The high cosine similarity between some single-base substitution mutational signatures and their characteristic flat profiles could suggest the presence of overfitting and mathematical artefacts. The newest version (v3.3) of the signature database available in the Catalogue Of Somatic Mutations In Cancer (COSMIC) provides a collection of 79 mutational signatures, which has more than doubled with respect to previous version (30 profiles available in COSMIC signatures v2), making more critical the associations between signatures and specific mutagenic processes. This study both provides a systematic assessment of the de novo extraction task through simulation scenarios based on the latest version of the COSMIC signatures and highlights, through a novel approach using archetypal analysis, which COSMIC signatures are redundant and more likely to be considered as mathematical artefacts. 29 archetypes were able to reconstruct the profile of all the COSMIC signatures with cosine similarity (Formula presented.) 0.8. Interestingly, these archetypes tend to group similar original signatures sharing either the same aetiology or similar biological processes. We believe that these findings will be useful to encourage the development of new de novo extraction methods avoiding the redundancy of information among the signatures while preserving the biological interpretation.

Unravelling the instability of mutational signatures extraction via archetypal analysis

Pancotti C.
First
;
Rollo C.;Birolo G.;Benevenuta S.;Fariselli P.
;
Sanavia T.
Last
2023-01-01

Abstract

The high cosine similarity between some single-base substitution mutational signatures and their characteristic flat profiles could suggest the presence of overfitting and mathematical artefacts. The newest version (v3.3) of the signature database available in the Catalogue Of Somatic Mutations In Cancer (COSMIC) provides a collection of 79 mutational signatures, which has more than doubled with respect to previous version (30 profiles available in COSMIC signatures v2), making more critical the associations between signatures and specific mutagenic processes. This study both provides a systematic assessment of the de novo extraction task through simulation scenarios based on the latest version of the COSMIC signatures and highlights, through a novel approach using archetypal analysis, which COSMIC signatures are redundant and more likely to be considered as mathematical artefacts. 29 archetypes were able to reconstruct the profile of all the COSMIC signatures with cosine similarity (Formula presented.) 0.8. Interestingly, these archetypes tend to group similar original signatures sharing either the same aetiology or similar biological processes. We believe that these findings will be useful to encourage the development of new de novo extraction methods avoiding the redundancy of information among the signatures while preserving the biological interpretation.
2023
13
1049501
1049511
archetypal analysis; cancer genomics; COSMIC; matrix factorization; mutational signatures
Pancotti C.; Rollo C.; Birolo G.; Benevenuta S.; Fariselli P.; Sanavia T.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1908710
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