Background

Mutations in cancers

somatic mutations are a major cause of tumorigenesis
- but mutations are noisy
two source of recurrent mutations:
- Background mutation rate
  - mutagens, DNA context, methylation etc
  - no selection pressure
- Functional selection pressure
  - selected!

background mutation Model is needed

Plan

Modelling Background mutation rate
- Expected: model BMR -> significance of each mutation
Analysis functional selected mutations
- Missense / Nonsense comparison
- Functional analysis

Modelling Background mutation rate(BMR)

Model 1

developed by (Chang et al. 2016) in nbt.
- trinucleotide mutation rate -> weight-averaged for codon
- [Not] cancer specific
- data process :
  - using all single nucleotide variants(SNVs)
  - removed hypermutated sites: positions bearing >=99% mutations in a gene
binomial model

\[ Prob(X=k)=\binom{n}{r}P_{c,g}^{k}(1-P_{c,g})^{n-k} \\ \]

center nucleotide mutation rate in a trinucleotide(t)
\[ P_t=\frac{C_t}{F_t} \\\text{ }C_t:\#of\_mut;F_t:\#of\_trinucleotide \]

codon mutation rate \(P_{c,g}\) of codon c and gene g:
\[ P_{c,g}=\frac{\frac{C_g}{N_{sample}}}{\sum_{t \in g}{N_{t,g}P_t}} \sum_{t \in c}{\frac{n_{t,c}}{n_c}P_t} \]

$N_{t,g}$ : #of tri in gene;  
$N_{sample}$ : sample size ;  
$n_{t,c}$ : # of mut in site t of codon c;  
$n_c$ : # of mut in codon c

Preliminary results

data: UCSC (238 samples, 68197 SNV mutations)

Model 2(to do)

From MutsigCV by (Lawrence et al. 2013)
- designed for genes
  - might require some tuning-up
- use silent mutations from target gene and its neighbors

Modelling BMR
- finish model 1 in complete dataset
- Combine features from experiment
Reports to finish.

Reference

Chang, Matthew T., Saurabh Asthana, Sizhi Paul Gao, Byron H. Lee, Jocelyn S. Chapman, Cyriac Kandoth, JianJiong Gao, et al. 2016. “Identifying Recurrent Mutations in Cancer Reveals Widespread Lineage Diversity and Mutational Specificity.” Nature Biotechnology 34 (2): 155–63. doi:10.1038/nbt.3391.

Lawrence, Michael S., Petar Stojanov, Paz Polak, Gregory V. Kryukov, Kristian Cibulskis, Andrey Sivachenko, Scott L. Carter, et al. 2013. “Mutational Heterogeneity in Cancer and the Search for New Cancer-Associated Genes.” Nature 499 (7457): 214–18. doi:10.1038/nature12213.

Workreport

Tongchuan Zhang

2017-04-13