Divergence of mutational signatures in association with breast cancer subtype

Gili Perry, Maya Dadiani, Smadar Kahana-Edwin, Anya Pavlovski, Barak Markus, Gil Hornung, Nora Balint-Lahat, Ady Yosepovich, Goni Hout-Siloni, Jasmine Jacob-Hirsch, Miri Sklair-Levy, Eitan Friedman, Iris Barshack, Bella Kaufman, Einav Nili Gal-Yam, Shani Paluch-Shimon

Research output: Contribution to journalArticlepeer-review

Abstract

Abnormal molecular processes occurring throughout the genome leave distinct somatic mutational patterns termed mutational signatures. Exploring the associations between mutational signatures and clinicopathological features can unravel potential mechanisms driving tumorigenic processes. We analyzed whole genome sequencing (WGS) data of tumor and peripheral blood samples from 37 primary breast cancer (BC) patients receiving neoadjuvant chemotherapy. Comprehensive clinico-pathologic features were correlated with genomic profiles and mutational signatures. Somatic mutational landscapes were highly concordant with known BC data sets. Remarkably, we observed a divergence of dominant mutational signatures in association with BC subtype. Signature 5 was overrepresented in hormone receptor positive (HR+) patients, whereas triple-negative tumors mostly lacked Signature 5, but expectedly overrepresented Signature 3. We validated these findings in a large WGS data set of BC, demonstrating dominance of Signature 5 in HR+ patients, mostly in luminal A subtype. We further investigated the association between Signature 5 and gene expression signatures, and identified potential networks, likely related to estrogen regulation. Our results suggest that the yet elusive Signature 5 represents an alternative mechanism for mutation accumulation in HR+ BC, independent of the homologous recombination repair machinery related to Signature 3. This study provides theoretical basis for further elucidating the processes promoting hormonal breast carcinogenesis.

Original languageEnglish
Pages (from-to)1056-1070
Number of pages15
JournalMolecular Carcinogenesis
Volume61
Issue number11
DOIs
StatePublished - Nov 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.

Funding

We thank the Cancer Research Center at Sheba Medical Center for the support. We thank Prof. Yuval Tabach and Dr. Sheera Adar from the Hebrew University of Jerusalem for the helpful discussion. This study was supported by a scholar grant from Suzan G. Komen to Prof. Bella Kaufman (SAC110019). Whole Genome sequencing costs were covered by Complete Genomics inc. Dr. Maya Dadiani is supported by the Nehemia Rubin Excellence in Biomedical Research—The TELEM Program. We thank the Cancer Research Center at Sheba Medical Center for the support. We thank Prof. Yuval Tabach and Dr. Sheera Adar from the Hebrew University of Jerusalem for the helpful discussion. This study was supported by a scholar grant from Suzan G. Komen to Prof. Bella Kaufman (SAC110019). Whole Genome sequencing costs were covered by Complete Genomics inc. Dr. Maya Dadiani is supported by the Nehemia Rubin Excellence in Biomedical Research—The TELEM Program.

FundersFunder number
Cancer Research Center at Sheba Medical Center
Nehemia Rubin Excellence in Biomedical Research
Hebrew University of JerusalemSAC110019

    Keywords

    • DNA repair
    • breast cancer
    • hormone-receptor-positive
    • mutational Signature 3
    • mutational Signature 5
    • triple-negative
    • whole genome sequencing

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