Comparative genomic analysis reveals bilateral breast cancers are genetically independent.

Bilateral breast cancer (BBC) poses a major challenge for oncologists because of the cryptic relationship between the two lesions. The purpose of this study was to determine the origin of the contralateral breast cancer (either dependent or independent of the index tumor). Here, we used ultra-deep whole-exome sequencing and array comparative genomic hybridization (aCGH) to study four paired samples of BBCs with different tumor subtypes and time intervals between the developments of each tumor. We used two paired primary breast tumors and corresponding metastatic liver lesions as the control. We tested the origin independent nature of BBC in three ways: mutational concordance, mutational signature clustering, and clonality analysis using copy number profiles. We found that the paired BBC samples had near-zero concordant mutation rates, which were much lower than those of the paired primary/metastasis samples. The results of a mutational signature analysis also suggested that BBCs are independent of one another. A clonality analysis using aCGH data further revealed that paired BBC samples was clonally independent, in contrast to clonal related origin found for paired primary/metastasis samples. Our preliminary findings show that BBCs in Han Chinese women are origin independent and thus should be treated separately.