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Mutational signatures

Mutational signatures are the characteristic patterns of somatic mutations observed in cancer genomes, representing the cumulative imprints left by specific mutational processes that operate during tumorigenesis, including those driven by environmental mutagens, replication errors, or defects in DNA repair mechanisms.^[1] These signatures manifest as distinct combinations of base substitutions—such as C>T transitions—within defined trinucleotide sequence contexts, enabling the classification of up to 96 possible mutation types based on the six main substitution classes and the flanking bases.^[1] The concept of mutational signatures emerged from comprehensive analyses of whole-genome sequencing data, with the first systematic cataloguing in 2013 identifying 21 such signatures across multiple cancer types by applying non-negative matrix factorization algorithms to millions of somatic mutations from over 7,000 tumors.^[1] This approach revealed varying mutation burdens, from as low as 0.001 mutations per megabase to over 400 in cancers linked to tobacco smoking or ultraviolet light exposure, and associated specific signatures with etiologies like Signature 4 (tobacco-induced) and Signature 7 (UV-induced).^[1] Subsequent advancements, including refined computational tools like SigProfiler, have expanded the repertoire, extracting 67 single-base substitution (SBS) signatures, 11 doublet-base substitution (DBS) signatures, and 17 insertion/deletion (ID) signatures from over 23,000 cancer samples in 2020, providing higher resolution through whole-genome data and better separation of overlapping processes.^[2] Today, mutational signatures are cataloged in authoritative databases like COSMIC (version 3.4, updated October 2023), which curates reference sets of high-confidence signatures across SBS (96 contexts), DBS (78 types), ID (83 types), copy number, structural variants, and even RNA-level changes to track mutational processes in human cancers.^[3] Their significance extends beyond etiology, informing clinical applications such as identifying patients with homologous recombination deficiency via Signature 3 for targeted therapies like PARP inhibitors, and revealing age-related signatures like SBS1 that accumulate spontaneously over a lifetime.^[2] Ongoing research continues to uncover new signatures tied to therapies (e.g., platinum chemotherapy) and non-cancer contexts, underscoring their role in dissecting the genomic landscape of disease.^[2]

Introduction and general concepts

Definition and overview

Mutational signatures are characteristic patterns of somatic mutations in cancer genomes that reflect the cumulative effects of specific mutational processes, including DNA damage from endogenous or exogenous sources and errors in DNA repair. These patterns manifest as combinations of mutation types, such as single base substitutions (SBS), small insertions and deletions (indels), and larger structural variants, each shaped by the underlying biological mechanisms acting over time. By analyzing the relative frequencies of these mutation types within trinucleotide contexts or other genomic features, signatures provide a genomic fingerprint of the processes driving mutagenesis.^[2] The concept of mutational signatures emerged from large-scale whole-genome sequencing efforts, with the first comprehensive identification occurring in 2013 through the analysis of 507 cancer samples across multiple tumor types. This pioneering work revealed over 20 distinct signatures, demonstrating that cancers accumulate mutations in predictable patterns rather than randomly, revolutionizing the study of somatic evolution.^[4] These signatures hold critical importance for oncology, as they enable the tracing of mutational causes back to specific etiologies, such as aging, environmental exposures, or therapeutic interventions, thereby enhancing understanding of cancer development and informing strategies for prevention and treatment.^[5] For instance, Signature 1 (SBS1), often described as a clock-like signature, arises from the spontaneous deamination of 5-methylcytosine to thymine, predominantly producing C>T transitions at CpG sites and correlating with patient age.^[6]

