Breast Cancer Biomarkers with Clinical Relevance Identified by Massively-parallel DNA and RNA Sequencing

Sammanfattning: Women have a 10% lifetime risk of developing breast cancer, and the disease has surpassed lung cancer as the most frequently diagnosed type of cancer in the world. Breast cancer originates in the epithelial cells of the mammary gland and tumor cells have undergone a series of genetic and phenotypic changes that confer tumor promoting properties.Genomic rearrangement is a common phenomenon in cancer, involving breakage and dysfunctional repair of chromosomes. With the aim to characterize such variants and their progression from primary to metastatic disease, we performed whole-genome sequencing of paired primary tumors and metastases (study I) and paired contralateral breast cancers (CBC) (study II). Metastasis rearrangement profiles bore a remarkable resemblance to the respective primary tumors (median 89% shared), indicating that the rearrangements were early events in tumor development, remaining stable throughout progression. Our study on CBC (study II) subsequently allowed us to identify 1 in 10 tumor pairs that likely represented metastatic spread rather than a new primary tumor (76% of rearrangements shared). One of the risk factors for breast cancer is high exposure to estrogens; signaling via estrogen receptor (ER) α is considered the most important driver for the 75% of tumors expressing this marker. Mutations in the gene for ERα are known to be common in endocrine therapy-refractory breast cancer and confer resistance to standard anti-hormonal treatment. In study III, we interrogated RNA-seq data from 3217 primary breast tumors from the SCAN-B initiative and found that 1% of tumors were positive for one of the mutations at surgery. For those patients that received adjuvant endocrine therapy, the mutations were associated to worse overall and relapse-free survival. In study IV, we further explored the SCAN-B dataset to investigate the phenotypic properties and prognosis associated to high expression of the much less well studied ERβ. We discovered that this receptor was not abundantly expressed, with 1/3 of tumors entirely negative. Further, we saw that patients with high levels of ERβ mRNA had slightly improved overall survival and that the expression of ERβ was associated to expression of genes involved in immune cell activation.In summary, we have employed sequencing technology to study breast cancer patient material to identify and assess the validity of genomic and transcriptomic changes that may both be of value as potential biomarkers, and in elucidating biological mechanisms that drive or suppress breast cancer progression.