Author
Suet Yi Leung
Other affiliations: University of Missouri, Queen Mary University of London, Chang Gung University ...read more
Bio: Suet Yi Leung is an academic researcher from University of Hong Kong. The author has contributed to research in topics: Cancer & Intercalation (chemistry). The author has an hindex of 68, co-authored 239 publications receiving 32462 citations. Previous affiliations of Suet Yi Leung include University of Missouri & Queen Mary University of London.
Papers published on a yearly basis
Papers
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TL;DR: BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers, with a single substitution (V599E) accounting for 80%.
Abstract: Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.
9,785 citations
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Wellcome Trust Sanger Institute1, European Bioinformatics Institute2, Harvard University3, Ludwig Institute for Cancer Research4, Erasmus University Rotterdam5, University of Pennsylvania6, University of Sydney7, Institute of Cancer Research8, University of Cambridge9, QIMR Berghofer Medical Research Institute10, Van Andel Institute11, University of Hong Kong12
TL;DR: More than 1,000 somatic mutations found in 274 megabases of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers reveal the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
Abstract: Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
2,732 citations
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TL;DR: expression patterns of microRNAs are systematically altered in colon adenocarcinomas and high miR-21 expression is associated with poor survival and poor therapeutic outcome.
Abstract: COLON ADENOCARCINOMA IS A major cause of cancer mortality worldwide1 Colorectal cancer is the third most common and second leading cause of cancer death in the United States2 Even though 5-year mortality rates have modestly declined over the last 3 decades,3 there is still a need to identify new prognostic biomarkers and therapeutic targets for this disease Currently, chemotherapy has significant therapeutic value, but surgery is the only curative form of treatment4
Ideal therapeutic targets should be causally associated with disease and amenable to designing therapeutic interventions, whereas ideal biomarkers should be easy to measure and have strong associations with clinical outcomes MicroRNAs could match both criteria5-8
MicroRNAs are 18- to 25-nucleotide, noncoding RNA molecules that regulate the translation of many genes9 Since their discovery,10,11 microRNAs have been found to regulate a variety of cellular processes including apoptosis,12-14 differentiation,10,11,15 and cell proliferation16 MicroRNAs may also have a causal role in carcinogenesis5,17,18 MicroRNA expression levels are altered in most tumor types,19,20 including colon tumors20-23 Experimental manipulation of specific microRNAs modulates tumor development in mouse-model systems16,24-26 The prognostic potential of microRNAs has also been demonstrated for chronic lymphocytic leukemia,6 lung cancer,7 pancreatic cancer,27 and neuroblastomas28
If aberrant microRNA expression is causal to carcinogenesis, inhibiting specific microRNAs may have therapeutic implications Modified antisense oligonucleotides can easily be designed to specifically inhibit microRNA function29 Antagomirs are one type of antisense oligonucleotide that has proven effective at inhibiting microRNA function in vivo in mice30 The ease of designing specific inhibitors of microRNA function makes them candidates for therapeutic targets
Given the therapeutic and prognostic potential for microRNAs in cancer, we evaluated microRNA profiles of colon tumors and paired nontumorous tissue to study their potential role in tumor formation, diagnosis, and response to chemotherapy in colon carcinoma
1,634 citations
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TL;DR: In a surveillance study for CoV in noncaged animals from the wild areas of the Hong Kong Special Administration Region, a CoV closely related to SARS-CoV is identified from 23 (39%) of 59 anal swabs of wild Chinese horseshoe bats by using RT-PCR and the presence of a 29-bp insertion in ORF 8 of bat-SARS- coV genome suggests that it has a common ancestor with civet SARS -CoV.
Abstract: Although the finding of severe acute respiratory syndrome coronavirus (SARS-CoV) in caged palm civets from live animal markets in China has provided evidence for interspecies transmission in the genesis of the SARS epidemic, subsequent studies suggested that the civet may have served only as an amplification host for SARS-CoV. In a surveillance study for CoV in noncaged animals from the wild areas of the Hong Kong Special Administration Region, we identified a CoV closely related to SARS-CoV (bat-SARS-CoV) from 23 (39%) of 59 anal swabs of wild Chinese horseshoe bats (Rhinolophus sinicus) by using RT-PCR. Sequencing and analysis of three bat-SARS-CoV genomes from samples collected at different dates showed that bat-SARS-CoV is closely related to SARS-CoV from humans and civets. Phylogenetic analysis showed that bat-SARS-CoV formed a distinct cluster with SARS-CoV as group 2b CoV, distantly related to known group 2 CoV. Most differences between the bat-SARS-CoV and SARS-CoV genomes were observed in the spike genes, ORF 3 and ORF 8, which are the regions where most variations also were observed between human and civet SARS-CoV genomes. In addition, the presence of a 29-bp insertion in ORF 8 of bat-SARS-CoV genome, not in most human SARS-CoV genomes, suggests that it has a common ancestor with civet SARS-CoV. Antibody against recombinant bat-SARS-CoV nucleocapsid protein was detected in 84% of Chinese horseshoe bats by using an enzyme immunoassay. Neutralizing antibody to human SARS-CoV also was detected in bats with lower viral loads. Precautions should be exercised in the handling of these animals.