Underlying mechanisms

Mutational processes in the genome arise from a combination of endogenous and exogenous sources that introduce DNA damage, which, if not properly repaired, results in permanent mutations. Endogenous mutagenesis includes spontaneous chemical alterations such as base deamination (e.g., cytosine to uracil, leading to C>T transitions, especially at CpG sites), hydrolysis creating abasic sites, and oxidative damage from reactive oxygen species (ROS) like hydroxyl radicals that generate lesions such as 8-oxoguanine (8-oxoG), causing G:C to T:A transversions.^[7] Replication errors during DNA synthesis also contribute, with polymerases occasionally inserting incorrect bases or slipping at repetitive sequences, at rates of approximately 10^{-6} to 10^{-8} errors per nucleotide per cell division.^[8] Exogenous factors encompass environmental agents like ionizing radiation, which produces ROS and double-strand breaks (DSBs), ultraviolet (UV) light forming cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts that lead to C>T or CC>TT mutations, and chemicals such as alkylating agents that add methyl groups to bases, resulting in G:C to A:T transitions.^[7] Cells counteract this damage through multiple DNA repair pathways, each specialized for specific lesion types. Base excision repair (BER) addresses small, non-helix-distorting base modifications, such as deaminated or oxidized bases: DNA glycosylases remove the damaged base, creating an abasic site that is incised by AP endonuclease (APE1), followed by nucleotide insertion via polymerase β (POLβ) and ligation.^[9] Nucleotide excision repair (NER) handles bulky, helix-distorting adducts like UV-induced dimers or chemical adducts; it involves damage recognition by XPC-RAD23B, unwinding by TFIIH, excision of a 24-32 nucleotide oligonucleotide by XPF-ERCC1 and XPG, and resynthesis by polymerases δ/ε.^[10] Mismatch repair (MMR) corrects base-base or insertion/deletion mismatches from replication, using MutSα (MSH2-MSH6) or MutSβ for recognition, exonuclease 1 (EXO1) for strand-specific excision, and resynthesis by POLδ.^[11] For DSBs, homologous recombination (HR) employs a sister chromatid template for accurate repair: the MRN complex resects ends, RAD51 forms a nucleoprotein filament to invade the homolog, and DNA synthesis restores the sequence.^[12] In contrast, non-homologous end joining (NHEJ) rapidly ligates DSB ends without a template, involving Ku70/80 binding, DNA-PKcs activation for end processing, and ligation by LIG4-XRCC4, often introducing small insertions or deletions.^[13] Failure or deficiency in these repair pathways allows damage to persist, directly linking specific lesions to mutation types. Unrepaired deamination or oxidation in BER-deficient contexts yields base substitutions, such as C>T from cytosine deamination or G to T from 8-oxoG mispairing with adenine during replication.^[14] NER defects leave bulky lesions that, upon replication, cause base substitutions like C:G to T:A from UV photoproducts via error-prone translesion synthesis.^[10] MMR inefficiency permits replication slippage in microsatellites, generating small insertions or deletions (indels) of 1-5 bases.^[11] DSBs unresolved by HR or erroneously joined by NHEJ produce structural variants (SVs), including deletions, duplications, inversions, or translocations, often with microhomology at junctions indicating NHEJ involvement.^[15] An additional layer of complexity is transcriptional strand bias, where mutations accumulate preferentially on the non-transcribed strand due to asymmetry in repair efficiency. Transcription-coupled NER (TC-NER), a subpathway of NER, prioritizes repair of lesions on the transcribed (template) strand by recruiting repair factors when RNA polymerase II stalls at damage sites, involving CSA and CSB proteins; this protects actively transcribed genes but leaves the non-transcribed strand more susceptible to mutagenesis.^[16]^[10] Consequently, processes like oxidative damage or certain replication errors exhibit higher mutation rates on the non-transcribed strand, influencing the overall mutational landscape.^[17]

Genomic data and mutation types

Base substitutions

Base substitutions, also known as single base substitutions (SBS) or single nucleotide variants (SNVs), refer to mutations where one nucleotide base in the DNA sequence is replaced by another. These changes can involve any of the four bases (A, C, G, T) substituting for the original, resulting in six possible substitution types when accounting for strand symmetry: C>A, C>G, C>T, T>A, T>C, and T>G.^[18]^[2] In mutational signature analysis, SBS mutations are classified based on their trinucleotide context to capture the immediate sequence environment influencing the mutation. This involves the mutated base flanked by one nucleotide on each side (5' and 3'), yielding 4 × 4 × 6 = 96 possible combinations, often represented as 96-channel vectors where each channel corresponds to the relative frequency of a specific substitution in its context. The Catalogue of Somatic Mutations in Cancer (COSMIC) employs this 96-channel framework as the standard for cataloging SBS signatures across cancer genomes.^[18]^[2]^[4] SBS mutations predominate among point mutations in cancer, comprising approximately 90% of such events, with insertions and deletions (indels) making up the remainder at about 10% frequency relative to substitutions. This prevalence underscores their central role in signature extraction from whole-genome sequencing data.^[2] Representative examples of SBS contexts include C>T transitions occurring at CpG dinucleotides, which arise from spontaneous deamination of 5-methylcytosine, a process reflected in signatures like COSMIC SBS1. Another prominent context is C>T or C>G substitutions at TpC motifs, characteristic of APOBEC cytidine deaminase activity and captured in signatures such as SBS2 and SBS13. These contexts highlight how sequence-specific patterns enable the dissection of underlying mutational processes without delving into their mechanistic details.^[4]^[2]

