Is loss of p53 a driver of ductal carcinoma in situ progression?

Abstract

Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive carcinoma. Multiple studies have shown that DCIS lesions typically possess a driver mutation associated with cancer development. Mutation in the TP53 tumour suppressor gene is present in 15-30% of pure DCIS lesions and in ~30% of invasive breast cancers. Mutations in TP53 are significantly associated with high-grade DCIS, the most likely form of DCIS to progress to invasive carcinoma. In this review, we summarise published evidence on the prevalence of mutant TP53 in DCIS (including all DCIS subtypes), discuss the availability of mouse models for the study of DCIS and highlight the need for functional studies of the role of TP53 in the development of DCIS and progression from DCIS to invasive disease.

Fig. 1. Schematic of breast cancer progression from a normal duct to an invasive carcinoma.

The pink ring structure surrounding each duct represents the myoepithelium. The pink cells represent the outer basal myoepithelium, and the purple cells represent the luminal epithelium. Yellow cells inside the ductal lumen represent abnormal epithelial cells, and red cells inside the ductal lumen represent epithelial cells harboring a TP53 mutation. Mutations in TP53 present as early as in atypical ductal hyperplasia [102]. Created with BioRender.com.

Fig. 2. Morphological subtypes of DCIS (solid, cribriform, papillary, micropapillary and comedo).

The pink ring structure surrounding each duct represents the basal myoepithelium. The purple cells represent the luminal epithelium. Red cells inside the ductal lumen represent malignant epithelial cells filling the breast duct. Grey cells inside the ductal lumen represent necrotic cells, as seen in the comedo subtype. Created with BioRender.com.

Fig. 3. Lollipop chart displaying frequency and distribution of TP53 mutations in DCIS (top) and breast cancer (bottom).

Both charts were created with use of cBioPortal [58, 59]. The green portion of the gene represents the transactivation domain; the red portion of the gene represents the DNA binding domain; and the blue portion represents the tetramerisation domain. The circle representing each mutation is colour-coded to represent the type of mutation, listed in the key below the charts. Missense mutations made up 73% of the mutations in the DCIS dataset and 58% of the mutations in the breast cancer dataset. Studies included in the DCIS dataset are; Abba et al., 2015; Pang et al., 2017; Pareja et al., 2020; Zhou et al., 2009. For breast cancer, the METABRIC breast cancer dataset was used.