Whole-Genome Sequencing of Breast Cancer Patients Demonstrates Segregation to Two Distinct Mutational Signatures

Mutational processes occurring throughout the genome result in distinct patterns of mutations termed mutational signatures. Although prevalent in cancer genomes, only some of these signatures can be traced back to known mechanisms driving cancer initiation and progression. Distinct breast cancer subtypes require different treatments and carry different outcomes. Characterizing genomic signatures of the various subtypes and understanding their underlying mechanisms may hold clinical opportunities.

We collected biopsies and blood samples from 37 primary breast cancer patients prior to commencement of neoadjuvant chemotherapy administration, sequenced their genomes via whole genome sequencing (WGS) and followed their clinical course post-treatment. Then, we analyzed the genomic data for mutations, copy number alterations, structural variations and mutational signatures.

The resulting profiles of somatic alterations mostly correspond with known breast cancer datasets. However, mutational signature analysis reveals novel findings correlating signatures with specific molecular subtypes. Whereas triple-negative breast cancer patients present mostly and expectedly Signature 3, they lack Signature 5 – which in turn dominates the mutational landscapes of hormone receptor positive patients, absent of Signature 3.

This study demonstrates the segregation of the dominant mutational processes according to breast cancer subtype. Our results suggest that the yet elusive Signature 5 represents an alternative mechanism for mutagenesis and breast cancer initiation, independent of the homologues recombination repair machinery related to Signature 3. Further research is necessary to unfold this mechanism, which may have therapeutic implications in the future.