inst/markdown/methods/CNVR-DDR.markdown

In CRI-iAtlas/iatlas-app: What the Package Does (One Line, Title Case)

Title: Copy Number and DNA Damage Scores

Description: All purity, ploidy, LOH and CNV calls used to generate the DNA damage scores used in this study and summarized below were generated by the TCGA Aneuploidy AWG using ABSOLUTE (Carter et al., 2012; Taylor et al., 2018). In brief, ABSOLUTE was run, using default parameters, on segmentation data generated from Affymetrix genome-wide human SNP6.0 arrays by hapseg and on SNV and indel calls from the MC3 variant file. All clonality calls for quantifying intratumoral heterogeneity (ITH) were also determined by ABSOLUTE, which models tumor copy number alterations and mutations as mixtures of subclonal and clonal components of varying ploidy. Specifically, for these analyses, ITH score was defined as the subclonal genome fraction (which measures the fraction of tumor genome that is not part of the "plurality" clone), as determined from ABSOLUTE.

Scores for copy number burden, aneuploidy, loss of heterozygosity, and homologous recombination deficiency (HRD) were derived (Knijnenburg et al., 2018). Copy number burden scores frac_altered and n_segs (fraction altered, and number of segments, respectively) represent the fraction of bases deviating from baseline ploidy (defined as above 0.1 or below -0.1 in log2 relative copy number (CN) space), and the total number of segments in each samples copy number profile, respectively. LOH_n_seg and LOH_frac_altered are the number of segments with LOH events and fraction of bases with LOH events, respectively. HRD score is a measure quantifying defects in homologous recombination that sums 3 separate metrics of genomic scarring: large (>15 Mb) non-arm-level regions with LOH, large-scale state transitions (breaks between adjacent segments of >10 Mb), and subtelomeric regions with allelic imbalance.

Aneuploidy scores were calculated as the sum total of amplified or deleted (collectively altered) arms (Taylor et al., 2018). To call arm alterations, sample chromosome arms were first stratified by sample tumor type, type of alteration being tested (amplification or deletion), and chromosome arm (1p, 1q, etc.). The samples are then clustered using an n-component Gaussian Mixture Model fitted on that particular arms start coordinate, end coordinate, and percentage length of longest joined segment in that arm for each sample (segments were joined until the joined segment either encompassed the entire chromosome or achieved >20% contamination by segments not of that alteration type) for each sample. For each clustering, number of clusters n was chosen from 2-9 based on lowest Bayesian Information Criterion. Arms were designated as as altered if they belonged to a cluster of arms with mean fraction altered >=80%. Each segment was designated amplified, deleted, or neutral based on its copy number relative to the samples rounded ploidy.

Reference List

Contributors: Galen Gao, Andrew Cherniack

CRI-iAtlas/iatlas-app documentation built on Feb. 7, 2025, 9:02 p.m.