Insertions, deletions, and structural variants

Insertions and deletions (indels) refer to small-scale genomic alterations involving the addition or removal of 1 to 50 base pairs, distinct from point mutations like base substitutions. In mutational signature analysis, indels are classified into 83 distinct types (ID1 to ID83) based on factors such as event length, the specific nucleotides affected, presence in repetitive sequences, and microhomology at breakpoints, as defined by the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium.^[2] These signatures capture patterns arising from replication errors, repair deficiencies, or other processes, with extraction typically performed using non-negative matrix factorization on catalogs from whole-genome sequencing data.^[19] For instance, ID2 predominantly features 1-base pair deletions of thymine in mononucleotide poly-T repeats, attributed to polymerase slippage during DNA replication of the template strand.^[2] Structural variants (SVs) encompass larger genomic rearrangements exceeding 1 kilobase, including deletions, tandem duplications, inversions, and translocations that disrupt chromosome structure. COSMIC catalogs 12 rearrangement signatures (RS1 to RS12), derived from patterns in over 10,000 whole-genome sequences, classifying SVs into 32 subtypes by size categories (1-10 kb, 10-100 kb, 100 kb-1 Mb, 1-10 Mb, >10 Mb), orientation, clustering (e.g., tandem or dispersed), and breakpoint complexity.^[20] These signatures reflect underlying mutational processes, such as breakage-fusion-bridge cycles or replication-based mechanisms, and are validated using multiple callers like Manta, Lumpy, and Delly to ensure accuracy.^[21] Analyzing indel and SV signatures presents unique challenges compared to single base substitutions, primarily due to their lower frequency in most tumor genomes—indels occur at rates 10-100 times lower than substitutions, while SVs vary widely but often number in the dozens per sample—necessitating larger cohorts for robust signature decomposition.^[2] Accurate detection requires high-confidence variant calling pipelines to distinguish true events from artifacts, particularly for clustered SVs or short indels in repetitive regions, and the lack of a universally intuitive classification system complicates feature engineering.^[22] Despite these hurdles, such analyses link indel and SV patterns to processes like homologous recombination deficiency, enhancing their utility in identifying tumor-specific mutagenic landscapes when integrated with larger datasets.^[23]

Tumor mutation catalogs

Tumor mutation catalogs are compiled from large-scale genomic datasets of cancer samples to enable the extraction and analysis of mutational signatures. Primary data sources include whole-genome sequencing (WGS) and whole-exome sequencing (WES) efforts from consortia such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). WGS provides comprehensive coverage of both coding and non-coding regions, capturing the full spectrum of mutations essential for accurate signature profiling, as the majority of somatic mutations occur outside exonic areas.^[2] In contrast, WES focuses on protein-coding exons but limits insight into non-coding mutational processes, though it remains widely used due to lower cost and higher depth.^[24] These datasets form the backbone of catalogs, with TCGA and ICGC collectively providing mutation profiles from over 15,000 tumors across diverse cancer types.^[25] Catalog construction begins with variant calling on aligned sequencing reads from tumor-normal pairs to identify somatic mutations. Tools such as MuTect for single nucleotide variants and Strelka for small indels perform this by comparing tumor and matched normal genomes to distinguish somatic alterations from germline variants and sequencing artifacts.^[26] Subsequent filtering steps remove low-confidence calls based on allele frequency, strand bias, and quality scores, ensuring high specificity. Mutations are then annotated with their trinucleotide contexts (e.g., the 5' and 3' flanking bases) to generate 96-channel profiles for base substitutions, facilitating signature analysis.^[2] This process yields structured catalogs of validated somatic mutations, often aggregated into public repositories like the NCI Genomic Data Commons or ICGC data portal for community access.^[25] Tumor mutation burden (TMB), defined as the total number of somatic mutations per megabase of genome interrogated, serves as a broad proxy for overall genomic instability in these catalogs. Typically calculated from nonsynonymous variants in exonic regions via WES, TMB correlates with neoantigen load and immunotherapy response but lacks granularity on underlying processes.^[27] Mutational signatures, derived from cataloged mutations, offer process-specific insights by deconvolving contributions from distinct etiologies, such as environmental exposures or replication errors, beyond mere TMB quantification.^[2] Robust signature extraction requires large cohort sizes to overcome noise and achieve statistical power, with thousands of samples needed to reliably identify rare or tissue-specific patterns. Current catalogs from TCGA and ICGC encompass over 10,000 tumors, enabling pan-cancer analyses that reveal conserved and novel signatures across histologies.^[25] For instance, the Pan-Cancer Analysis of Whole Genomes (PCAWG) consortium analyzed 2,658 WGS samples, demonstrating how scaled catalogs enhance signature resolution.^[2]

