Pre-diagnostic exposures, mutational signatures, and immune profiles in triple-negative breast cancer: An overview of the PREMISE-TN project

Triple negative breast cancer (TNBC) exhibits distinct evolutionary pathways reflected in heterogeneous mutational and immune profiles. To better understand the relationships between prediagnostic exposures, inherited genetic variation, mutational and immune profiles in TNBCs, the PRediagnostic Exposures, Mutations, Immune SignaturEs-Triple Negative (PREMISE-TN) project performed whole exome sequencing (WES) of matched formalin-fixed paraffin embedded tumor tissue and germline DNA samples from 322 TNBC patients from four prospective cohort studies, the Nurses' Health Study (NHS, NHS II) and the Cancer Prevention Study (CPS II, CPS3). After excluding 66 mis-matched tumor normal-pairs and 32 pairs where either the tumor or blood sample did not reach the target coverage (70% of bases covered at 20x), 224 pairs were available for analysis. The median sequencing depth for tumor samples in these pairs was 111.2x (range=7.4x-481x); the median for blood samples was 283.4x (range=156.2x-652.1x). Mutational calling and sequencing quality assessment and control is underway. Patients' age at diagnosis ranged from 34-86 years (median=58), and year of diagnosis ranged from 1976-2018 (median=2004). 56 (28.7%) of the patients were premenopausal at diagnosis. Most tumors (n=162, 88.5%) were stage I-II; 19 (10.3%) were stage III and 1 (0.5%) was stage IV. PREMISE-TN integrated somatic mutational profiles with other data from these cohorts, including: germline genome-wide association study data, breast cancer risk factors, tumor immune signatures, and radiologic and pathologic phenotypes derived from digital images. Preliminary studies identified associations between germline polygenic risk scores (PRS) and breast tumor immune features, including inverse associations between PRS for immune-mediated conditions and interferon signaling in both breast tumors and adjacent normal tissue. Other studies examined the influence of reproductive factors on the breast tumor microenvironment. Future work will assess associations of these features with tumor mutational profiles. The data resource generated by PREMISE-TN will enable the investigation of how genetic and nongenetic risk factors influence breast tumor mutational signatures and immune response.