caused by post zygotic somatic mutations in PIK3CA, a gene involved in the receptor tyrosine kinase phosphatidylinositol 3-kinase (PI3)-AKT growth-signaling pathway. Prenatal ultrasound findings of lymphovascular malformations, segmental overgrowth and skeletal defects can raise suspicion for CLOVES syndrome, but molecular confirmation of PIK3CA mutations on prenatally obtained samples is challenging because of somatic mosaicism. We detected a mosaic disease-causing mutation in PIK3CA by sequencing of DNA extracted from cultured amniotic cells, but not from DNA directly prepared from an amniotic fluid sample in a fetus with prenatally suspected CLOVES syndrome. The infant was born prematurely and displayed severe lymphovascular malformations and segmental overgrowth consistent with a clinical diagnosis of CLOVES syndrome; he passed away at 29 days of life. We discuss the complexities and limitations of genetic testing for somatic mosaic mutations in the prenatal period and highlight the potential need for multiple approaches to arrive at a molecular diagnosis. © 2014 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.36672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496426PMC
October 2014

Clinical application of amplicon-based next-generation sequencing in cancer.

Cancer Genet 2013 Dec 11;206(12):413-9. Epub 2013 Oct 11.

Department of Molecular and Human Genetics, Dan Duncan Cancer Center, Baylor College of Medicine, Houston, TX. Electronic address:

Next-generation sequencing (NGS) technology has revolutionized genomic research by decreasing the cost of sequencing while increasing the throughput. The focus now is on potential clinical applications of NGS technology for diagnostics and therapeutics. Clinical applications of NGS in cancer can detect clinically actionable genetic/genomic alterations that are critical for cancer care. These alterations can be of diagnostic, prognostic, or therapeutic significance. In certain cancers, patient risk and prognosis can be predicted based on the mutation profile identified by NGS. Many targeted therapies have been developed for cancer patients who bear specific mutations; however, choosing the right NGS technique for the appropriate clinical application can be challenging, especially in clinical oncology, where the material for NGS tests is often limited and the turnaround time (TAT) for cancer tests is constrained to a few days. Currently, amplicon-based NGS approaches have emerged as the best fit for clinical oncology. In this review, we focus on amplicon-based library preparation, sequencing, sequence data alignment and annotation, and post-analytic interpretation and reporting.
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http://dx.doi.org/10.1016/j.cancergen.2013.10.003DOI Listing
December 2013

Tumor necrosis factor receptor 1 functions as a tumor suppressor.

Am J Physiol Gastrointest Liver Physiol 2012 Jan 3;302(2):G195-206. Epub 2011 Nov 3.

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Tulane University School of Medicine, New Orleans, LA 70112, USA.

Tumor necrosis factor (TNF) is a key player in inflammatory bowel disease and has been variably associated with carcinogenesis, but details of the cross talk between inflammatory and tumorigenic pathways remain incompletely understood. It has been shown that, in C57BL/6 mice, signaling via TNF receptor 1 (TNFR1) is protective from injury and inflammation in experimental colitis. Therefore, we hypothesized that loss of TNFR1 signaling would confer increased risk of developing colitis-associated carcinoma. Using three models of murine tumorigenesis based on repeated bouts of inflammation or systemic tumor initiator, we sought to determine the roles of TNF and TNFR1 with regard to neoplastic transformation in the colon in wild-type (WT), TNFR1 knockout (R1KO), and TNF knockout (TNFKO) mice. We found R1KO animals to have more severe disease, as defined by weight loss, hematochezia, and histology. TNFKO mice demonstrated less weight loss but were consistently smaller, and rates and duration of hematochezia were comparable to WT mice. Histological inflammation scores were higher and neoplastic lesions occurred more frequently and earlier in R1KO mice. Apoptosis is not affected in R1KO mice although epithelial proliferation following injury is more ardent even before tumorigenesis is apparent. Lastly, there is earlier and more intense expression of activated β-catenin in these mice, implying a connection between TNFR1 and Wnt signaling. Taken together, these findings show that in the context of colitis-associated carcinogenesis TNFR1 functions as a tumor suppressor, exerting this effect not via apoptosis but by modulating activation of β-catenin and controlling epithelial proliferation.
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http://dx.doi.org/10.1152/ajpgi.00209.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3341116PMC
January 2012

The importance of and a method for including transfection efficiency into real-time PCR data analyses.

