Truncating mutations of PPM1D are found in blood DNA samples of lung cancer patients

British Journal of Cancer
A ZajkowiczM Rusin

Abstract

PPM1D (WIP1) negatively regulates by dephosphorylation many proteins including p53 tumour suppressor. The truncating mutations (nonsense and frameshift) in exon 6 of PPM1D were found recently in blood cells of patients with breast, ovarian or colorectal cancer. These mutants code for gain-of-function PPM1D with retained phosphatase activity. Their significance in carcinogenesis is unknown. The exon 6 of PPM1D was sequenced in blood DNA of 543 non-small-cell lung cancer patients (NSCLC). The functional significance of selected PPM1D alterations (Arg458X, Lys469Glu) was compared with the wild-type gene and examined by recombinant DNA techniques, immunoblotting and luciferase reporter assays. The frameshift mutations were found in five NSCLC patients (5/543; 0.92%), all of them had squamous cell carcinomas (5/328; 1.5%). All patients with the mutations were exposed, before the blood collection, to the DNA damaging agents as a part of chemotherapeutic regimen. Functional tests demonstrated that truncating mutation Arg458X causes enhancement of dephosphorylation activity of PPM1D toward serine 15 of p53, whereas Lys469Glu version is equivalent to the wild-type. Neither version of PPM1D (wild-type, Arg458X, Lys469Glu) significantly m...Continue Reading

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Citations

Jul 13, 2016·Genes, Chromosomes & Cancer·Marta CardosoManuel R Teixeira
Dec 9, 2016·Current Opinion in Hematology·Arnold Ganser, Michael Heuser
Sep 7, 2018·Circulation Journal : Official Journal of the Japanese Circulation Society·Soichi SanoKenneth Walsh
Nov 7, 2019·Annual Review of Pathology·Megan A EvansKenneth Walsh
Feb 18, 2016·Oncotarget·Anastasia R GoloudinaOleg N Demidov
Apr 26, 2017·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Soňa PecháčkováLibor Macurek
Mar 10, 2019·Journal of Human Genetics·Mitchell J MachielaStephen J Chanock
Aug 31, 2018·Nature Genetics·Clare TurnbullRichard S Houlston
Jan 10, 2017·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Christopher J GibsonBenjamin L Ebert
Feb 23, 2021·British Journal of Haematology·Simon HusbyKirsten Grønbæk
Jan 17, 2017·Seminars in Hematology·Max JanSiddhartha Jaiswal
Mar 21, 2021·Nature Communications·Patryk SkowronMichael D Taylor
Jul 11, 2020·Pharmacology & Therapeutics·Rui KamadaKazuyasu Sakaguchi

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Methods Mentioned

BETA
blood draw
PCR
transfection
transfecting
Assay

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