Endogenous mutational processes

Age-related and spontaneous mutagenesis represents a fundamental endogenous process contributing to the accumulation of somatic mutations over time, independent of external exposures. These processes manifest primarily through three clock-like mutational signatures: SBS1, SBS5, and SBS18. SBS1 is characterized by C>T transitions predominantly at CpG dinucleotides, arising from the spontaneous deamination of 5-methylcytosine (5mC) to thymine, which creates a G:T mismatch if unrepaired.^[2] This signature accumulates linearly with chronological age in both normal and cancerous tissues across diverse cell types, reflecting ongoing endogenous DNA damage. SBS5 features a broader spectrum of base substitutions, including T>C and A>G transitions, and also exhibits a strong positive correlation with age, though its precise etiology remains under investigation. SBS18 is characterized by C>A transversions at TpCpT contexts, likely resulting from oxidative DNA damage by reactive oxygen species (ROS).^[28]^[29] The underlying mechanisms of these signatures involve intrinsic cellular processes that generate DNA lesions during normal metabolism. For SBS1, the deamination of 5mC occurs spontaneously and is exacerbated by incomplete repair via base excision repair pathways, leading to persistent mismatches during replication.^[30] SBS5 is a clock-like signature that accumulates independently of cell divisions, possibly due to endogenous damage such as reactive oxygen species (ROS), though its precise etiology remains under investigation. Oxidative stress, a byproduct of cellular respiration, contributes to spontaneous mutagenesis by producing reactive oxygen species (ROS) that oxidize DNA bases, creating abasic sites or modified nucleotides that fuel signatures such as SBS18 and potentially SBS5 if not fully repaired. These processes are particularly pronounced in post-mitotic tissues, such as neurons and oligodendrocytes, where reduced proliferative activity limits dilution of mutations but allows accumulation from unrepaired damage over extended lifespans.^[31] Evidence for these signatures underscores their universality and utility as molecular clocks. SBS1, SBS5, and SBS18 are detected in virtually all human tissues, both normal and neoplastic, with mutation burdens increasing predictably with age—typically by dozens of events per year across the genome. In proliferative tissues, SBS1 mutations correlate with the estimated number of stem cell divisions, serving as a proxy for mitotic history.^[32] This clock-like behavior enables estimation of lifetime cell divisions, highlighting how spontaneous mutagenesis drives baseline genomic instability that can predispose to oncogenesis without external influences.^[33]

APOBEC cytidine deaminase activity

APOBEC cytidine deaminases are a family of enzymes primarily involved in innate antiviral defense by editing viral genomes through cytidine deamination, converting cytosine (C) to uracil (U) in single-stranded DNA. In cancer, dysregulated APOBEC activity, particularly from APOBEC3A and APOBEC3B, leads to off-target mutagenesis in host genomic DNA, contributing to hypermutation and tumor evolution. This process generates characteristic mutational signatures dominated by C>T and C>G transitions at TCW trinucleotide motifs (where W is A or T), reflecting the enzymes' preference for deaminating cytosines flanked by thymine.^[34]^[35] The primary APOBEC-associated signatures are SBS2 and SBS13. SBS2 is characterized by C>T mutations at TCW contexts, arising when DNA replication incorporates adenine opposite unrepaired uracil, resulting in a C-to-T transition after proofreading. In contrast, SBS13 features C>G transversions at the same motifs, occurring when base excision repair removes the uracil to create an abasic site, followed by error-prone translesion synthesis (e.g., by polymerase REV1) that inserts guanine opposite the lesion. These signatures often co-occur and are linked to episodic bursts of mutagenesis, such as kataegis, potentially triggered by inflammation, viral infections, or replication stress.^[36]^[37]^[35] SBS2 and SBS13 are enriched in multiple cancer types, notably breast and lung cancers, where they account for a substantial fraction of somatic mutations—up to 25% in some breast tumors and similarly high in non-small cell lung cancer. APOBEC3B upregulation, often due to copy number gains or transcriptional activation, correlates with signature prevalence, while germline deletions in the APOBEC3A/B locus modulate risk in breast and bladder cancers. A related but distinct pattern, captured in SBS12, shows similarities in cytosine involvement but differs in context preferences and is observed at lower levels in liver cancers, though its precise link to APOBEC remains under investigation.^[34]^[2]^[38] Clinically, APOBEC signatures contribute to elevated tumor mutational burden (TMB), often exceeding 10 mutations per megabase, which enhances neoantigen presentation and correlates with improved responses to immune checkpoint inhibitors, such as PD-1/PD-L1 blockade, in breast and lung cancers. For instance, tumors with dominant APOBEC activity show prolonged progression-free survival in immunotherapy cohorts, independent of other signatures. However, this hypermutator phenotype can also drive aggressive evolution and resistance to targeted therapies.^[39]^[40]

DNA repair deficiencies

DNA repair deficiencies in key pathways, such as homologous recombination (HR), mismatch repair (MMR), and non-homologous end joining (NHEJ), generate distinct mutational signatures by allowing unrepaired or error-prone repair of DNA damage to persist in the genome. These deficiencies often arise from germline or somatic mutations in repair genes, leading to increased mutation rates and specific patterns observable in cancer genomes.^[2] Homologous recombination deficiency (HRD), commonly caused by mutations in BRCA1 or BRCA2, is characterized by single base substitution signature SBS3, which features a balanced profile across trinucleotide contexts but is enriched in breast, ovarian, and pancreatic cancers.^[41] Indel signature ID8, involving deletions of 10 or more base pairs with 1 base pair microhomology, and rearrangement signature RS3, marked by small tandem duplications and clustered structural variants, also reflect HRD due to reliance on alternative error-prone repair mechanisms like microhomology-mediated end joining. These signatures are prevalent in BRCA1/2-mutated tumors, where HRD leads to genomic instability, including loss of heterozygosity and copy number alterations, and serve as biomarkers for sensitivity to PARP inhibitors in ovarian and breast cancers.^[2]^[42] Mismatch repair deficiency (MMRd), often from mutations in MLH1, MSH2, MSH6, or PMS2, produces signatures SBS6, SBS15, SBS20, and SBS26, all linked to microsatellite instability (MSI) and a bias toward C>A transversions at specific motifs.^[43] These patterns arise from unrepaired replication errors and polymerase slippage, resulting in hypermutation and elevated tumor mutational burden, particularly in colorectal, endometrial, and gastric cancers.^[2] MSI-high tumors with MMRd signatures predict enhanced efficacy of immune checkpoint inhibitors, such as pembrolizumab, due to increased neoantigen load and immunogenicity.^[44] Errors in non-homologous end joining (NHEJ), the primary pathway for repairing double-strand breaks without a template, contribute to signature SBS17, characterized by C>T and C>A substitutions, often alongside rearrangements featuring blunt-end joins.^[45] NHEJ deficiencies, such as those from LIG4 or XRCC4 mutations, promote imprecise ligation, leading to small insertions or deletions at break sites, though these signatures are less common and sometimes co-occur with other repair defects.^[2]

