Establishment of a Radiogenomics Consortium

TY - JOUR

T1 - Establishment of a Radiogenomics Consortium

AU - West, Catharine

AU - Rosenstein, Barry S.

N1 - Funding Information: Catharine West ∗ ∗ [email protected] Barry S. Rosenstein † On behalf of: Jan Alsner, David Azria, Gillian Barnett, Adrian Begg, Søren Bentzen, Neil Burnet, Jenny Chang-Claude, Eric Chuang, Charlotte Coles, Kim De Ruyck, Dirk De Ruysscher, Alison Dunning, Rebecca Elliott, Laura Fachal, Janet Hall, Karin Haustermans, Carsten Herskind, Tobias Hoelscher, Takashi Imai, Mayumi Iwakawa, Don Jones, Cecilia Kulich on behalf of EQUAL-ESTRO, Jan-Hans Langendijk, Peter O'Neill, Mahmut Ozsahin, Matthew Parliament, Andrzej Polanski, Barry Rosenstein, Daniela Seminara, Paul Symonds, Chris Talbot, Hubert Thierens, Ana Vega, Catharine West, & John Yarnold. ∗ School of Cancer and Imaging Sciences, The University of Manchester, The Chrisite Hospital, Wilmslow Road, Withington, Manchester, M20 4BX, United Kingdom † Department of Radiation Oncology, Mount Sinai School of Medicine, New York, NY ∗ Reprint requests to: Catharine West, School of Cancer and Imaging Sciences, The University of Manchester, The Chrisite Hospital, Wilmslow Road, Withington, Manchester, M20 4BX, United Kingdom A Radiogenomics Consortium was established in Manchester, United Kingdom, November 17 and 18, 2009, in conjunction with the 15th L. H. Gray Workshop with investigators from throughout the world participating in the conference. The unifying interest of these researchers is the identification of genetic variants, primarily single nucleotide polymorphisms (SNPs), associated with the development of normal tissue toxicities resulting from radiation therapy. There are two overall goals for this field of research. The first is to develop an assay capable of predicting which cancer patients are most likely to develop radiation injuries resulting from treatment with a standard radiotherapy protocol. The second aim is to obtain information to assist with the elucidation of the molecular pathways responsible for radiation-induced normal tissue toxicities through identification of genes possessing SNPs associated with the development of radiation-induced adverse effects. The workshop included radiation biologists, radiation oncologists, epidemiologists, and geneticists. As this effort continues, it is anticipated that individuals with expertise in radiation physics, statistics, and bioinformatics will also play a critical role in the consortium. The group was brought together by a long-standing interest to understand the variability in the susceptibility of cancer patients for the development of adverse effects following radiation therapy. It has been known for many years that patients vary in their sensitivity to radiation and that genetics plays an important role influencing this variation. In the 1990s, radiation biologists examined various endpoints to serve as the basis for an assay to predict radiosensitivity, but no consistent finding emerged for any of the assays (1) . Toward the end of that decade, interest increasingly focused on investigating genetic variation. Common SNPs form a major, easily assayable source of genetic variability between individuals. An SNP begins as a single base change (point mutation) in an individual, which if not deleterious may become prevalent in a population. A base change observed in at least 1% of a population is termed SNP, with less prevalent alternations usually referred to as “rare variants.” It should also be noted that copy number variants, which are also being examined in ongoing studies, represent an important source of genetic variation but were not the focus of this meeting. Several small studies have suggested that possession of particular alleles of SNPs in relevant candidate genes may be associated with an increased risk of developing radiation toxicity (1, 2) . However, as occurred for the previous era of cell-based predictive assays, contradictory reports are emerging. It is clearly important that the radiation biology/oncology/epidemiology community learn lessons from the previous era of predictive assay research and from experts who have carried out similar genetic association studies in other diseases or traits. In particular, researchers in the field must recognize that a large number of patients need to be studied to obtain definitive answers regarding the involvement of individual SNPs and genes to determine a patient's likelihood of developing radiation toxicity. The success of the human genome project and the subsequent HAPMAP project, which has identified the majority of SNPs found in human populations, along with the development of relatively low-cost, high-density SNP genotyping arrays, has made it possible to perform genomewide association studies (GWAS). This has led to the identification of the genetic basis for an inherited susceptibility for many traits and diseases (3, 4) . GWAS have an inherent “multiple testing” problem, necessitating the establishment of numerous consortia, all with the goal of collecting the large number of samples required for adequate statistical power. The need for such large numbers of samples makes it essential to collaborate and share data at an international level. A further rationale underlying the need for a GWAS—and hence an international consortium—is that previous GWAS have identified genes that were not anticipated to be involved in a particular phenotype. In addition, many important disease loci have been identified in “gene deserts” nowhere near recognizable genes. Thus, if we confine our research only to candidate genes for which the proteins are already known to be involved in radiation effects, we will miss the opportunity to identify novel genes or other loci not expected to be involved in the development of specific radiation responses. Researchers were brought together by the workshop to summarize their work to date and ongoing projects. There was representation from the major collaborative groups performing genotyping studies in the United Kingdom (RAPPER), the United States (GenePARE), and Japan (RadGenomics). Representatives also attended from the U.S. National Cancer Institute, the U.S. National Institutes of Health, and the GENEPI-ENTB consortium, which is a European Union–funded project created to establish the infrastructure for collecting data and samples from radiation therapy patients. The scientific hypothesis underlying the development of the consortium is that a patient's likelihood of developing toxicity following radiation therapy is influenced by common genetic variation, reported by SNPs. The rationale underlying the consortium is that members of the international scientific community must work together to provide definitive answers regarding the importance of individual SNPs through the performance of adequately powered GWAS, which require many thousands of patients. The consortium will provide a forum for sharing best practice in terms of collecting toxicity and confounding variable data (particularly dose–volume histogram data), in genotyping, and for the analysis of genetic associations with toxicity. By working together, the consortium should raise the quality of SNP association studies and facilitate the eventual pooling of data for an adequately powered GWAS. A short-term goal of the consortium has already been identified: to perform a meta-analysis of existing data to confirm or refute reported involvement of well-studied candidate SNPs with specific manifestations of radiation toxicity. A small coordinating committee has been created to facilitate this short-term goal. In addition, it was agreed that the next meeting of the consortium will be held in the United States in 2010.

PY - 2010/4

Y1 - 2010/4

UR - https://www.scopus.com/pages/publications/77949548585

U2 - 10.1016/j.ijrobp.2009.12.017

DO - 10.1016/j.ijrobp.2009.12.017

M3 - Article

C2 - 20338472

AN - SCOPUS:77949548585

SN - 0360-3016

VL - 76

SP - 1295

EP - 1296

JO - International Journal of Radiation Oncology Biology Physics

JF - International Journal of Radiation Oncology Biology Physics

IS - 5

ER -