scholarly journals Breast Cancer Patient Prognosis Is Determined by the Interplay between TP53 Mutation and Alternative Transcript Expression: Insights from TP53 Long Amplicon Digital PCR Assays

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1531
Author(s):  
Annette Lasham ◽  
Nicholas Knowlton ◽  
Sunali Y. Mehta ◽  
Antony W. Braithwaite ◽  
Cristin G. Print

The TP53 gene locus is capable of producing multiple RNA transcripts encoding the different p53 protein isoforms. We recently described multiplex long amplicon droplet digital PCR (ddPCR) assays to quantify seven of eight TP53 reference transcripts in human tumors. Here, we describe a new long amplicon ddPCR assay to quantify expression of the eighth TP53 reference transcript encoding ∆40p53α. We then applied these assays, alongside DNA sequencing of the TP53 gene locus, to tumors from a cohort of New Zealand (NZ) breast cancer patients. We found a high prevalence of mutations at TP53 splice sites in the NZ breast cancer cohort. Mutations at TP53 intron 4 splice sites were associated with overexpression of ∆133TP53 transcripts. Cox proportional hazards survival analysis showed that interplay between TP53 mutation status and expression of TP53 transcript variants was significantly associated with patient outcome, over and above standard clinical and pathological information. In particular, patients with no TP53 mutation and a low ratio of TP53 transcripts t2 to t1, which derive from alternative intron 1 acceptor splice sites, had a remarkably good outcome. We suggest that this type of analysis, integrating mutation and transcript expression, provides a step-change in our understanding of TP53 in cancer.

2020 ◽  
Vol 41 (8) ◽  
pp. 1017-1029 ◽  
Author(s):  
Jessica Beck ◽  
Casmir Turnquist ◽  
Izumi Horikawa ◽  
Curtis Harris

Abstract Cellular senescence and the associated secretory phenotype (SASP) promote disease in the aged population. Targeting senescent cells by means of removal, modulation of SASP or through cellular reprogramming represents a novel therapeutic avenue for treating cancer- and age-related diseases such as neurodegeneration, pulmonary fibrosis and renal disease. Cellular senescence is partly regulated by the TP53 gene, a critical tumor suppressor gene which encodes 12 or more p53 protein isoforms. This review marks a significant milestone of 40 years of Carcinogenesis publication history and p53 research and 15 years of p53 isoform research. The p53 isoforms are produced through initiation at alternative transcriptional and translational start sites and alternative mRNA splicing. These truncated p53 isoform proteins are endogenously expressed in normal human cells and maintain important functional roles, including modulation of full-length p53-mediated cellular senescence, apoptosis and DNA repair. In this review, we discuss the mechanisms and functions of cellular senescence and SASP in health and disease, the regulation of cellular senescence by p53 isoforms, and the therapeutic potential of targeting cellular senescence to treat cancer- and age-associated diseases.


2020 ◽  
Author(s):  
Yong Li ◽  
Junjun Wu ◽  
Jun Lei ◽  
Fan Zhou ◽  
Xiangbao Yin ◽  
...  

Abstract Background: Detection of tumor-specific mutations in exosomal DNA (exoDNA), a promising liquid biopsy material, has been used to assess the prognosis of hepatocellular carcinoma (HCC) patients. This study was the first to use a droplet digital PCR (ddPCR) platform to detect tumor-specific mutations in circulating exoDNA and to evaluate the prognosis of HCC patients.Methods: Blood samples from 40 HCC patients were obtained between 2018 and 2019, with clinically annotated follow-up until 2020. A ddPCR platform was used to detect an HCC tumor-specific mutation in the TP53 gene. We analyzed the correlation between TP53 mutation detected in circulating exoDNA and patient clinical data. The ratio of mutant droplets/total droplets (MD/TD) was calculated according to ddPCR results.Results: TP53 mutations in circulating exoDNA were detected in 33 of the 40 patients (82.5%). Patients with high MD/TD (>62.5%) were more likely to show microvascular invasion (P=0.028) and high MD/TD predicted a shorter recurrence-free survival time (P<0.001).Conclusions: High MD/TD of TP53 detected in serum was associated with microvascular invasion and might be used to predict the prognosis of HCC patients. The diagnostic performance of detecting exosome-derived tumor DNA will likely improve when more mutations in other tumor-specific genes are combined.


Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3422
Author(s):  
Sebastien M. Joruiz ◽  
Jessica A. Beck ◽  
Izumi Horikawa ◽  
Curtis C. Harris

The TP53 gene is a critical tumor suppressor and key determinant of cell fate which regulates numerous cellular functions including DNA repair, cell cycle arrest, cellular senescence, apoptosis, autophagy and metabolism. In the last 15 years, the p53 pathway has grown in complexity through the discovery that TP53 differentially expresses twelve p53 protein isoforms in human cells with both overlapping and unique biologic activities. Here, we summarize the current knowledge on the Δ133p53 isoforms (Δ133p53α, Δ133p53β and Δ133p53γ), which are evolutionary derived and found only in human and higher order primates. All three isoforms lack both of the transactivation domains and the beginning of the DNA-binding domain. Despite the absence of these canonical domains, the Δ133p53 isoforms maintain critical functions in cancer, physiological and premature aging, neurodegenerative diseases, immunity and inflammation, and tissue repair. The ability of the Δ133p53 isoforms to modulate the p53 pathway functions underscores the need to include these p53 isoforms in our understanding of how the p53 pathway contributes to multiple physiological and pathological mechanisms. Critically, further characterization of p53 isoforms may identify novel regulatory modes of p53 pathway functions that contribute to disease progression and facilitate the development of new therapeutic strategies.


PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0250986
Author(s):  
Yoon Jin Cha ◽  
Dooreh Kim ◽  
Soong June Bae ◽  
Sung Gwe Ahn ◽  
Joon Jeong ◽  
...  

Background Yes-associated protein 1 (YAP1) is a key effector molecule regulated by the Hippo pathway and described as a poor prognostic factor in breast cancer. Tumor protein 53 (TP53) mutation is well known as a biomarker related to poor survival outcomes. So far clinical characteristics and survival outcome according to YAP1 and TP53 mutation have been poorly identified in breast cancer. Patients and methods Retrospectively, 533 breast tumor tissues were collected at the Seoul St Mary’s hospital and Gangnam Severance Hospital from 1992 to 2017. Immunohistochemistry with YAP1 and p53 specific antibodies were performed, and the clinical data were analyzed. Results Mutant p53 pattern was associated with aggressive tumor features and advanced anatomical stage. Inferior overall survival (OS) and recurrence free survival (RFS) were related with mutant p53 pattern cases with low nuclear YAP1 expression (P = 0.0009 and P = 0.0011, respectively). Multivariate analysis showed that mutant p53 pattern was an independent prognostic marker for OS [hazard ratios (HR): 2.938, 95% confidence intervals (CIs): 1.028–8.395, P = 0.044] and RFS (HR: 1.842, 95% CIs: 1.026–3.304). However, in cases with high nuclear YAP1 expression, there were no significantly difference in OS and RFS according to p53 staining pattern. Conclusion We found that mutant p53 pattern is a poor prognostic biomarker in breast tumor with low nuclear YAP1 expression. Our findings suggest that interaction between nuclear YAP1 and p53 expression pattern impact survival outcomes.


2020 ◽  
Author(s):  
Yong Li ◽  
Junjun Wu ◽  
Jun Lei ◽  
Fan Zhou ◽  
Xiangbao Yin ◽  
...  

Abstract Background: Detection of tumor-specific mutations in exosomal DNA (exoDNA), a promising liquid biopsy material, has been used to assess the prognosis of hepatocellular carcinoma (HCC) patients. This study was the first to use a droplet digital PCR (ddPCR) platform to detect tumor-specific mutations in circulating exoDNA and to evaluate the prognosis of HCC patients.Methods: Blood samples from 40 HCC patients were obtained between 2018 and 2019, with clinically annotated follow-up until 2020. A ddPCR platform was used to detect an HCC tumor-specific mutation in the TP53 gene. We analyzed the correlation between TP53 mutation detected in circulating exoDNA and patient clinical data. The ratio of mutant droplets/total droplets (MD/TD) was calculated according to ddPCR results.Results: TP53 mutations in circulating exoDNA were detected in 33 of the 40 patients (82.5%). Patients with high MD/TD (>62.5%) were more likely to show microvascular invasion (P=0.028) and high MD/TD predicted a shorter recurrence-free survival time (P<0.001).Conclusions: High MD/TD of TP53 detected in serum was associated with microvascular invasion and might be used to predict the prognosis of HCC patients. The diagnostic performance of detecting exosome-derived tumor DNA will likely improve when more mutations in other tumor-specific genes are combined.


2020 ◽  
Vol 16 (34) ◽  
pp. 2863-2878
Author(s):  
Yang Liu ◽  
Qian Du ◽  
Dan Sun ◽  
Ruiying Han ◽  
Mengmeng Teng ◽  
...  

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.


Tumor Biology ◽  
2006 ◽  
Vol 27 (5) ◽  
pp. 252-260
Author(s):  
Gregor Westhof ◽  
Michael Olbrecht ◽  
Manfred Wolff ◽  
Sven Schiermeier ◽  
Ralf C. Zimmermann ◽  
...  

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