Cooperative Genomic Events Driving Mutant TP53-Driven DCIS Progression

Rhiannon Lynn Morrissey, BS (Advisor: Guillermina Lozano, PhD)

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 p53^R245W induced breast cancer (equivalent to the TP53^R248W 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 human 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. RNAscope revealed increased expression of Tmem267 in DCIS as compared to normal ducts, and a statistically significant increase in Tmem267 expression in mammary tumors. We nominate TMEM267 as a cooperating event with mutant TP53 in DCIS progression.

Advisory Committee:

• Guillermina Lozano, PhD, Chair
• Adel El-Naggar, MD
• Jeffrey Frost, PhD
• Florencia McAllister, MD
• Nicholas Navin, PhD
• Alastair Thompson, MD 

Join via Zoom (Please contact Ms. Morrissey for her Zoom meeting info.)