Abstract 3892: Multi-sample whole genome sequencing unveils complex mutational dynamics and clonal evolutionary patterns in young onset breast cancer from Nigeria

Abstract

Abstract Background: Breast cancer (BC) is a heterogenous disease, and the rising global epidemic of premenopausal BC remains poorly understood. Mutational landscape and evolutionary dynamics of BC from diverse geography and populations are largely unknown, preventing the global acceleration of progress towards precision prevention. Methods: To examine etiology and heterogeneity of BC in indigenous Africans, 43 multi-region tumor samples and blood samples from 18 Nigerian women with BC (mean age 53 +/-12.7) were analyzed. Whole Genome Sequencing (WGS) was performed to identify somatic single nucleotide variants, insertions and deletions (ID), copy number alterations (CN), and structural variants (SV). Five mutational signature types (single base substitutions (SBS), double base substitutions (DBS), ID, CN, and SV), were analyzed and compared to COSMIC human cancer signatures. Multi-DPclust was used to classify mutations to clonal and subclonal cluster and create mutational phylogenetic trees. Results: Driver gene analysis highlighted key driver genes, such as TP53, GATA3, and PIK3CA, corroborating prior findings. The most common signature was clock-like (CL) SBS5, followed by APOBEC-related SBS2 and SBS13. Other notable signatures included hypoxia-linked SBS18 and HRD-related DBS13. Signature profiles showed moderate heterogeneity across samples, with distinct patterns observed across mutational clusters. Intra-cluster correlation coefficients for signatures within samples from same patient range from 0.37 to 0.99 (median 0.84). TP53 and GATA3 mutations are common in clonal (early) clusters, with GATA3 often appearing in consecutive subclones. The CL SBS5 signature was prevalent early, while SBS18, linked to hypoxia, became prominent late, highlighting evolving mutational processes across disease progression. Distinct BC subtypes also displayed unique mutational profiles. HR+/HER2+ tumors exhibited higher levels of signature SBS91, while HR-/HER2- tumors exhibited higher levels of the HRD signature SBS3 compared to the rest of the tumors. HR-/HER2- tumors demonstrated lower levels of the mismatch repair-related signature ID1 but higher levels of the HRD signature ID6 and TOP2A signature ID8. Significant differences were observed in SV signatures, with higher SV9 signature activities in HR+/HER2+ tumors and elevated BRCA-related SV3 signature activities in HR-/HER2- tumors. Heterogeneity was also evident in the DBS and CN mutational signatures, further highlighting tumor complexity. Conclusion: This analysis sheds light on the diverse mutational dynamics within and across molecular subtypes, providing insights into the mutational evolution of BC in a non-screen detected young onset population. Ongoing work integrating WGS and transcriptome data will be presented at the conference. Citation Format: Avraam Tapinos, Toshio Yoshimatsu, Ilona Siljander, Mustapha A. Ajan, Ayodele Sanni, Atara Ntekim, Abayomi Odetunde, Elisabeth Sveen, Jeffrey Mueller, Galina Khramtsova, Sulin Wu, Dorothy Nyamai, Mihai Giurcanu, Dezheng Huo, Yonglan Zheng, David C. Wedge, Olufunmilayo I. Olopade. Multi-sample whole genome sequencing unveils complex mutational dynamics and clonal evolutionary patterns in young onset breast cancer from Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3892.