Biotechnol Bioeng 2008 Jul;100(4):765-72

Laboratory for Gene Therapy and Cellular Engineering, Department of Chemical & Biomolecular Engineering, Tulane University, 6823 St. Charles Ave., 300 Lindy Boggs Center, New Orleans, Louisiana 70118, USA.

The polymerase chain reaction (PCR) is widely used to ascertain absolute or relative changes in the expression levels of specific genes as a function of cell type or in response to changes in environmental stimuli. Real-time PCR is an advance which allows for the analysis of gene expression over a wide range of initial cDNA concentrations, where the cDNA is the product of reverse transcriptase reactions applied to RNA samples. With the advent and advances in gene delivery technologies, it is now common for the cellular responses under scrutiny to be initiated via the expression of an exogenously delivered gene. When transfection (or transduction) is a part of the procedure used to prepare cell samples for real-time PCR, it is necessary to take the efficiency of gene delivery into account. Here a robust mathematical model for such analyses is derived, and validated with theoretical and experimental support. Comparison to existing analysis methods is presented to demonstrate the high significance of noting transfection, loading, and primer PCR efficiencies when processing PCR data.
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http://dx.doi.org/10.1002/bit.21811DOI Listing
July 2008

Natural variation in Arabidopsis thaliana as a tool for highlighting differential drought responses.

PLoS One 2008 Feb 27;3(2):e1705. Epub 2008 Feb 27.

Station de Génétique et d'Amélioration des plantes, Institut Scientifique de Recherche Agronomique (INRA), Versailles, France.

To test whether natural variation in Arabidopsis could be used to dissect out the genetic basis of responses to drought stress, we characterised a number of accessions. Most of the accessions belong to a core collection that was shown to maximise the genetic diversity captured for a given number of individual accessions in Arabidopsis thaliana. We measured total leaf area (TLA), Electrolyte Leakage (EL), Relative Water Content (RWC), and Cut Rosette Water Loss (CRWL) in control and mild water deficit conditions. A Principal Component Analysis revealed which traits explain most of the variation and showed that some accessions behave differently compared to the others in drought conditions, these included Ita-0, Cvi-0 and Shahdara. This study relied on genetic variation found naturally within the species, in which populations are assumed to be adapted to their environment. Overall, Arabidopsis thaliana showed interesting phenotypic variations in response to mild water deficit that can be exploited to identify genes and alleles important for this complex trait.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0001705PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2246160PMC
February 2008

Changes in DNA base sequences in the mutant of Arabidopsis thaliana induced by low-energy N(+) implantation.

Sci China C Life Sci 2003 Oct;46(5):503-12

Institute of Botany, Chinese Academy of Sciences, Beijing, China.

To reveal the mutation effect of low-energy ion implantation on Ambidopsis thaliana in vivo, T80II, a stable dwarf mutant, derived from the seeds irradiated by 30 keV N(+) with the dose of 80 X 10(15) ions/cm(2) was used for Random Amplified Polymorphic DNA (RAPD) and base sequence analysis. The results indicated that among total 397 RAPD bands observed, 52 bands in T80II were different from those of wild type showing a variation frequency 13.1%. In comparison with the sequences of A. thaliana in GenBank, the RAPD fragments in T80II were changed greatly in base sequences with an average rate of one base change per 16.8 bases. The types of base changes included base transition, transversion, deletion and insertion. Among the 275 base changes detected, single base substitutions (97.09%) occurred more frequently than base deletions and insertions (2.91%). And the frequency of base transitions (66.55%) was higher than that of base transversions (30.55%). Adenine, thymine, guanine or cytosine could be replaced by any of other three bases in cloned DNA fragments in T80II. It seems that thymine was more sensitive to the irradiation than other bases. The flanking sequences of the base changes in RAPD fragments in T80II were analyzed and the mutational "hotspot" induced by low-energy ion implantation was discussed.
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http://dx.doi.org/10.1360/02yc0177DOI Listing
October 2003