Intratumour heterogeneity of p53 expression; causes and consequences

Abstract

Genomic alterations in different types of cancer have been identified by comprehensive sequencing methodologies, revealing TP53 as the most frequently mutated gene across the majority of human cancer types. Cytotoxic treatments are still major cancer therapy strategies but cancer recurrence due to therapy resistance is a major challenge. Resistant cell populations may be associated with TP53 mutant clones exhibiting abnormal p53 expression patterns in tumours. Given data that levels of mutant p53 influence cancer cell growth and survival, understanding the mechanisms underlying intratumour heterogeneity of p53 can be exploited to design strategies that improve patient survival. The patterns of p53 protein examined by immunohistochemistry of both premalignant and malignant tissues are complex, ranging from intense staining of all tumour cell nuclei to complete absence of staining and with many intermediate phenotypes. Animal models that express only mutant proteins and adoption of international standards for terminology have brought greater clarity to understanding the causes of variation and are at the same time demonstrating the utility of p53 in oncology. In addition to p53 mutation, MDM2 and chaperone activities, gene copy number and TP53 mRNA levels linked to proliferative activity and differentiation are all now established as causes of variation in p53 staining, with clinical implications. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

miR‑378 in combination with ultrasonic irradiation and SonoVue microbubbles transfection inhibits hepatoma cell growth

“…Cyclin D1, a member of the Cyclin family and also a proto-oncogene, promotes cell G1/S phase via cdK, thereby promoting cancer development (24)(25)(26). p53 is a tumor suppressor gene located at 17p in human chromosomes and is normally expressed at low levels in the nucleus (27)(28)(29)(30). Mutated p53 genes have been found in various human tumors, including in Hcc (27)(28)(29)(30).…”

“…p53 is a tumor suppressor gene located at 17p in human chromosomes and is normally expressed at low levels in the nucleus (27)(28)(29)(30). Mutated p53 genes have been found in various human tumors, including in Hcc (27)(28)(29)(30). p53 proteins are involved in several cellular processes, including gene transcription, dna repair, cell cycle, genome stabilization, chromosome segregation, senescence, apoptosis and angiogenesis (27)(28)(29)(30).…”

Ex Vivo Organoid Cultures Reveal the Importance of the Tumor Microenvironment for Maintenance of Colorectal Cancer Stem Cells

“…The p53 IHC staining was assessed as previously described [63,64]. IHC patterns of wild type p53 is characterized by variable proportions of tumor cell nuclei showing a mixture of negative, weak and strong p53 staining.…”

“…The CY pattern is characterized by diffuse cytoplasmic staining with lack of strong nuclear staining. CA is characterized by absence of nuclear staining of tumor cells but detectable nuclear staining of p53 in non-malignant stromal cells such as fibroblasts and lymphocytes [63,64].…”

Genes in Tumor Formation

“…TP53 is known to be the most frequently mutated gene across the majority of human cancer types. Therapy resistance to cytotoxic treatments is one of the consequences [21]. In premalignant and malignant tissues, TP53 can be absent in some cells, or over-expressed in others, meaning a heterogeneity of gene expression levels.…”