Tissue-specific microRNA expression alters cancer susceptibility conferred by a TP53 noncoding variant
Authors: Steven Rosenfeld
Lei Wang
Weiqun Chen
Ya Cao
Zijun Y Xu-Monette
Shuanglin Liu
Zhaoyang Zeng
Qipan Deng
Ling Li
Chi Zhang
Xinfang Yu
Yong Li
Hui Hu
Mingzhi Zhang
Eric Hsi
Ken H Young
Shideng Bao
Zhongxin Lu
Journal: Nature Communications (2019)
Discipline: Multidisciplinary
Keywords: noncoding polymorphism; TP53; soft tissue sarcoma; breast cancer; mouse line
Affiliations: Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA., Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Department of Medical Laboratory, Central Hospital of Wuhan, Wuhan, China., Key Laboratory of Carcinogenesis and Invasion, Ministry of Education, Xiangya Hospital; Cancer Research Institute, Xiangya School of Medicine, Central South University; Key Laboratory of Carcinogenesis, Chinese Ministry of Health, Changsha, China., Department of Pathology, Division of Hematopathology, Duke University Medical Center, Durham, NC, USA., Department of Oncology, the First Affiliated Hospital of Zhengzhou University; Lymphoma Diagnosis and Treatment Center of Henan Province, Zhengzhou, China., Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA., Department of Medical Laboratory, Central Hospital of Wuhan, Wuhan, China. ., Department of Medicine, Section of Epidemiology and Population Sciences, Baylor College of Medicine, Houston, TX, USA. ., Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. .

Abstract:  A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was previously associated with moderate risk of brain tumors and other neoplasms. We find a positive association between this variant and soft tissue sarcoma. In sharp contrast, it is protective against breast cancer. We generated a mouse line carrying this variant and found that it accelerates spontaneous tumorigenesis and glioma development, but strikingly, delays mammary tumorigenesis. The variant creates a miR-382-5p targeting site and compromises a miR-325-3p site. Their differential expression results in p53 downregulation in the brain, but p53 upregulation in the mammary gland of polymorphic mice compared to that of wild-type littermates. Thus, this variant is at odds with Li-Fraumeni Syndrome mutants in breast cancer predisposition yet consistent in glioma predisposition. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression. 

Retracted: No

PubPeer comments:
 Figure 3a showsP53 expression in different tissue types, with GAPDH expression in the same tissue as the control protein. However, the Brain and Mammary GAPDH panels appear to look very similar (marked in red), and possibly the Colon GAPDH panel (marked in paler red) as well. These three blots, although with different exposures, have in common a darker background at the right of the panel, and a slightly larger space between the third and fourth bands, a downward curved fourth band, and a little upwards tip of the sixth band. The original blots in the source data file show the same similarity. Is there a possibility that these might be different exposures (films) of the same blot? ![file] , 
 Figure 3a, an additional finding. * Yellow boxes: the Lung tissue p53 panel looks very similar to the mirror image of the NPT-II blot representing the U87 cell line in Figure S6a. ![file] Here is a close up from the panels shown in the Source Data file, with the NPT-II panel shown in mirror image. There is a characteristic triangular shaped dark background spot, and a little slanted stripe above one of the bands that was not included in Figure S6a s NPT-II panel. ![file] , 
 Dear Dr. Bik, Thank you very much. We are investigating these blots and will provide a response here and to the journal. Best Regards On behalf of the Authors , 
 #3 Any update? , 
 Although the investigation seems to be ongoing, could the authors also examine Figure 3b? While serial samples might be stained differently, I m unable to discern any difference between the two marked images, suggesting these are of the same sample. *** ![file] ,