Bio Clinical Databases Somatic Signatures

Goal: Extract de novo mutational signatures and decompose to COSMIC reference signatures from somatic VCFs.

Approach: Generate a 96-trinucleotide-context mutation matrix with SigProfilerMatrixGenerator, extract signatures via NMF with SigProfilerExtractor, and fit to COSMIC with SigProfilerAssignment.

Install and Generate Matrix

from SigProfilerMatrixGenerator import install as genInstall
from SigProfilerMatrixGenerator.scripts import SigProfilerMatrixGeneratorFunc as matGen

# Install reference genome (one-time)
genInstall.install('GRCh38')

# Generate mutational matrix from VCF
# Input: Directory containing VCF files
# Output: SBS96 matrix (96 trinucleotide contexts)
matrices = matGen.SigProfilerMatrixGeneratorFunc(
    project='my_project',
    genome='GRCh38',
    vcfFiles='/path/to/vcf_directory',
    plot=True,
    exome=False  # Set True for WES
)

Extract Signatures

from SigProfilerExtractor import sigpro as sig

# De novo signature extraction
# Determines optimal number of signatures automatically
sig.sigProfilerExtractor(
    input_type='matrix',
    output='extraction_output',
    input_data='my_project/output/SBS/my_project.SBS96.all',
    reference_genome='GRCh38',
    minimum_signatures=1,
    maximum_signatures=10,
    nmf_replicates=100,
    cpu=-1  # Use all cores
)

Decompose to COSMIC Signatures

from SigProfilerAssignment import Analyzer as Analyze

# Fit to known COSMIC signatures
Analyze.cosmic_fit(
    samples='my_project/output/SBS/my_project.SBS96.all',
    output='assignment_output',
    input_type='matrix',
    genome_build='GRCh38',
    signature_database='SBS_GRCh38_GRCh38'
)

MutationalPatterns (R)

Goal: Analyze mutational spectra and fit to COSMIC signatures using the MutationalPatterns R package.

Approach: Load VCFs as GRanges, generate a 96-context mutation matrix against the reference genome, then fit to known COSMIC signatures or extract de novo via NMF.

Load and Analyze

library(MutationalPatterns)
library(BSgenome.Hsapiens.UCSC.hg38)

# Load VCF files
vcf_files <- list.files('vcf_dir', pattern = '\\.vcf$', full.names = TRUE)
sample_names <- gsub('.vcf', '', basename(vcf_files))

vcfs <- read_vcfs_as_granges(
    vcf_files,
    sample_names,
    ref_genome = 'BSgenome.Hsapiens.UCSC.hg38'
)

# Generate 96-context mutation matrix
mut_mat <- mut_matrix(vcf_list = vcfs, ref_genome = 'BSgenome.Hsapiens.UCSC.hg38')

# Visualize spectrum
plot_96_profile(mut_mat)

Fit to COSMIC Signatures

# Load COSMIC signatures (v3.2)
cosmic_sigs <- get_known_signatures(muttype = 'snv')

# Fit samples to signatures
fit_result <- fit_to_signatures(mut_mat, cosmic_sigs)

# Plot contribution
plot_contribution(fit_result$contribution, cosmic_sigs, mode = 'absolute')

# Relative contribution
plot_contribution(fit_result$contribution, cosmic_sigs, mode = 'relative')

De Novo Extraction

# Extract de novo signatures using NMF
# Determine optimal rank
estimate <- estimate_rank(mut_mat, rank_range = 2:8, nrun = 50)
plot(estimate)

# Extract signatures
nmf_res <- extract_signatures(mut_mat, rank = 4, nrun = 100)

# Compare to COSMIC
cos_sim <- cos_sim_matrix(nmf_res$signatures, cosmic_sigs)
plot_cosine_heatmap(cos_sim)

COSMIC Signature Etiology

Goal: Interpret extracted signatures by mapping them to known mutagenic processes (e.g., UV, smoking, MMR deficiency).

Approach: Look up each dominant signature in a COSMIC etiology reference table and filter by contribution threshold.

# Common COSMIC signatures and their etiologies
SIGNATURE_ETIOLOGY = {
    'SBS1': 'Spontaneous deamination (age-related)',
    'SBS2': 'APOBEC activity',
    'SBS3': 'Defective HR/BRCA1/2',
    'SBS4': 'Tobacco smoking',
    'SBS5': 'Unknown (age-related)',
    'SBS6': 'MMR deficiency',
    'SBS7a': 'UV exposure',
    'SBS7b': 'UV exposure',
    'SBS10a': 'POLE mutation',
    'SBS10b': 'POLE mutation',
    'SBS13': 'APOBEC activity',
    'SBS15': 'MMR deficiency',
    'SBS17a': 'Unknown',
    'SBS17b': 'Unknown',
    'SBS18': 'ROS damage',
    'SBS22': 'Aristolochic acid',
    'SBS26': 'MMR deficiency',
    'SBS44': 'MMR deficiency',
}

def interpret_signatures(contributions):
    '''Interpret signature contributions'''
    interpretations = []
    for sig, contrib in contributions.items():
        if contrib > 0.05:  # >5% contribution threshold
            etiology = SIGNATURE_ETIOLOGY.get(sig, 'Unknown')
            interpretations.append({
                'signature': sig,
                'contribution': contrib,
                'etiology': etiology
            })
    return sorted(interpretations, key=lambda x: x['contribution'], reverse=True)

Signature Categories

Cosine Similarity

Goal: Quantify how closely an extracted signature matches a COSMIC reference signature.

Approach: Compute cosine similarity between the two 96-dimensional signature vectors.

import numpy as np

def cosine_similarity(sig1, sig2):
    '''Calculate cosine similarity between two signatures'''
    dot_product = np.dot(sig1, sig2)
    norm1 = np.linalg.norm(sig1)
    norm2 = np.linalg.norm(sig2)
    return dot_product / (norm1 * norm2)

# Threshold: >0.8 considered similar
# >0.9 considered same signature

Clinical Applications

Goal: Translate dominant mutational signatures into actionable clinical recommendations (e.g., PARP inhibitor eligibility).

Approach: Map signature identities to therapy implications and recommended confirmatory tests.

def signature_clinical_implications(dominant_signatures):
    '''Clinical implications of mutational signatures'''
    implications = []

    for sig in dominant_signatures:
        if sig == 'SBS3':
            implications.append({
                'signature': 'SBS3',
                'implication': 'HR deficiency - may respond to PARP inhibitors',
                'testing': 'Consider BRCA1/2 testing'
            })
        elif sig in ['SBS6', 'SBS15', 'SBS26', 'SBS44']:
            implications.append({
                'signature': sig,
                'implication': 'MMR deficiency - may respond to immunotherapy',
                'testing': 'Consider MSI testing'
            })
        elif sig in ['SBS2', 'SBS13']:
            implications.append({
                'signature': sig,
                'implication': 'APOBEC activity - associated with high TMB',
                'testing': 'Consider TMB assessment'
            })

    return implications

Related Skills

• clinical-databases/tumor-mutational-burden - TMB calculation
• variant-calling/somatic-variant-calling - Input variants
• data-visualization/heatmaps-clustering - Signature visualization