The TP53 mutation rate differs in breast cancers that arise in women with high or low mammographic density

Abstract

Mammographic density (MD) influences breast cancer risk, but how this is mediated is unknown. Molecular differences between breast cancers arising in the context of the lowest and highest quintiles of mammographic density may identify the mechanism through which MD drives breast cancer development. Women diagnosed with invasive or in situ breast cancer where MD measurement was also available (n = 842) were identified from the Lifepool cohort of >54,000 women participating in populationbased mammographic screening. This group included 142 carcinomas in the lowest quintile of MD and 119 carcinomas in the highest quintile. Clinico-pathological and family history information were recorded. Tumor DNA was collected where available (n = 56) and sequenced for breast cancer predisposition and driver gene mutations, including copy number alterations. Compared to carcinomas from low-MD breasts, those from high-MD breasts were significantly associated with a younger age at diagnosis and features associated with poor prognosis. Low-and high-MD carcinomas matched for grade, histological subtype, and hormone receptor status were compared for somatic genetic features. Low-MD carcinomas had a significantly increased frequency of TP53 mutations, higher homologous recombination deficiency, higher fraction of the genome altered, and more copy number gains on chromosome 1q and losses on 17p. While high-MD carcinomas showed enrichment of tumor-infiltrating lymphocytes in the stroma. The data demonstrate that when tumors were matched for confounding clinico-pathological features, a proportion in the lowest quintile of MD appear biologically distinct, reflective of microenvironment differences between the lowest and highest quintiles of MD.

Genetic landscape of interval and screen detected breast cancer

“…We did not, however, find evidence to indicate that women with IBC are at a lower PGS-defined breast cancer risk which has been reported by another analysis 41 . Similarly, while it has been proposed that IBC may be associated with a different immune response to SDBC 42 , our analysis of genetically mediated immune evasion or T-cell tumour infiltration provides no support for such an assertion.…”

“…Our findings are consistent with recently published studies reporting higher rates of TP53 mutations and dHR in IBC 9 , 10 . Cheasley et al 9 also reported cancers in low mammographic density breasts ( n = 142) had a higher frequency of TP53 mutations, dHR, higher fraction of the genome altered, more copy number gains and were more likely to be interval breast cancers when compared to cancers in high mammographic density breasts ( n = 119) 42 .…”

Nanomaterial-assisted CRISPR gene-engineering – A hallmark for triple-negative breast cancer therapeutics advancement

“…Its gene product “p53” protein showed 90% missense mutation from CpG sites that span 190 diverse codons in the TP53 gene exon that code the DNA-binding region of the p53 protein [ 68 ]. As a result, p53 losses its function, no or poor DNA binding, and restricted transcription [ 69 , 72 , 73 ] caused enhancement in tumour-infiltrating lymphocytes in the stroma [ 73 ], epithelial-mesenchymal transition, high rate of tumorigenesis, cellular invasion/migration, drug resistance, rapid cell division in TNBC cell lines [ 74 , 75 ], and large-sized tumour growth in females [ 76 ]. Similarly, the R330 frame-shift mutation in the coding region at the C-terminus of the GATA3 gene leads to variations in epithelial to mesenchymal tissues causing overexpression and abnormal regulation of breast cell growth and progression.…”