Elucidating Cooperative Genetic Events in DCIS Progression in Mutant p53-Driven Breast Cancer [WGS]
Ductal carcinoma in situ (DCIS) is a mammary lesion characterized by abnormal epithelial cells occurring in mammary ducts while still being confined to the luminal space. Not all DCIS becomes invasive, and no strategy currently exists in patients to stratify indolent DCIS from DCIS at risk of progression. The standard of care includes surgical resection and radiation therapy, which constitutes overtreatment for most women whose DCIS would not progress forward. Several studies of human DCIS and breast cancer suggest that TP53 mutations occur early in DCIS, suggesting a critical role for mutant TP53 in driving disease progression. Using a somatic mouse model of Trp53R245W induced breast cancer (equivalent to the TP53R248W hotspot mutation in humans), we identified DCIS lesions. Through exome-sequencing and low-pass whole genome sequencing, we identified genomic changes shared between DCIS and invasive tumors. This comparison nominated seven murine candidate genes, with eight human orthologs. We assessed the cooperativity of these genes with mutant TP53 in MCF-10A cells using acinar morphogenesis and migration assays. Overexpression of TMEM267 in cells with mutant TP53 caused a significant increase in the filled duct, DCIS-like phenotype. We nominate TMEM267 as a cooperating event with mutant TP53 in DCIS progression. Overall design: Paired end Low-Pass Whole Genome Sequencing of MaPR245W/+ murine mammary tumors and DCIS lesions