Institution
Fred Hutchinson Cancer Research Center
Nonprofit•Cape Town, South Africa•
About: Fred Hutchinson Cancer Research Center is a nonprofit organization based out in Cape Town, South Africa. It is known for research contribution in the topics: Population & Transplantation. The organization has 12322 authors who have published 30954 publications receiving 2288772 citations. The organization is also known as: Fred Hutch & The Hutch.
Topics: Population, Transplantation, Cancer, Breast cancer, Prostate cancer
Papers published on a yearly basis
Papers
More filters
••
TL;DR: Risk of HPV-associated cancers was elevated among persons with AIDS and increased with increasing immunosuppression and the increasing incidence for anal cancer during 1996-2004 indicates that prolonged survival may be associated with increased risk of certain HPV- associated cancers.
Abstract: Results Among persons with AIDS, we observed statistically significantly elevated risk of all HPV-associated in situ (SIRs ranged from 8.9, 95% CI = 8.0 to 9.9, for cervical cancer to 68.6, 95% CI = 59.7 to 78.4, for anal cancer among men) and invasive (SIRs ranged from 1.6, 95% CI = 1.2 to 2.1, for oropharyngeal cancer to 34.6, 95% CI = 30.8 to 38.8, for anal cancer among men) cancers. During 1996 – 2004, low CD4 T-cell count was associated with statistically significantly increased risk of invasive anal cancer among men (relative risk [RR] per decline of 100 CD4 T cells per cubic millimeter = 1.34, 95% CI = 1.08 to 1.66, P = .006) and non – statistically significantly increased risk of in situ vagina or vulva cancer (RR = 1.52, 95% CI = 0.99 to 2.35, P = .055) and of invasive cervical cancer (RR = 1.32, 95% CI = 0.96 to 1.80, P = .077). Among men, incidence (per 100 000 person-years) of in situ and invasive anal cancer was statistically significantly higher during 1996 – 2004 than during 1990 – 1995 (61% increase for in situ cancers, 18.3 cases vs 29.5 cases, respectively; RR = 1.71, 95% CI = 1.24 to 2.35, P < .001; and 104% increase for invasive cancers, 20.7 cases vs 42.3 cases, respectively; RR = 2.03, 95% CI = 1.54 to 2.68, P < .001). Incidence of other cancers was stable over time. Conclusions Risk of HPV-associated cancers was elevated among persons with AIDS and increased with increasing immunosuppression. The increasing incidence for anal cancer during 1996 – 2004 indicates that prolonged survival may be associated with increased risk of certain HPV-associated cancers.
432 citations
••
TL;DR: Southern hybridization data provide evidence for a cell cycle-dependent change in telomere structure and demonstrate that TG1-3 tails, generated during replication of a linear plasmid in vivo, are capable of mediating telomeres-telomere interactions.
431 citations
••
Harvard University1, University of South Florida2, University of Southern California3, University College London4, German Cancer Research Center5, Baylor College of Medicine6, Fred Hutchinson Cancer Research Center7, Translational Genomics Research Institute8, Medical College of Wisconsin9, University of Oslo10, University of Cambridge11
TL;DR: In this article, the authors propose principles for the initial functional characterization of cancer risk loci, with a focus on non-coding variants, and define post-GWAS functional characterization.
Abstract: Genome wide association studies (GWAS) have identified more than 200 mostly new common low-penetrance susceptibility loci for cancers. The predicted risk associated with each locus is generally modest (with a per-allele odds ratio typically less than 2) and so, presumably, are the functional effects of individual genetic variants conferring disease susceptibility. Perhaps the greatest challenge in the ‘post-GWAS’ era is to understand the functional consequences of these loci. Biological insights can then be translated to clinical benefits, including reliable biomarkers and effective strategies for screening and disease prevention. The purpose of this article is to propose principles for the initial functional characterization of cancer risk loci, with a focus on non-coding variants, and to define ‘post-GWAS’ functional characterization.
