The Landscape of Chromosome Instability in Breast Cancers and Associations with the Tumor Mutation Burden: An Analysis of Data from TCGA

Abstract

Background

Chromosomal instability (CIN) is a defining characteristic of cancer and is part of the genetic instability of cancer. CIN results in both numeric alterations of chromosomes also called aneuploidy and in gains or losses of parts of chromosome arms but both usually coexist. The frequency and distribution of CIN varies between cancer types and even in the same cancer and breast cancer is no exception. Its presence may provide prognostic and therapeutic opportunities.

Methods

CIN as measured with a score named Aneuploidy Score (AS) derived from single nucleotide polymorphism array studies was examined using the breast cancer study from the Cancer Genome Atlas (TCGA). Correlations of the AS with sub-types of breast cancer and with the tumor mutation burden (TMB) were examined. Specific copy number alterations contributing to the AS and their associations with sub-types were also investigated.

Results

Most breast cancers (about 75% in the series) present some degree of CIN, having an AS of above 5. The remaining 25% have AS of 5 or below. Luminal A sub-type is over-represented in cancers with low AS while the reverse is true for cancers with high AS where the percentage of the three other sub-types, luminal B, Her2 positive and basal is higher. Common gains of chromosomal arms are observed in 1q, 8q and 16p and losses are commonly present in 16q, 17p and 8p but with variability among sub-types. A chromosome loss characterizing basal cancers is observed at 5q. No association of AS with TMB is observed in breast cancer. AS was not predictive for survival outcomes in the entire cohort of breast cancers, but PFS was significant worse in luminal B cancers with high AS.

Conclusion

The copy number alterations landscape of breast cancer reveals specific abnormalities in each sub-type and may help further characterize these sub-types in order to refine classification of these cancers and promote prognostic and therapeutic advancements in the clinic.

Keywords:

• Breast cancer
• aneuploidy score
• aneuploidy
• chromosomal instability
• tumor mutation burden

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.