Dataset Information

Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment.

ABSTRACT: Current technology permits an unbiased massive analysis of somatic genetic alterations from tumor DNA as well as the generation of individualized mouse xenografts (Avatar models). This work aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer.We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. Avatar models were used as an in vivo platform to test proposed treatment strategies.Successful exome sequencing analyses have been obtained for 23 patients. Tumor-specific mutations and copy-number variations were identified. All samples profiled contained relevant genomic alterations. Tumor was implanted to create an Avatar model from 14 patients and 10 succeeded. Occasionally, actionable alterations such as mutations in NF1, PI3KA, and DDR2 failed to provide any benefit when a targeted drug was tested in the Avatar and, accordingly, treatment of the patients with these drugs was not effective. To date, 13 patients have received a personalized treatment and 6 achieved durable partial remissions. Prior testing of candidate treatments in Avatar models correlated with clinical response and helped to select empirical treatments in some patients with no actionable mutations.The use of full genomic analysis for cancer care is encouraging but presents important challenges that will need to be solved for broad clinical application. Avatar models are a promising investigational platform for therapeutic decision making. While limitations still exist, this strategy should be further tested.

SUBMITTER: Garralda E

PROVIDER: S-EPMC4322867 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment.

Garralda Elena E Paz Keren K López-Casas Pedro P PP Jones Siân S Katz Amanda A Kann Lisa M LM López-Rios Fernando F Sarno Francesca F Al-Shahrour Fátima F Vasquez David D Bruckheimer Elizabeth E Angiuoli Samuel V SV Calles Antonio A Diaz Luis A LA Velculescu Victor E VE Valencia Alfonso A Sidransky David D Hidalgo Manuel M

Clinical cancer research : an official journal of the American Association for Cancer Research 20140314 9

<h4>Background</h4>Current technology permits an unbiased massive analysis of somatic genetic alterations from tumor DNA as well as the generation of individualized mouse xenografts (Avatar models). This work aimed to evaluate our experience integrating these two strategies to personalize the treatment of patients with cancer.<h4>Methods</h4>We performed whole-exome sequencing analysis of 25 patients with advanced solid tumors to identify putatively actionable tumor-specific genomic alterations. ...[more]

PMID: 24634382

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Project description:BACKGROUND: Pathway analysis of a set of genes represents an important area in large-scale omic data analysis. However, the application of traditional pathway enrichment methods to next-generation sequencing (NGS) data is prone to several potential biases, including genomic/genetic factors (e.g., the particular disease and gene length) and environmental factors (e.g., personal life-style and frequency and dosage of exposure to mutagens). Therefore, novel methods are urgently needed for these new data types, especially for individual-specific genome data. METHODOLOGY: In this study, we proposed a novel method for the pathway analysis of NGS mutation data by explicitly taking into account the gene-wise mutation rate. We estimated the gene-wise mutation rate based on the individual-specific background mutation rate along with the gene length. Taking the mutation rate as a weight for each gene, our weighted resampling strategy builds the null distribution for each pathway while matching the gene length patterns. The empirical P value obtained then provides an adjusted statistical evaluation. PRINCIPAL FINDINGS/CONCLUSIONS: We demonstrated our weighted resampling method to a lung adenocarcinomas dataset and a glioblastoma dataset, and compared it to other widely applied methods. By explicitly adjusting gene-length, the weighted resampling method performs as well as the standard methods for significant pathways with strong evidence. Importantly, our method could effectively reject many marginally significant pathways detected by standard methods, including several long-gene-based, cancer-unrelated pathways. We further demonstrated that by reducing such biases, pathway crosstalk for each individual and pathway co-mutation map across multiple individuals can be objectively explored and evaluated. This method performs pathway analysis in a sample-centered fashion, and provides an alternative way for accurate analysis of cancer-personalized genomes. It can be extended to other types of genomic data (genotyping and methylation) that have similar bias problems.

Dataset Information

Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment.

Publications

Integrated next-generation sequencing and avatar mouse models for personalized cancer treatment.

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