By December 2010, there were 1,212 published GWAS studies1 reporting significant (P < 5 × 10−8) associations for 210 traits (Table 1), and the Catalog of Published GWAS states that by March 2011, 812 publications reported 3,977 SNP associations1. This is likely a small fraction of the common susceptibility loci of low penetrance that will eventually be identified. Despite these successes in identifying risk loci, the causal variant and/or the molecular basis of risk etiology has been determined for only a small fraction of these associations2–4. Plausible candidate genes can be based on proximity to risk loci, but few have so far been defined in a more systematic manner (Supplementary Table 1).
Table 1
The genomic context in which a variant is found can be used as preliminary functional analysis
Increased investment in post-GWAS functional characterization of risk loci5 has now been advocated across diseases and for cardiovascular disease and diabetes6. For cancer biology, the complex interplay between genetics and the environment in many cancers poses a particularly exciting challenge for post-GWAS research. Here we suggest a systematic strategy for understanding how cancer-associated variants exert their effects. We mostly refer to SNPs throughout the paper, but we recognize that other types of common genetic (for example, copy number variants) or epigenetic variation may influence risk.
Our understanding of the way in which a risk variant initiates disease pathogenesis progresses from statistical association between genetic variation and trait or disease variation to functionality and causality. The functional consequences of variants in protein-coding regions causing most monogenic disorders are more readily interpreted because we know the genetic code. For non-Mendelian or multifactorial traits, most of the common DNA variants have so far mapped to non-protein–coding regions2, where our understanding of functional consequences and causality is more rudimentary.
Our hypothesis is that the trait-associated alleles exert their effects by influencing transcriptional output (such as transcript levels and splicing) through multiple mechanisms. We emphasize appropriate assays and models to test the functional effects of both SNPs and genes mapping to cancer predisposition loci. Although much of what is written is applicable to alleles discovered for any trait, the section on modeling gene effects will emphasize measuring cancer-related phenotypes.
At some loci, multiple, independently associated risk alleles rather than single risk alleles may be functionally responsible for the occurrence of disease. Genotyping susceptibility loci (and their correlated variants) in multiple populations with different linkage disequilibrium (LD) structures may prove effective in substantially reducing the number of potentially causative variants (that is, the same causal variant may segregate in multiple populations), as shown for the FGFR2 locus in breast cancer7, but for most loci there will remain a set of potentially causative variants that cannot be separated at the statistical level from case-control genotype data.
A susceptibility locus should be re-sequenced to ascertain all genetic variation, identifying candidate functional or causal variants and identifying candidate causal genes. Ideally, the identification of a causal SNP would be the next step to reveal the molecular mechanisms of risk modification. Practically, however, it is unclear what the criteria for causality should be, particularly in non-protein–coding regions. Thus, although we propose a framework set of analyses (Box 1), we acknowledge that the techniques and methods will continue to evolve with the field.
Box 1
Strategies to progress from tag SNP to mechanism
Target resequencing efforts using linkage disequilibrium (LD) structure.
Use other populations to refine LD regions (for example African ancestry with shorter LD and more heterogeneity).
Determine expression levels of nearby genes as a function of genotype at each locus (eQTL).
Characterize gene regulatory regions by multiple empirical techniques bearing in mind that these are tissue and context specific.
Combine regulatory regions with risk loci using coordinates from multiple reference genomes to capture all variation within the shorter regulatory regions that correlates with the tag SNP at each locus.
Multiple experimental manipulations in model systems are needed to progressively implicate transcription units (genes) in mechanisms relevant to the associated loci:
Knockouts of regulatory regions in animal (difficult and may be limited by functional redundancy, but new targeting methods in rat are promising) models followed by genome-wide expression analysis.
Use chromatin association methods (3C, CHIA-PET) of regulatory regions to determine the identity of target genes (compare with eQTL data).
Targeted gene perturbations in somatic cell models.
Explore fully genome-wide eQTL and miRNA quantitative variation correlation in relevant tissues and cells.
Explore epigenetic mechanisms in the context of genome-wide genetic polymorphism.
Employ cell models and tissue reconstructions to evaluate mechanisms using gene perturbations and polymorphic variants. The human cancer cell xenograft has re-emerged as a minimal in vivo validation of these models.
