Identification of somatic mutations in cancer through Bayesian-based analysis of sequenced genome pairs

• Published in: BMC genomics Vol. 14; no. 1; p. 302
• Main Authors: Christoforides, Alexis, Carpten, John D, Weiss, Glen J, Demeure, Michael J, Von Hoff, Daniel D, Craig, David W
• Format: Journal Article
• Language: English
• Published: London BioMed Central 04.05.2013; BioMed Central Ltd
• Subjects: Algorithms; Animal Genetics and Genomics; Bayes Theorem; Bayesian statistical decision theory; Biomedical and Life Sciences; Cancer; Feedback; Gene mutations; Genetic aspects; Genomes; Genomics - methods; Genotype & phenotype; Heterogeneity; Humans; Life Sciences; Medical research; Methodology; Methodology Article; Methods; Microarrays; Microbial Genetics and Genomics; Models, Biological; Mutation; Neoplasms - genetics; Plant Genetics and Genomics; Proteomics; R&D; Research & development; Single nucleotide polymorphisms; Tissue analysis; Transcriptomics; Tumors; Iran; Next generation sequencing; Somatic mutation detection; Cancer genomics
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/1471-2164-14-302

Background The field of cancer genomics has rapidly adopted next-generation sequencing (NGS) in order to study and characterize malignant tumors with unprecedented resolution. In particular for cancer, one is often trying to identify somatic mutations – changes specific to a tumor and not within an individual’s germline. However, false positive and false negative detections often result from lack of sufficient variant evidence, contamination of the biopsy by stromal tissue, sequencing errors, and the erroneous classification of germline variation as tumor-specific. Results We have developed a generalized Bayesian analysis framework for matched tumor/normal samples with the purpose of identifying tumor-specific alterations such as single nucleotide mutations, small insertions/deletions, and structural variation. We describe our methodology, and discuss its application to other types of paired-tissue analysis such as the detection of loss of heterozygosity as well as allelic imbalance. We also demonstrate the high level of sensitivity and specificity in discovering simulated somatic mutations, for various combinations of a) genomic coverage and b) emulated heterogeneity. Conclusion We present a Java-based implementation of our methods named Seurat, which is made available for free academic use. We have demonstrated and reported on the discovery of different types of somatic change by applying Seurat to an experimentally-derived cancer dataset using our methods; and have discussed considerations and practices regarding the accurate detection of somatic events in cancer genomes. Seurat is available at https://sites.google.com/site/seuratsomatic .