Abstract 4805: Whole genome sequencing of primary breast cancers and matched distant metastases

Abstract

Metastatic disease is the main cause of death for breast cancer patients, but it is still unclear whether primary tumor characteristics are predictive of the metastasis phenotype. Our aim was to investigate, by analyzing chromosomal structural variation, the clonal similarities between primary breast tumors and their matched distant metastases. For 11 patients, we performed low-coverage (∼10x) whole-genome sequencing on 11 primary breast tumors and 13 matched distant metastases to enumerate chromosomal rearrangements. The tumor genomes (n = 24) harbored a median of 85 (range 18-405) chromosomal rearrangements per tumor, with a median of 82 (26-310) in primaries compared to 87 (18-405) in distant metastases. Similarity between tumors was assessed based on presence or absence of chromosomal rearrangements. Concordance between matched primaries and distant metastases from the same patient was high, with a median of 89% rearrangements being shared (range 61-100%). Nearly all of the rearrangements were patient-specific, with very little overlap when comparing all possible pairings of tumors from different patients (median 3%). The tumors exhibited different genomic patterns of rearrangements: some carried events scattered throughout the genome while other tumors had events in densely clustered foci - chromothripsis-like hotspots - at a few chromosomal locations. Irrespective of the type of rearrangement profile of the tumor genomes, the patterns were highly conserved between the primary tumor and metastasis from the same patient, although in general metastases acquired additional rearrangement events. Our study suggests that analysis of structural variation in tumor genomes could be useful for identifying tumor origin, facilitating cancer detection via measurement of rearrangements in circulating tumor DNA, and estimating degree of relatedness between primary tumors and metastases. Moreover, our finding that distant metastases have a close clonal relationship to the primary tumor at the level of chromosomal structure is most consistent with chromosomal rearrangements being early events in breast cancer progression that remain stable during the development from a primary tumor to its distant metastasis.

Christian Brueffer

Bioinformatician and Data Scientist

Freelance Bioinformatician and Data Scientist with interests including disease biology and diagnostics, particularly in cancer, and open source bioinformatics.