P63 expression in human tumors and normal tissues: a tissue microarray study on 10,200 tumors

Stefan Steurer,Sören Weidemann,Katharina Möller,Franziska Büscheck,Doris Höflmayer,David Dum,Eike Burandt,Andreas M Luebke,Ronald Simon,Claudia Riemann,Martina Kluth,Sarah Minner,Till S Clauditz,Christoph Fraune,Christian Bernreuther,Waldemar Wilczak,Michael Rink,Anne Menz,Andrea Hinsch,Ria Uhlig,Margit Fisch,Rainer Krech,Guido Sauter,Patrick Lebok,Claudia Hube‐Magg ,Till Krech,Andreas Marx

doi:10.1186/s40364-021-00260-5

Abstract

BackgroundTumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. p63 immunohistochemistry is broadly used for tumor classification but published data on its expression in cancer is conflicting.MethodsTo comprehensively catalogue p63 expression, tissue microarrays (TMAs) containing 12,620 tissue samples from 115 tumor entities and 76 normal tissue types were analyzed.Resultsp63 expression was seen in various normal tissues including squamous epithelium and urothelium. At least occasional weak p63 positivity could be detected in 61 (53%) of 115 different tumor types. The frequencies of p63 positivity was highest in squamous cell carcinomas irrespective of their origin (96–100%), thymic tumors (100%), urothelial carcinomas (81–100%), basal type tumors such as basal cell carcinomas (100%), and various salivary gland neoplasias (81–100%). As a rule, p63 was mostly expressed in cancers derived from p63 positive normal tissues and mostly not detectable in tumors derived from p63 negative cancers. However, exceptions from this rule occurred. A positive p63 immunostaining in cancers derived from p63 negative tissues was unrelated to aggressive phenotype in 422 pancreatic cancers, 160 endometrium cancers and 374 ovarian cancers and might be caused by aberrant squamous differentiation or represent stem cell properties. In 355 gastric cancers, aberrant p63 expression occurred in 4% and was linked to lymph node metastasis (p = 0.0208). Loss of p63 in urothelial carcinomas - derived from p63 positive urothelium - was significantly linked to advanced stage, high grade (p < 0.0001 each) and poor survival (p < 0.0001) and might reflect clinically relevant tumor dedifferentiation.ConclusionThe high prevalence of p63 expression in specific tumor types makes p63 immunohistochemistry a suitable diagnostic tool. Loss of p63 expression might constitute a feature of aggressive cancers.

Highlights

Tumor protein 63 (p63) is a transcription factor of the p53 gene family encoded by the TP63 gene located at chromosome 3q28. p63 regulates the activity of a multitude of genes involved in growth and development of the ectoderm and derived structures and tissues, such as basal layer keratins and cell cycle control genes [1]
P63 is routinely used for tumor type determination, for example distinguishing squamous cell carcinoma from adenocarcinoma in lung biopsies, or urothelial carcinomas from renal cell carcinoma in tumors arising in the kidney as well as determining the tumor origin of metastases from unknown primary tumors
On our normal tissue tissue microarray (TMA), a sufficient number of samples was always interpretable per tissue type to determine the normal tissue p63 expression

Summary

Introduction

Tumor protein 63 (p63) is a transcription factor of the p53 gene family encoded by the TP63 gene located at chromosome 3q28. p63 regulates the activity of a multitude of genes involved in growth and development of the ectoderm and derived structures and tissues, such as basal layer keratins and cell cycle control genes [1]. The fraction of p63 positive cases ranged from 0 to 77% in small cell lung cancer [19, 78], from 50 to 100% in squamous cell lung cancer [22, 52], 0 to 84% in Merkel cell carcinoma [30, 56], 0 to 82% in papillary thyroid carcinoma [36, 74], 1.4 to 100% in colorectal adenocarcinoma [9, 45], 0 to 100% in urothelial carcinoma [41, 76], 0 to 100% in mucinous ovarian carcinoma [7, 79], and from 0 to 25% in endometroid ovarian carcinoma [7, 79] These conflicting data are likely to be caused by the use of different antibodies, immunostaining protocols, and criteria to determine p63 positivity in these studies. Tumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. Tumor protein 63 (p63) is a transcription factor of the p53 gene family involved in differentiation of several tissues including squamous epithelium. p63 immunohistochemistry is broadly used for tumor classification but published data on its expression in cancer is conflicting

Methods

Results

Discussion

Conclusion