Regional hypermutation, referred to as “kataegis,” occurs frequently in breast cancer.
Major finding: Regional hypermutation, referred to as “kataegis,” occurs frequently in breast cancer.
Concept: A tumor's mutational and evolutionary history can be inferred from its genome sequence.
Impact: Most mutations are found in only a subset of the multiple subclones within each breast tumor.
Little is known about the mutational processes that underlie the evolution of breast cancer. To better understand breast cancer development, Nik-Zainal and colleagues performed whole-genome sequencing on 21 primary breast cancers representing different breast cancer subtypes (estrogen receptor-positive, HER2-positive, triple-negative, BRCA1-mutant, and BRCA2-mutant) and characterized the location and type of somatic mutations for each tumor. In one study, the authors used bioinformatic algorithms to infer the order of mutations based on their prevalence among sequencing reads, with the reasoning that genetic alterations present in a high fraction of reads represent early events in tumor evolution. These findings suggested that breast tumors are composed of multiple discrete subclones representing various percentages of the total tumor mass, although expansion of one dominant subclonal lineage representing over 50% of the tumor cells may be the final rate-limiting step in breast cancer development. The other study based on these 21 tumors focused more closely on their mutation signatures to better understand the underlying DNA damage and repair processes. A mathematical analysis of the complete genome sequences indicated that 5 biologically distinct classes of base substitutions were present in the tumors and contributed to each tumor's catalog of somatic mutations to a different extent, either contemporaneously or at different stages in tumor evolution. Interestingly, clusters of cytosine substitutions at TpC dinucleotides were overrepresented in many of the tumors and frequently occurred on the same DNA strand. This phenomenon of localized hypermutation, referred to as “kataegis” (from the Greek word for “thunderstorm”), was observed in more than half of the breast cancers analyzed but was not seen in previously published melanoma and lung cancer genomes. Combined, these whole-genome studies advance our understanding of breast cancer evolution as well as the mutational mechanisms that contribute to tumorigenesis.