title: Mutation pattern is an influential factor on functional mutation rates in cancer.
abstract: BACKGROUND
  Mutation rates are consistently varied in cancer genome and play an important role in tumorigenesis, however, little has been known about their function potential and impact on the distribution of functional mutations. In this study, we investigated genomic features which affect mutation pattern and the function importance of mutation pattern in cancer.
  
  
  METHODS
  Somatic mutations of clear-cell renal cell carcinoma, liver cancer, lung cancer and melanoma and single nucleotide polymorphisms (SNPs) were intersected with 54 distinct genomic features. Somatic mutation and SNP densities were then computed for each feature type. We constructed 2856 1-Mb windows, in which each row (1-Mb window) contains somatic mutation, SNP densities and 54 feature vectors. Correlation analyses were conducted between somatic mutation, SNP densities and each feature vector. We also built two random forest models, namely somatic mutation model (CSM) and SNP model to predict somatic mutation and SNP densities on a 1-Kb scale. The relation of CSM and SNP scores was further analyzed with the distributions of deleterious coding variants predicted by SIFT and Mutation Assessor, non-coding functional variants evaluated with FunSeq 2 and GWAVA and disease-causing variants from HGMD and ClinVar databases.
  
  
  RESULTS
  We observed a wide range of genomic features which affect local mutation rates, such as replication time, transcription levels, histone marks and regulatory elements. Repressive histone marks, replication time and promoter contributed most to the CSM models, while, recombination rate and chromatin organizations were most important for the SNP model. We showed low mutated regions preferentially have higher densities of deleterious coding mutations, higher average scores of non-coding variants, higher fraction of functional regions and higher enrichment of disease-causing variants as compared to high mutated regions.
  
  
  CONCLUSIONS
  Somatic mutation densities vary largely across cancer genome, mutation frequency is a major indication of function and influence on the distribution of functional mutations in cancer.
authors: Department of Urology, Ganzhou Hospital Affiliated to Nanchang University, Ganzhou, Jiangxi province China.
authors: Chuance
authors: C
authors: Du
authors: Department of Rehabilitation, Ganzhou Hospital Affiliated to Nanchang University, Nan Chang, Jiangxi province China.
authors: Xiaoyuan
authors: X
authors: Wu
authors: Department of Thyroid and Breast, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072 China.
authors: Jia
authors: J
authors: Li
keywords: Clear-cell renal cell carcinoma; Functional variants; Liver cancer; Lung cancer; Melanoma; Mutation pattern; Random forest