Dataset Information

Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity.

ABSTRACT: The overall goal of radiogenomics is the identification of genomic markers that are predictive for the development of adverse effects resulting from cancer treatment with radiation. The principal rationale for a focus on toxicity in radiogenomics is that for many patients treated with radiation, especially individuals diagnosed with early-stage cancers, the survival rates are high, and therefore a substantial number of people will live for a significant period of time beyond treatment. However, many of these patients could suffer from debilitating complications resulting from radiotherapy. Work in radiogenomics has greatly benefited from creation of the Radiogenomics Consortium (RGC) that includes investigators at multiple institutions located in a variety of countries. The common goal of the RGC membership is to share biospecimens and data so as to achieve large-scale studies with increased statistical power to enable identification of relevant genomic markers. A major aim of research in radiogenomics is the development of a predictive instrument to enable identification of people who are at greatest risk for adverse effects resulting from cancer treatment using radiation. It is anticipated that creation of a predictive assay characterized by a high level of sensitivity and specificity will improve precision radiotherapy and assist patients and their physicians to select the optimal treatment for each individual.

SUBMITTER: Rosenstein BS

PROVIDER: S-EPMC5657449 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity.

Rosenstein Barry S BS

Seminars in radiation oncology 20171001 4

The overall goal of radiogenomics is the identification of genomic markers that are predictive for the development of adverse effects resulting from cancer treatment with radiation. The principal rationale for a focus on toxicity in radiogenomics is that for many patients treated with radiation, especially individuals diagnosed with early-stage cancers, the survival rates are high, and therefore a substantial number of people will live for a significant period of time beyond treatment. However, ...[more]

PMID: 28865512

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Project description:This study investigated relationships between neuroblastomas (NBs) imaging phenotypes, tumor genomic profile and patient outcome.This IRB-approved retrospective observational study included 133 NB patients (73 M, 60 F; median age 15 months, range 0-151) treated in a single institution between 1998 and 2012. A consensus review of imaging (CT-scan, MRI) categorized tumors according to both the primarily involved compartment (i.e., neck, chest, abdomen or pelvis) and the sympathetic anatomical structure the tumors rose from (i.e., cervical, paravertebral or periarterial chains, or adrenal gland). Tumor shape, volume and image-defined surgical risk factors (IDRFs) at diagnosis were recorded. Genomic profiles were assessed using array-based comparative genomic hybridization and divided into three groups: "numerical-only chromosome alterations" (NCA), "segmental chromosome alterations" (SCA) and "MYCN amplification" (MNA). Statistical analyses included Kruskal-Wallis, Chi2 and Fisher's exact tests and the Kaplan-Meier method with log-rank tests and Cox model for univariate and multivariate survival analyses.A significant association between the sympathetic structure origin of tumors and genomic profiles was demonstrated. NBs arising from cervical sympathetic chains were all NCA. Paravertebral NBs were NCA or SCA in 75% and 25%, respectively and none were MNA. Periarterial NBs were NCA, SCA or MNA in 33%, 56% and 11%, respectively. Adrenal NBs were NCA, SCA or MNA in 16%, 36% and 48%, respectively. Among MNA NBs, 92% originated from the adrenal gland. The sympathetic anatomical classification was significantly better correlated to overall survival than the compartmental classification (P < .0003). The tumor volume of MNA NBs was significantly higher than NCA or SCA NBs (P < .0001). Patients with initial volume less than 160 mL had significantly better overall survival (P < .009). A "single mass" pattern was significantly more frequent in NCA NBs (P = .0003). The number of IDRFs was significantly higher in MNA NBs (P < .0001).Imaging phenotypes of neuroblastomas, including tumor origin along the sympathetic system, correlate with tumor genomic profile and patient outcome.

Project description:BackgroundA total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies.MethodsWe conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided.ResultsMeta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts.ConclusionsThis study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.

Dataset Information

Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity.

Publications

Radiogenomics: Identification of Genomic Predictors for Radiation Toxicity.

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