Above all, resist the temptation to equate any partial functional evidence as sufficient. Published claims of functional relevance should be fully evaluated using the steps detailed above.
431 citations
••
Memorial Sloan Kettering Cancer Center1, Keio University2, Beth Israel Deaconess Medical Center3, Mount Sinai Hospital4, Yale University5, Fox Chase Cancer Center6, New Generation University College7, University of Chicago8, New York University9, Imperial College London10, Radboud University Nijmegen11, University of Barcelona12, Peter MacCallum Cancer Centre13, University of Michigan14, University of São Paulo15, Fred Hutchinson Cancer Research Center16, University of Duisburg-Essen17, Northern General Hospital18, University of Caen Lower Normandy19, Churchill Hospital20, Queen's University21, University of Sydney22, Sungkyunkwan University23, Seoul National University24, Kyorin University25, University of Copenhagen26, Nippon Medical School27, Katholieke Universiteit Leuven28, British Hospital29, University of Texas MD Anderson Cancer Center30, University of Antwerp31, Hyogo College of Medicine32, University of Western Australia33, Glenfield Hospital34, Cleveland Clinic35, Icahn School of Medicine at Mount Sinai36, University of Turin37, Université libre de Bruxelles38, Juntendo University39, National Cancer Research Institute40, Mayo Clinic41, Princess Margaret Cancer Centre42, Sinai Grace Hospital43, Netherlands Cancer Institute44, Hiroshima University45, City of Hope National Medical Center46, Georgetown University47, University of Tokushima48, University of Pisa49, Osaka University50
TL;DR: Codes for the primary tumor categories of AIS and minimally invasive adenocarcinoma (MIA) and a uniform way to measure tumor size in part‐solid tumors for the eighth edition of the tumor, node, and metastasis classification of lung cancer are proposed.
431 citations
••
TL;DR: This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.
Abstract: Current strategies for the immunotherapy of melanoma include augmentation of the immune response to tumor antigens represented by melanosomal proteins such as tyrosinase, gp100, and MART-1. The possibility that intentional targeting of tumor antigens representing normal proteins can result in autoimmune toxicity has been postulated but never demonstrated previously in humans. In this study, we describe a patient with metastatic melanoma who developed inflammatory lesions circumscribing pigmented areas of skin after an infusion of MART-1–specific CD8+ T cell clones. Analysis of the infiltrating lymphocytes in skin and tumor biopsies using T cell–specific peptide–major histocompatibility complex tetramers demonstrated a localized predominance of MART-1–specific CD8+ T cells (>28% of all CD8 T cells) that was identical to the infused clones (as confirmed by sequencing of the complementarity-determining region 3). In contrast to skin biopsies obtained from the patient before T cell infusion, postinfusion biopsies demonstrated loss of MART-1 expression, evidence of melanocyte damage, and the complete absence of melanocytes in affected regions of the skin. This study provides, for the first time, direct evidence in humans that antigen-specific immunotherapy can target not only antigen-positive tumor cells in vivo but also normal tissues expressing the shared tumor antigen.
430 citations
Authors
Showing all 12368 results
Name | H-index | Papers | Citations |
---|---|---|---|
Walter C. Willett | 334 | 2399 | 413322 |
Robert Langer | 281 | 2324 | 326306 |
Meir J. Stampfer | 277 | 1414 | 283776 |
JoAnn E. Manson | 270 | 1819 | 258509 |
David J. Hunter | 213 | 1836 | 207050 |
Peer Bork | 206 | 697 | 245427 |
Eric Boerwinkle | 183 | 1321 | 170971 |
Ruedi Aebersold | 182 | 879 | 141881 |
Bruce M. Psaty | 181 | 1205 | 138244 |
Aaron R. Folsom | 181 | 1118 | 134044 |
David Baker | 173 | 1226 | 109377 |
Frederick W. Alt | 171 | 577 | 95573 |
Lily Yeh Jan | 162 | 467 | 73655 |
Yuh Nung Jan | 162 | 460 | 74818 |
Charles N. Serhan | 158 | 728 | 84810 |