Exogenous and environmental exposures

Ultraviolet radiation

Ultraviolet (UV) radiation from sun exposure is a primary environmental carcinogen responsible for inducing distinct mutational signatures in human cancers, particularly those of the skin. These signatures reflect DNA damage primarily caused by UVB wavelengths (280–315 nm), which penetrate the epidermis and generate photoproducts such as cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts. These lesions, if unrepaired, lead to characteristic base substitutions during replication or translesion synthesis. The most prominent UV-associated signature is SBS7 (including subtypes SBS7a–d), characterized by C>T transitions at dipyrimidine sites, such as TC>TT or CC>TT, resulting from CPD-induced mispairing where cytosine deaminates to uracil, pairing with adenine instead of guanine.^[46]^[47] SBS7 is highly prevalent in sun-exposed skin cancers, with the highest contributions observed in melanomas, where it can account for over 80% of substitutions in some tumors. The signature's intensity is amplified by deficiencies in nucleotide excision repair (NER), the primary pathway for removing UV photoproducts; in melanomas, reduced NER activity leads to persistence of these lesions and elevated mutation rates compared to other skin cancers like basal cell carcinoma.^[48] The contribution of UV signatures exhibits a dose-response relationship with cumulative lifetime exposure, as evidenced by higher SBS7 loads in tumors from individuals with chronic sun exposure, such as outdoor workers or those in sunny climates, correlating positively with mutation burden in epidermal samples. This pattern supports UV's role in both initiation and progression of skin cancers, with signature prevalence increasing exponentially with age and exposure intensity in normal skin tissues.^[49]

Alkylating agents and chemotherapy

Alkylating agents, a class of chemotherapeutic drugs, introduce alkyl groups onto DNA bases, primarily guanine at the O6 position, leading to the formation of O6-methylguanine (O6-meG) adducts. These adducts cause mispairing with thymine during DNA replication, resulting in C>T transitions if unrepaired. This process is particularly prominent when O6-alkylguanine-DNA alkyltransferase (MGMT) or mismatch repair (MMR) pathways are deficient, amplifying mutagenesis. Base excision repair (BER) plays a role in repairing some alkylated lesions but is detailed elsewhere.^[50] Signature 11 (SBS11) exemplifies this damage, featuring C>T and C>A substitutions enriched at TpC trinucleotides (e.g., TCC, TCA, TCT contexts). It is strongly associated with exposure to temozolomide (TMZ), an S_N1-type alkylator used in glioblastoma treatment, where it appears in nearly all hypermutated post-treatment tumors. Similarly, procarbazine, another alkylator employed in regimens for anaplastic gliomas and Hodgkin lymphoma, induces SBS11-like patterns, as observed in experimental models of bone marrow mutagenesis. Recent studies (as of 2024) have shown procarbazine induces higher mutation burdens and novel signatures in Hodgkin lymphoma. SBS11's persistence in tumor genomes serves as a biomarker of prior alkylating chemotherapy, aiding in reconstructing patient treatment histories and assessing secondary malignancy risks.^[51]^[52]^[53] Signature 9 (SBS9), characterized by T>C transitions at TCC trinucleotides, arises from error-prone replication by DNA polymerase η (pol η), a translesion synthesis enzyme involved in bypassing DNA lesions including those from alkyl damage. In lymphomas treated with alkylators like bendamustine, SBS9 is observed alongside other signatures, reflecting pol η's role in tolerating replication stress post-adduct formation, though it may also contribute to somatic hypermutation in lymphoid cells. This signature's presence in post-chemotherapy samples highlights how therapeutic alkylators can inadvertently promote mutagenesis via TLS polymerases.^[54]^[55]^[56] Therapeutically, these signatures inform glioma and lymphoma management, where TMZ or procarbazine efficacy correlates with MGMT status, but unrepaired adducts drive resistance and relapse through hypermutation. Detecting SBS11 or SBS9 in relapsed tumors indicates alkylator exposure, guiding avoidance of similar agents to prevent further genomic instability.^[51]

Tobacco and other carcinogens

Tobacco smoke is a major source of environmental carcinogens that induce specific mutational signatures in human cancers, particularly in tissues directly exposed such as the lung and bladder. Among these, signature 4 (SBS4) is characterized by C>A transversions predominantly at CpCpT trinucleotide contexts and is attributed to DNA adducts formed by benzopyrene diol epoxide (BPDE), a metabolite of the polycyclic aromatic hydrocarbon benzopyrene present in cigarette smoke. This signature is prominently observed in lung squamous cell carcinomas and adenocarcinomas from smokers, where it correlates with cumulative smoking exposure measured in pack-years, contributing significantly to the overall mutation burden in these tumors. Experimental models exposed to tobacco mutagens replicate the SBS4 profile, confirming its causal link to smoking-related DNA damage.^[57] In addition to inhaled tobacco smoke, smokeless forms like chewing tobacco generate distinct mutational patterns. Signature 29 (SBS29), featuring C>A mutations in YCY motifs (where Y denotes pyrimidine), is associated with tobacco chewing and is frequently detected in oral cavity and pharyngeal cancers among users in regions with high prevalence of this habit.^[2] Unlike SBS4, SBS29 shows a different distribution of C>A preferences, reflecting variations in the chemical composition and local exposure from smokeless tobacco products.^[58] Beyond tobacco, other environmental carcinogens produce analogous strand-biased signatures through adduct formation. Aristolochic acid, a phytotoxin found in certain traditional herbal remedies, induces signature 22 (SBS22), marked by A>T transversions at TW dinucleotide contexts (W = A or T), and is etiologically linked to upper urinary tract carcinomas in exposed populations, such as those in Balkan nephropathy-endemic areas or users of aristolochic acid-containing medicines. Similarly, aflatoxin B1, a mycotoxin produced by Aspergillus fungi contaminating foodstuffs like peanuts and corn in humid climates, causes signature 24 (SBS24) with C>A transversions enriched at TpCN trinucleotide contexts, predominantly in hepatocellular carcinomas from high-exposure regions in sub-Saharan Africa and Southeast Asia. Epidemiological analyses reveal that the contribution of SBS4 to tumor mutation burdens decreases with time since smoking cessation, as quitting halts further accumulation of tobacco-induced mutations while the signature persists as a record of prior exposure.^[59] This temporal decline underscores the preventive benefit of cessation in reducing ongoing genotoxic damage from these carcinogens.

Analysis methods and resources

Signature extraction and attribution

Signature extraction involves identifying the underlying mutational processes from catalogs of somatic mutations across tumor samples, typically represented as a matrix where rows correspond to mutation types and columns to samples. The most widely adopted method is non-negative matrix factorization (NMF), which decomposes this matrix V (of dimensions m \times n, where m is the number of mutation types and n the number of samples) into two non-negative matrices: W (of dimensions n \times k, representing the activity weights of k signatures across samples) and S (of dimensions k \times m, representing the signature profiles themselves), such that V \approx W S. This factorization assumes that the observed mutations result from a linear combination of independent mutational processes, with the goal of minimizing the reconstruction error while ensuring non-negativity to reflect biological plausibility. Seminal work established NMF as the foundation for de novo extraction of signatures from large cohorts, enabling the discovery of processes like spontaneous deamination and UV-induced damage. Attribution assigns contributions from a predefined set of known signatures (e.g., from the COSMIC database) to individual samples or cohorts, often using non-negative least squares (NNLS) regression to fit the observed mutation spectrum as a weighted sum of reference profiles. Cosine similarity is commonly employed to measure how well the reconstructed spectrum matches the observed data, with thresholds (e.g., >0.90) indicating reliable fits. Tools like SigProfiler facilitate both de novo extraction and attribution; its SigProfilerExtractor module uses hierarchical NMF with bootstrapping to determine the optimal number of signatures and provides high accuracy in recovering known profiles from simulated data. Similarly, deconstructSigs employs NNLS for rapid attribution in single samples, allowing decomposition into COSMIC signatures and visualization of contributions, which has proven effective for identifying repair deficiencies like BRCA1/2 mutations. For subclonal analysis, SciClone clusters mutations by variant allele frequencies to infer clonal architecture, enabling attribution of signatures to specific subclones and tracking evolutionary changes in process activity across tumor regions. Key challenges include overfitting, particularly in samples with low mutation burdens (<100 mutations), where NMF may extract spurious signatures due to noise, leading to unstable decompositions. Multi-process overlap further complicates attribution, as correlated signatures (e.g., SBS1 and SBS5, both age-related) can yield ambiguous weights, reducing resolution in distinguishing co-occurring etiologies. Validation strategies mitigate these issues; bootstrap resampling, which repeatedly factorizes subsampled matrices to estimate signature stability, helps assess robustness and select the number of components via metrics like cophenetic correlation. Extracted or attributed signatures are benchmarked against the COSMIC v3.3 reference set, which includes 49 single-base substitution (SBS), 58 indel (ID), and other signatures derived from thousands of tumors, ensuring consistency with validated profiles.

