Mutational signatures

[5] Deciphering mutational signatures in cancer provides insight into the biological mechanisms involved in carcinogenesis and normal somatic mutagenesis.

More recently, mutational signatures profiling has proven successful in guiding oncological management and use of targeted therapies (e.g. immunotherapy in mismatch repair deficient of diverse cancer types,[8] platinum and PARP inhibitor to exploit synthetic lethality in homologous recombination deficient breast cancer).

Signature 3, seen in homologous recombination (HR) deficient tumour, is associated with increased burden of large indels (up to 50 nucleotides) with overlapping microhomology at the breakpoints.

[4] Signature 1 features a predominance of C>T transition (genetics) in the Np[C>T]G trinucleotide contexts and correlates with the age of patient at time of cancer diagnosis.

[13] The exact roles and mechanisms underlying APOBEC-mediated genome editing are not yet fully delineated, but activation-induced cytidine deaminase(AID)/APOBEC complex is thought to be involved in host immune response to viral infections and lipid metabolism.

[16] Somatic enrichment for transversion mutations (G:C>T:A) has been associated with base excision repair (BER) deficiency and linked to defective MUTYH, a DNA glycosylase, in colorectal cancer.

[18] Selected exogenous genotoxins/carcinogens and their mutagen-induced DNA damage and repair mechanisms have been linked to specific molecular signatures.

Signature 9 has been identified in chronic lymphocytic leukemia and malignant B-cell lymphoma and feature enrichment for T>G transversion events.

[25] During the 1990s, Curtis Harris at the US National Cancer Institute and Bert Vogelstein at the Johns Hopkins Oncology Center in Baltimore reviewed data showing that different types of cancer had their own unique suite of mutations in p53, which were likely to have been caused by different agents,[3][26] such as the chemicals in tobacco smoke or ultraviolet light from the sun.

These were detailed maps showing all the genetic changes and mutations that had occurred within two individual cancers—a melanoma from the skin and a lung tumor.

The forensic scientist might strike it lucky and find a set of perfect prints on a windowpane or door handle that match a known killer.

However, they are much more likely to uncover a mish-mash of fingerprints belonging to a whole range of folk—from the victim and potential suspects to innocent parties and police investigators—all laid on top of each other on all sorts of surfaces.

[28] This is very similar to cancer genomes where multiple mutational patterns are commonly overlaid one over another making the data incomprehensible.

Alexandrov demonstrated that mutational patterns from individual mutagens found in a tumor can be distinguished from one another using a mathematical approach called blind source separation.

Conceptual workflow of somatic mutational signatures identification. Diverse mutagenesis processes shape the somatic landscape of tumors. Deciphering the underlying patterns of cancer mutations allows to uncover relationships between these recurrent patterns of mutations and infer possible causal mutational processes.
The 96 mutation types concept from Alexandrov et al. [ 4 ] Considering the 5' flanking base (A, C, G, T), the 6 substitution classes (C>A, C>G, C>T, T>A, T>C, T>G) and 3' flanking base (A, C, G, T) leads to a 96 mutation types classification (4 x 6 x 4 = 96). The 16 possible mutation types of the substitution class C>A are shown as an example.
Role of MUTYH in base excision repair and somatic signature. Defective MUTYH in colorectal cancer leads to enrichment for transversion mutations (G:C>T:A), [ 17 ] which has been linked to COSMIC Signature 18 described by Alexandrov et al [ 4 ] (Signature 18 plot R code ). [ 10 ]