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. 2025 Mar:53:102315.
doi: 10.1016/j.tranon.2025.102315. Epub 2025 Feb 4.

Decoding mutational signatures in breast cancer: Insights from a multi-cohort study

Margaux Betz  1 , Andréa Witz  2 , Julie Dardare  3 , Cassandra Michel  2 , Vincent Massard  4 , Romain Boidot  5 , Pauline Gilson  2 , Jean-Louis Merlin  2 , Alexandre Harlé  2
Affiliations

Decoding mutational signatures in breast cancer: Insights from a multi-cohort study

Margaux Betz et al. Transl Oncol. 2025 Mar.

Abstract

Purpose: Diagnosis and treatment decisions of hormonal breast cancers (BC) are now guided by genomic mutations determination, combined into mutational signatures, and provide insight into the patients' genomic landscape. This work aims to compare genomic data and signatures extracted from tissue samples collected in the CICLADES study to existing cohorts. Ultimately, the goal is to prove the accuracy of smaller cohorts and provide new relevant data.

Materials and methods: DNA from patients of the CICLADES cohort was extracted, sequenced, and custom filtering was applied to the resulting files. Genomic data was pulled from 6 BC cohorts available on cBioPortal.com. In total, 2303 samples were analyzed. Mutational signatures were extracted and matched to known signatures of the Catalogue of Somatic Mutations in Cancer (COSMIC). Tumor Mutation Burden (TMB) and hypermutation were estimated and compared between samples.

Results: PIK3CA and TP53 represented the two genes highly mutated across all cohorts. TMB was similar between the CICLADES and CBSM groups, however the MSKCC population showed a significantly higher TMB than both. Nine signatures were extracted, with recurring Single Base Substitutions (SBS) signatures like SBS1, SBS2 and SBS5. The presence of APOBEC-specific signatures was concordant with cohorts presenting APOBEC enrichment. The mean number of mutations was significantly higher in enriched samples for each analyzed cohort.

Conclusion: The use of comprehensive genomic profiling provided accurate evaluation of the TMB and extraction of signatures consistent with published literature. The genomic analysis of the tissue samples of the CICLADES cohort brings new and relevant data, comparable to results found in bigger cohorts.

Keywords: Breast cancer; Genomic database; Mutational signature; Next generation sequencing.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
A. Listing of 7 genes of interest and their percentage of mutated samples for each group analyzed. B. and C. Dual representation of the commonly mutated genes between the groups. B. Upset plot generated with the top 15 mutated genes of each group, created with the UpsetR package [26] (v1.4.0). The top plot shows the size of each intersection, while the bottom blot shows from which groups the intersections are occurring C. Venn diagram generated with the same top 15 mutated genes of each group, created with the VennDiagram package [27] (v1.7.3). The number of genes in each intersection is listed with its corresponding percentage.
Fig. 2
Fig. 2
Violin plots depict the distribution of the TMB within the analyzed samples. Data is represented in number of mutations per Mega base (Mb). ***: P < 0.001 and ns not significant (Mann-Whitney u-test).
Fig. 3
Fig. 3
Representation of the exposure of each signature within the analyzed groups. The contribution of each signature is fractioned by normalizing its exposure to the total exposure of each sample, represented by one stack. A. Exposure of the 19 analyzed samples of the CICLADES group. B. Exposure of the 1128 analyzed samples of the MSKCC group. C. Exposure of the 762 analyzed samples of the CBSM group. D. Exposure of the 176 analyzed samples of the METABRIC group.
Fig. 4
Fig. 4
Box plot representation of the distribution of number of mutations between APOBEC enriched and APOBEC not-enriched samples. Data is represented in log10 number of mutations per sample, ***: P < 0.001 (Mann-Whitney u-test).
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