Databases and computational tools

The Catalogue of Somatic Mutations in Cancer (COSMIC) maintains a comprehensive database of reference mutational signatures, curated from large-scale genomic datasets and peer-reviewed studies. In its latest version 3.4 (released October 2023 as part of COSMIC v98), the catalog includes 86 single-base substitution (SBS) signatures defined across 96 trinucleotide contexts, 11 doublet-base substitution (DBS) signatures across 78 types, 58 insertion/deletion (ID) signatures categorized into 83 feature types, and 12 rearrangement (RS) signatures based on structural variant patterns. These signatures are assigned etiologies where possible, such as age-related deamination for SBS1 or UV exposure for SBS7, drawing from experimental validations and clinical associations to aid in interpreting mutational processes. The catalog was initially derived using non-negative matrix factorization on the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset and has been iteratively updated with new signatures validated against thousands of tumor samples. The PCAWG dataset serves as a foundational benchmark resource for mutational signature analysis, encompassing whole-genome sequencing data from over 2,600 primary tumors across 38 cancer types, paired with normal tissues. This consortium effort, published in 2020, provides standardized mutation catalogs that enabled the extraction and validation of the core COSMIC signatures, including SBS, ID, and RS profiles, and remains widely used for testing signature attribution methods due to its scale and diversity. Researchers access PCAWG data through portals like the European Genome-phenome Archive, facilitating reproducible analyses of signature contributions in pan-cancer contexts. Several computational tools support the analysis and visualization of mutational signatures, primarily implemented as R packages for integration with genomic workflows. The Yet Another Package for Signature Analysis (YAPSA) enables supervised decomposition of mutation catalogs into known signatures, incorporating confidence intervals for exposures and stratified analyses by genomic features, with built-in support for COSMIC and PCAWG reference sets. Similarly, sigfit applies Bayesian inference to fit and extract signatures from count data, offering flexible modeling of exposures and handling of catalog uncertainties, which improves robustness in low-mutation samples. MutationalPatterns provides comprehensive functions for generating 96-context SBS spectra, detecting strand biases, and attributing signatures via non-negative matrix factorization, with visualization capabilities such as heatmaps to display mutation type frequencies across samples. Recent updates to these resources, post-2022, have expanded COSMIC's experimental signatures section to integrate non-cancer data from model organisms and controlled exposures, enhancing etiology assignments for processes like oxidative damage or replication errors observed in both normal and tumor genomes. This inclusion supports broader applications in germline and somatic mutagenesis studies, while tools like YAPSA and MutationalPatterns have incorporated these extended catalogs for more accurate cross-context analyses.

Applications and emerging areas

Role in cancer etiology and therapy

Mutational signatures provide critical insights into cancer etiology by serving as molecular footprints of underlying mutagenic processes, enabling the retrospective identification of causative exposures or defects. For example, signature SBS4, dominated by C>A transversions at CpCpA trinucleotides, is a hallmark of tobacco smoking and has been detected in lung, head and neck, and bladder cancers, correlating with cumulative exposure levels and aiding in etiological classification beyond self-reported history.^[60] Similarly, homologous recombination deficiency (HRD) signatures, such as those reflecting BRCA1/2-associated patterns (e.g., SBS3), trace germline or somatic defects in DNA repair, which are prevalent in up to 50% of high-grade serous ovarian cancers and inform hereditary risk assessment.^[61] In terms of prognosis, specific signatures predict tumor aggressiveness, recurrence risk, and overall survival across cancer types. APOBEC-related signatures (SBS2 and SBS13), arising from cytidine deaminase activity, are associated with worse outcomes in breast, ovarian, and non-small cell lung cancers due to their role in accelerating subclonal evolution and immune evasion, with high APOBEC burden linked to reduced progression-free survival in multiple myeloma.^[62] Microsatellite instability (MSI) signatures, characterized by elevated insertions/deletions at homopolymer repeats (e.g., ID1, ID2), indicate mismatch repair deficiency and correlate with favorable prognosis in colorectal cancer but heterogeneous outcomes in others, often tied to hypermutated profiles that influence metastatic potential.^[63] Mutational signatures facilitate therapeutic decision-making through patient stratification and monitoring of treatment effects. HRD signatures predict sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, as evidenced by improved progression-free survival in ovarian cancer patients with high HRD scores (e.g., via loss of heterozygosity or signature analysis), even in BRCA-wild-type cases, guiding targeted therapy selection.^[64] MSI signatures serve as biomarkers for immune checkpoint inhibitor response, with MSI-high tumors showing objective response rates exceeding 40% to PD-1 blockade in pan-cancer cohorts, including endometrial and colorectal cancers.^[65] Additionally, therapy-induced signatures like SBS11, featuring T>C transitions from temozolomide alkylation, emerge post-chemotherapy in gliomas and other tumors, signaling potential resistance mechanisms such as MGMT promoter methylation and informing adjustments to avoid hypermutator phenotypes.^[66] In precision oncology clinical trials, mutational signatures are increasingly integrated for trial enrichment and companion diagnostics. For instance, HRD signature testing has been pivotal in trials like PAOLA-1 for ovarian cancer, where patients with HRD-positive profiles (detected via genomic scarring or substitution patterns) exhibited doubled progression-free survival with PARP inhibitor plus bevacizumab combinations, supporting FDA approvals for signature-based eligibility.^[61] This approach extends to basket trials evaluating PARP inhibitors in HRD-enriched non-ovarian cancers, enhancing therapeutic precision while minimizing off-target toxicities.^[67]

