title: HapMuC: somatic mutation calling using heterozygous germ line variants near candidate mutations.
abstract: BACKGROUND
  Identifying somatic changes from tumor and matched normal sequences has become a standard approach in cancer research. More specifically, this requires accurate detection of somatic point mutations with low allele frequencies in impure and heterogeneous cancer samples. Although haplotype phasing information derived by using heterozygous germ line variants near candidate mutations would improve accuracy, no somatic mutation caller that uses such information is currently available.
  
  
  RESULTS
  We propose a Bayesian hierarchical method, termed HapMuC, in which power is increased by using available information on heterozygous germ line variants located near candidate mutations. We first constructed two generative models (the mutation model and the error model). In the generative models, we prepared candidate haplotypes, considering a heterozygous germ line variant if available, and the observed reads were realigned to the haplotypes. We then inferred the haplotype frequencies and computed the marginal likelihoods using a variational Bayesian algorithm. Finally, we derived a Bayes factor for evaluating the possibility of the existence of somatic mutations. We also demonstrated that our algorithm has superior specificity and sensitivity compared with existing methods, as determined based on a simulation, the TCGA Mutation Calling Benchmark 4 datasets and data from the COLO-829 cell line.
  
  
  METHODS
  The HapMuC source code is available from http://github.com/usuyama/hapmuc.
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Usuyama
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Shiraishi
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Kume
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Ogawa
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.affiliation: Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655 and Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
mesh_terms: D000465:Algorithms; D001499:Bayes Theorem; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis / Q000379:methods*; D005787:Gene Frequency; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide