TOPAS_Clustered_DNA_Damage

This repository contains a TOPAS-nBio application that can be used to simulate clustered DNA damage due to the direct and indirect action of ionizing radiation.

• v2:
• v1:

Table of Contents

• Authors
• Features
• Description
• Dependencies
• Installation
• Instructions
• Output
• License
• Component Details
• Changes from Last Version

Authors

Logan Montgomery, Christopher M Lund, James Manalad, Anthony Landry, John Kildea

Contact email: logan.montgomery@mail.mcgill.ca, james.manalad@mail.mcgill.ca

Features

• Complete TOPAS parameter file required to run simulations.
• Full human nuclear DNA model (implemented as a custom geometry component).
• Algorithm to record clustered DNA damage (implemented as a custom scorer).
• Physics constructor (implemented as a custom physics module).
• Energy spectra and relative dose data files for secondary particles produced by neutrons and x-rays in human tissue.
• All code is thoroughly documented.

Description

• This application is intended to be used to simulate the induction of clustered DNA damage in a human nucleus.
• We developed this application to compare neutron-induced direct and indirect clustered DNA damage with x-ray induced DNA damage in order to invesigate the energy dependence of neutron RBE.
• Specifically, the application produces yields of the following DNA damage:
  1. Single strand breaks (SSBs)
  2. Base lesions
  3. Double strand breaks (DSBs)
  4. Complex DSB clusters (clusters containing at least 1 DSB).
  5. Non-DSB clusters (clusters that don't contain any DSBs).
• Most simulation parameters can be modified using the included parameter file.
• Details about each component of this application are provided below.

Dependencies

• TOPAS v3.6.1
• TOPAS-nBio 1.0

Note: This application was developed on Ubuntu 20.04.2.

Installation

1. Download the latest version from the releases page.
2. Install the dependencies.
3. Install TOPAS_Clustered_DNA_Damage as any other TOPAS extension as per the instructions provided by TOPAS.
   1. Place this repository in your topas_extensions directory.
   2. Recompile TOPAS, e.g:
      • cd /path/to/topas
      • cmake -DTOPAS_EXTENSIONS_DIR=/path/to/topas_extensions
      • make

Instructions

1. Enter desired settings for the application by editing the parameter file (DNAParameters.txt)
2. Run the application (topas DNAParameters.txt)

Output

File	Description
damage_yields.phsp	Yields of five types of DNA damage stratified according to their damage cause: direct action, indirect action, or both (hybrid)
run_summary.csv	Details about the simulation run
data_comp_dsb.csv	Cluster properties of every recorded complex DSB cluster
data_non_dsb.csv	Cluster properties of every recorded non-DSB cluster

License

• This project is provided under the MIT license. See the LICENSE file for more info.
• When using any component of this application, please be sure to cite our papers:
  • Montgomery L, Lund CM, Landry A, Kildea J (2021). Towards the characterization of neutron carcinogenesis through direct action simulations of clustered DNA damage. Phys Med Biol 66(20); 205011.
    • DOI: https://doi.org/10.1088/1361-6560/ac2998
  • Manalad J, Montgomery L, Kildea J (2022). (coming soon)
    • DOI: (coming soon)

Component details

Nuclear DNA model

• Source code file is located here.
• Full human nuclear DNA model containing ~6.3 Gbp.
• Cubic shape constructed using voxels.
• Each voxel contains 20 chromatin fibres.
• Every fibre contains 18,000 DNA base pairs.
• Nucleus is enclosed in a spherical cell volume (fibroblast model).

Clustered DNA damage scorer

• Source code file is located here.
• Simulates direct and indirect prompt DNA damage.
• During the chemical stage:
  • All radical tracks generated inside DNA and histone volumes are immediately terminated.
  • DNA and histone volumes can "scavenge" (terminate) radiolytic species.
• Records the five types of DNA damage mentioned above and their respective damage-inducing action.
• Damage definitions (separation distances, energy thresholds, indirect damage probabilities) can be modified in the parameter file as shown here.
• Other user-modifiable simulation parameters:
  • Toggles to score direct and indirect damage, and histone scavenging.
  • Molecule species scavenged by the DNA and histone volumes.
• Default behaviour is to terminate simulation after a fixed number of histories.
  • Can alternatively terminate simulation after a certain dose deposition in the nucleus.
• Supports multithreading.
• Default parameter values related to indirect action and the chemical stage are described below.

Physics module

• Source code file is located here.
• Combines the GEANT4-DNA physics constructors: G4EmDNAPhysics_option2 and G4EmDNAPhysics_option4.
• Physics models from G4EmDNAPhysics_option4 for electrons between 10 eV and 10 keV.
• Physics models from G4EmDNAPhysics_option2 for electrons between 10 keV and 1 MeV.

Secondary particle data files

• In a previous study, we evaluated the energy spectra and relative dose contributions of secondary particles produced by neutrons & 250 keV x-rays in human tissue.
• For details, see our paper:
  • Lund CM, Famulari G, Montgomery L, Kildea J (2020). A microdosimetric analysis of the interactions of mono-energetic neutrons with human tissue. Physica Medica 73; 29-42.
    • DOI: https://doi.org/10.1016/j.ejmp.2020.04.001
• These data are included as TOPAS parameter files in this repository.
  • Spectra are located here.
  • Relative dose values are located here.
• Naming convention of these files:
  • e.g. spectrum_n1MeV_inner_proton.txt
    • n1MeV: initial 1 MeV neutrons.
    • inner: irradiated the innermost scoring volume in human tissue.
    • proton: protons produced as secondary particles.
• These files can be referenced in the main parameter file DNAParameters.txt to irradiate the nuclear DNA model.

Changes from last version

Nuclear DNA model:

• Unique identification of histone volumes via their composing material was added.

Clustered DNA damage scorer:

• Simulation of indirect action events and indirect damage scoring using the model described in:
  • Zhu H et al. (2020). Cellular response to proton irradiation: a simulation study with TOPAS-nBio. Radiation Research 194; 9-21.
    • DOI: https://doi.org/10.1667/rr15531.1
• Constraints simulated by default during the chemical stage:
  • All radical tracks generated inside DNA and histone volumes are immediately terminated.
  • ·OH radical tracks are terminated after an indirect action event (whether or not DNA damage was inflicted).
  • Radical tracks (·OH, e^-_aq, and H· specifically) are terminated immediately upon diffusion into a histone volume.
• By default, only ·OH radicals can damage DNA volumes with a damage probability of 40%.
  • The damage probabilities of other radiolytic species with backbone or nitrogenous base volumes can be modified via the parameter file.
• Other user-modifiable simulation parameters:
  • Toggle to score direct damage.
  • Toggle to score indirect damage.
  • Toggle for histone scavenging.
  • Molecule species scavenged by the DNA volumes.
  • Molecule species scavenged by the histone volumes.
• The DNA damage clustering algorithm was updated to account for indirect and hybrid lesions.
• Multithreading support for indirect action simulations to decrease simulation time.