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Min-Han Tan

Bio: Min-Han Tan is an academic researcher from Agency for Science, Technology and Research. The author has contributed to research in topics: Cancer & Renal cell carcinoma. The author has an hindex of 40, co-authored 173 publications receiving 8967 citations. Previous affiliations of Min-Han Tan include Singapore General Hospital & National Center for Charitable Statistics.


Papers
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Journal ArticleDOI
08 Mar 2007-Nature
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

Journal ArticleDOI
TL;DR: The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis.
Abstract: Summary Background The International Metastatic Renal-Cell Carcinoma Database Consortium model offers prognostic information for patients with metastatic renal-cell carcinoma. We tested the accuracy of the model in an external population and compared it with other prognostic models. Methods We included patients with metastatic renal-cell carcinoma who were treated with first-line VEGF-targeted treatment at 13 international cancer centres and who were registered in the Consortium's database but had not contributed to the initial development of the Consortium Database model. The primary endpoint was overall survival. We compared the Database Consortium model with the Cleveland Clinic Foundation (CCF) model, the International Kidney Cancer Working Group (IKCWG) model, the French model, and the Memorial Sloan-Kettering Cancer Center (MSKCC) model by concordance indices and other measures of model fit. Findings Overall, 1028 patients were included in this study, of whom 849 had complete data to assess the Database Consortium model. Median overall survival was 18·8 months (95% 17·6–21·4). The predefined Database Consortium risk factors (anaemia, thrombocytosis, neutrophilia, hypercalcaemia, Karnofsky performance status Interpretation The Database Consortium model is now externally validated and can be applied to stratify patients by risk in clinical trials and to counsel patients about prognosis. Funding None.

751 citations

Journal ArticleDOI
TL;DR: Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations, and a comprehensive approach is proposed to surveillance of patients withPTEN mutations.
Abstract: Purpose: Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN hamartoma tumor syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biologic insights on human germline PTEN mutations, and to better inform current surveillance recommendations on the basis of expert opinion. Experimental Design: A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype–phenotype analyses were carried out. Results: Elevated SIRs were found for carcinomas of the breast [25.4, 95% confidence interval (CI), 19.8–32.0], thyroid (51.1, 38.1–67.1), endometrium (42.9, 28.1–62.8), colorectum (10.3, 5.6–17.4), kidney (30.6, 17.8–49.4), and melanoma (8.5, 4.1–15.6). Estimated lifetime risks were, respectively, 85.2% (95% CI, 71.4%–99.1%), 35.2% (19.7%–50.7%), 28.2% (17.1%–39.3%), 9.0% (3.8%–14.1%), 33.6% (10.4%–56.9%), and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, whereas colorectal cancer was associated with nonsense mutations. Conclusion: Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations. The genotype–phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations. Clin Cancer Res; 18(2); 400–7. ©2012 AACR .

711 citations

Journal ArticleDOI
TL;DR: It is identified that fumarate can directly up-regulate antioxidant response element (ARE)-controlled genes and is up-regulated upon FH knockdown as well as in FH null cell lines, and AKR1B10 overexpression is also a prominent feature in both hereditary and sporadic PRCC2.

347 citations

Journal ArticleDOI
TL;DR: The first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing is presented, further supported biologically by protein correlation.
Abstract: Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score—the Cleveland Clinic (CC) score—resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.

328 citations


Cited by
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Journal ArticleDOI
Michael S. Lawrence1, Petar Stojanov1, Petar Stojanov2, Paz Polak1, Paz Polak2, Paz Polak3, Gregory V. Kryukov1, Gregory V. Kryukov3, Gregory V. Kryukov2, Kristian Cibulskis1, Andrey Sivachenko1, Scott L. Carter1, Chip Stewart1, Craig H. Mermel2, Craig H. Mermel1, Steven A. Roberts4, Adam Kiezun1, Peter S. Hammerman2, Peter S. Hammerman1, Aaron McKenna5, Aaron McKenna1, Yotam Drier, Lihua Zou1, Alex H. Ramos1, Trevor J. Pugh1, Trevor J. Pugh2, Nicolas Stransky1, Elena Helman6, Elena Helman1, Jaegil Kim1, Carrie Sougnez1, Lauren Ambrogio1, Elizabeth Nickerson1, Erica Shefler1, Maria L. Cortes1, Daniel Auclair1, Gordon Saksena1, Douglas Voet1, Michael S. Noble1, Daniel DiCara1, Pei Lin1, Lee Lichtenstein1, David I. Heiman1, Timothy Fennell1, Marcin Imielinski1, Marcin Imielinski2, Bryan Hernandez1, Eran Hodis2, Eran Hodis1, Sylvan C. Baca1, Sylvan C. Baca2, Austin M. Dulak1, Austin M. Dulak2, Jens G. Lohr2, Jens G. Lohr1, Dan A. Landau7, Dan A. Landau2, Dan A. Landau1, Catherine J. Wu2, Jorge Melendez-Zajgla, Alfredo Hidalgo-Miranda, Amnon Koren2, Amnon Koren1, Steven A. McCarroll2, Steven A. McCarroll1, Jaume Mora8, Ryan S. Lee2, Ryan S. Lee9, Brian D. Crompton2, Brian D. Crompton9, Robert C. Onofrio1, Melissa Parkin1, Wendy Winckler1, Kristin G. Ardlie1, Stacey Gabriel1, Charles W. M. Roberts9, Charles W. M. Roberts2, Jaclyn A. Biegel10, Kimberly Stegmaier1, Kimberly Stegmaier2, Kimberly Stegmaier9, Adam J. Bass1, Adam J. Bass2, Levi A. Garraway1, Levi A. Garraway2, Matthew Meyerson1, Matthew Meyerson2, Todd R. Golub, Dmitry A. Gordenin4, Shamil R. Sunyaev3, Shamil R. Sunyaev2, Shamil R. Sunyaev1, Eric S. Lander6, Eric S. Lander2, Eric S. Lander1, Gad Getz1, Gad Getz2 
11 Jul 2013-Nature
TL;DR: A fundamental problem with cancer genome studies is described: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds and the list includes many implausible genes, suggesting extensive false-positive findings that overshadow true driver events.
Abstract: Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.

4,411 citations

Journal ArticleDOI
TL;DR: Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients.
Abstract: Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

3,399 citations

Journal ArticleDOI
TL;DR: Analysis of genomic and clinical outcome data from 218 prostate cancer tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score.

3,310 citations

Journal ArticleDOI
09 Apr 2009-Nature
TL;DR: This work has shown that the complete DNA sequence of large numbers of cancer genomes will be possible to obtain and will provide a detailed and comprehensive perspective on how individual cancers have developed.
Abstract: All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells. Over the past quarter of a century much has been learnt about these mutations and the abnormal genes that operate in human cancers. We are now, however, moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes. These studies will provide us with a detailed and comprehensive perspective on how individual cancers have developed.

3,156 citations