Non-cancer applications and future directions

Mutational signatures have been observed in normal human tissues, where they accumulate gradually with age due to endogenous processes. The signature SBS1, characterized by C>T transitions at CpG sites resulting from spontaneous deamination of 5-methylcytosine, dominates the mutational landscape in healthy cells such as neurons and stem cells across various organs.^[68] In aging brains, SBS1 mutations increase linearly with chronological age, reaching thousands of somatic variants per cell by late adulthood, providing insights into baseline genomic instability.^[69] These patterns extend to applications in evolutionary biology, where SBS1 and related clock-like signatures help reconstruct the timing and drivers of human genetic variation over millennia, distinguishing endogenous from exogenous processes in germline and somatic evolution.^[70] In non-cancer diseases, particularly inherited DNA repair deficiencies, mutational signatures reveal heightened susceptibility to specific mutagens. For instance, in xeroderma pigmentosum (XP), a disorder impairing nucleotide excision repair, UV-induced signatures (SBS7 and SBS7a) predominate even in non-malignant skin cells exposed to sunlight, leading to accelerated mutation accumulation and serving as biomarkers for disease progression and environmental sensitivity.^[71] Similarly, viral integrations contribute distinct signatures in chronic infections; hepatitis B virus (HBV) integration generates rearrangement signatures (e.g., RS1) in liver cells, extending beyond oncogenesis to model persistent inflammatory damage in non-cancerous tissues during viral persistence.^[72] Emerging research has expanded the catalog of mutational signatures, with the COSMIC database incorporating additional profiles in its version 3.4 update (October 2023), which established 49 single-base substitution signatures, enhancing resolution for subtle processes.^[73] Advances in DNA damage mapping, including high-resolution techniques for alkylation and oxidative lesions, now enable improved high-resolution mapping of mutational burdens, facilitating early detection of genotoxic exposures in vivo.^[74] Artificial intelligence approaches, such as deep neural networks for signature decomposition, are predicting novel signatures by analyzing complex mutation spectra, improving de novo discovery in heterogeneous datasets. Recent advances include tools like joint inference methods for indels and substitutions (2025) and refined fitting algorithms such as RESOLVE (2025), improving accuracy in heterogeneous datasets.^[75]^[23]^[76] Looking forward, integration of mutational signatures with single-cell sequencing promises granular resolution of heterogeneity in normal and diseased tissues, allowing reconstruction of clone-specific processes at the cellular level.^[77] Non-human applications are gaining traction in environmental toxicology, where signatures from model organisms exposed to pollutants delineate chemical-specific mutagenesis, aiding regulatory assessments of ecological risks.^[78]

History and development

The concept of mutational signatures began to take shape with advances in next-generation sequencing in the early 2010s, enabling the analysis of entire cancer genomes. The first systematic extraction of mutational signatures occurred in 2012, when researchers analyzed whole-genome sequences from 21 breast cancers and used non-negative matrix factorization (NMF) to identify five distinct single nucleotide variant (SNV) signatures reflecting underlying mutational processes.^[79] This approach was expanded in 2013 through a pan-cancer study of over 7,000 tumors, which cataloged 21 mutational signatures across various cancer types, linking some to environmental factors like tobacco and UV exposure.^[1] Subsequent work in 2015 further explored the etiologies, associating signatures with age, smoking, and other exposures using data from thousands of cancers.^[5] The field advanced significantly with the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium's 2020 publication, which analyzed over 23,000 cancer genomes and refined the catalog to include 49 single-base substitution signatures, along with doublet substitutions and indels, improving resolution and attribution.^[2] The Catalogue of Somatic Mutations in Cancer (COSMIC) database began integrating these signatures in 2013 and has since become the primary repository, with version 3.4 released in October 2023 incorporating expanded sets for SBS, DBS, ID, and other variant types.^[3] Post-2020 developments include experimental validation using models like CRISPR organoids to link signatures to specific mutagens, and projects such as Cancer Grand Challenges' Mutographs (launched 2020, reporting in 2024-2025) identifying novel signatures from normal tissues and global cohorts.^[80] As of 2025, ongoing research continues to uncover therapy-induced and rare signatures, enhancing applications in precision oncology.^[81]

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No information is available for this page. · Learn why
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Cellular and Molecular Pathology Branch, Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, ...