1,419 citations
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TL;DR: It was found that the incidence of gastric cancer development at the population level was similar between participants receiving H pylori eradication treatment and those receiving placebo during a period of 7.5 years in a high-risk region of China.
Abstract: ContextAlthough chronic Helicobacter pylori infection
is associated with gastric cancer, the effect of H pylori treatment on prevention of gastric cancer development in chronic carriers
is unknown.ObjectiveTo determine whether treatment of H pylori infection
reduces the incidence of gastric cancer.Design, Setting, and ParticipantsProspective, randomized, placebo-controlled, population-based primary
prevention study of 1630 healthy carriers of H pylori infection
from Fujian Province, China, recruited in July 1994 and followed up until
January 2002. A total of 988 participants did not have precancerous lesions
(gastric atrophy, intestinal metaplasia, or gastric dysplasia) on study entry.InterventionPatients were randomly assigned to receive H pylori eradication treatment: a 2-week course of omeprazole, 20 mg, a combination
product of amoxicillin and clavulanate potassium, 750 mg, and metronidazole,
400 mg, all twice daily (n = 817); or placebo (n = 813).Main Outcome MeasuresThe primary outcome measure was incidence of gastric cancer during follow-up,
compared between H pylori eradication and placebo
groups. The secondary outcome measure was incidence of gastric cancer in patients
with or without precancerous lesions, compared between the 2 groups.ResultsAmong the 18 new cases of gastric cancers that developed, no overall
reduction was observed in participants who received H pylori eradication treatment (n = 7) compared with those who did not (n =
11) (P = .33). In a subgroup of patients with no
precancerous lesions on presentation, no patient developed gastric cancer
during a follow-up of 7.5 years after H pylori eradication
treatment compared with those who received placebo (0 vs 6; P = .02). Smoking (hazard ratio [HR], 6.2; 95% confidence interval
[CI], 2.3-16.5; P<.001) and older age (HR, 1.10;
95% CI, 1.05-1.15; P<.001) were independent risk
factors for the development of gastric cancer in this cohort.ConclusionsWe found that the incidence of gastric cancer development at the population
level was similar between participants receiving H pylori eradication treatment and those receiving placebo during a period
of 7.5 years in a high-risk region of China. In the subgroup of H pylori carriers without precancerous lesions, eradication of H pylori significantly decreased the development of gastric
cancer. Further studies to investigate the role of H pylori eradication in participants with precancerous lesions are warranted.
1,357 citations
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28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1(PfPMP1)与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员,通过启动转录不同的var基因变异体为抗原变异提供了分子基础。
18,940 citations
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TL;DR: Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends thatclinical molecular genetic testing should be performed in a Clinical Laboratory Improvement Amendments–approved laboratory, with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or the equivalent.
17,834 citations
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TL;DR: It is demonstrated that SARS-CoV-2 uses the SARS -CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming, and it is shown that the sera from convalescent SARS patients cross-neutralized Sars-2-S-driven entry.
15,362 citations
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TL;DR: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
Abstract: BACKGROUND Most patients with non-small-cell lung cancer have no response to the tyrosine kinase inhibitor gefitinib, which targets the epidermal growth factor receptor (EGFR). However, about 10 percent of patients have a rapid and often dramatic clinical response. The molecular mechanisms underlying sensitivity to gefitinib are unknown. METHODS We searched for mutations in the EGFR gene in primary tumors from patients with non-small-cell lung cancer who had a response to gefitinib, those who did not have a response, and those who had not been exposed to gefitinib. The functional consequences of identified mutations were evaluated after the mutant proteins were expressed in cultured cells. RESULTS Somatic mutations were identified in the tyrosine kinase domain of the EGFR gene in eight of nine patients with gefitinib-responsive lung cancer, as compared with none of the seven patients with no response (P<0.001). Mutations were either small, in-frame deletions or amino acid substitutions clustered around the ATP-binding pocket of the tyrosine kinase domain. Similar mutations were detected in tumors from 2 of 25 patients with primary non-small-cell lung cancer who had not been exposed to gefitinib (8 percent). All mutations were heterozygous, and identical mutations were observed in multiple patients, suggesting an additive specific gain of function. In vitro, EGFR mutants demonstrated enhanced tyrosine kinase activity in response to epidermal growth factor and increased sensitivity to inhibition by gefitinib. CONCLUSIONS A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene, which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib. These mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor. Screening for such mutations in lung cancers may identify patients who will have a response to gefitinib.
10,879 citations
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TL;DR: Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
Abstract: Receptor tyrosine kinase genes were sequenced in nonsmall cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene EGFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gefitinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. EGFR mutations were found in additional lung cancer samples from U.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinibinsensitive tumors or cell lines. These results suggest that EGFR mutations may predict sensitivity to gefitinib. Protein kinase activation by somatic mutation or
9,265 citations