Association of TP53 polymorphisms on the risk of Wilms tumor

Abstract

Our results demonstrate an association between PIN3 and age at diagnosis, as well as an association of PEX4 and risk of development of WT.

Review of prognostic and predictive aspects of mutated TP53 in Wilms’ tumor biology with morphological report and molecular analysis of 37-year-old man’s nephroblastoma

“…Thus, the H&E picture was characteristic enough for a straightforward diagnosis of nephroblastoma, soapplianceofWT1stainingwasofonlyconfirma-tivevalueinourcase.ThatiswhyWT1analysiswas notfurtherdeveloped,particularlyatthegenelevel. TP53mutationsaresupposedtobeassociatedwith anaplasiainWilms'tumor(anaplasticsubtypeordiffuse anaplasia) [5,20]. However, in our case there wasnoanaplasiabuttherewasahighfrequencyof TP53 mutation in tumor tissue.…”

“…Moreover, a novel intronicmutation,IVS2+37C>T,wasfoundinonly onepatient(2.2%)inbloodsamples [5].Characteristically,thePIN3duplicatedallelewasafeatureof 20-month later occurring nephroblastomas. TP53 somaticmutationwasrelatedtopoorsurvivalprobability of 37.5% in reference to 85.0% for patients withoutsomaticmutationswithnostatisticalsignificance [5].OccurrenceofTP53PEX4Cwasassoci-atedwithhigherriskforWTonset [5].Wedetected polymorphismsinTP53p.Pro72Arg,althoughwith anunknownimpactonthedevelopmentofAWT.In conclusion,ourgeneticanalysisrevealedmutationin theTP53gene,whichsuggeststhatcarcinogenesisin thecaseofchildrenwithWTandAWTcouldfollow asimilarmolecularbackground. Diffuseanaplasiaisanominousprognosticfactor in comparison with non-anaplastic tumors, or with focalanaplasia [5].However,inourcasenoanaplasia was detected in the histopathological report.…”

“…It is possible that thewildtypeallelewaslostduringcarcinogenesisin tumortissue.However,thisspeculationrequiresfurthermolecularstudies.Ontheotherhand,wecould maketheconclusionthatp.R249MTP53mutation detectedinthetumorofourcaseappearstobeoneof theearliestmutationsindevelopmentofthistumor, becauseitwasdetectedbothintheprimaryandmetastaticlesioninsuchahighpercentageoftumorcells. Unfortunately,itwasnotpossibletotestDNAfrom a blood sample to distinguish germline or somatic statusofthismutation.ItwassuggestedthatTP53 mutations and gene polymorphisms (PIN2, PIN3, and PEX4) affected the risk of development, patient'sageatonsetofthetumor,andsurvivalinWT [5].ThatiswhyAndradeet alperformedsequencing ofTP53exons2-11in46bloodDNAsamplesand 31freshtumorDNAsamplesfrom52patientswith WTtodetectTP53pathogenicmissensemutations (p.V197M,p.R213Q,p.R248W,andp.R337C)inup to 12.9% of samples [5]. The mutation (p.R249M) detectedinourcaseissituatednexttothep.R248W mutation mentioned above.…”

“…Thefeaturesofadultnephroblastomaincludeheterogeneous appearance, calcifications, fields of necrosis and hemorrhagic foci in magnetic resonance (MR) thatenablescorrectstagingofthetumor [3].However, no kind of imaging -whether it is combined MR,ultrasonography(US)and/orcomputedtomography(CT)-providessufficientlyspecificresultsto favoraclinicaldiagnosisofAWToverincomparably morecommonrenalcarcinomas [3].AWTisanextremely rare and aggressive renal malignancy with afewwell-establishedprognostic factorsofnephroblastoma [4].Amongthemtherearecertainlystagingandhistopathologicaltypingofadultnephroblastomawithapotentimpactonpatients'survival [5]. Namely, if the Wilms' tumor is bilateral, patients' survival is generally two-fold shorter [5].…”

“…Namely, if the Wilms' tumor is bilateral, patients' survival is generally two-fold shorter [5]. Furthermore, extracapsular extension and blood vessel invasion of blastemal nephroblastoma was associated withsuddendeatha77-year-oldmalepatientduring thefirstcourseofpostoperativechemotherapy [6].It isdifficulttoestimatetheaveragesurvivalofpatients withAWT,butitisworthmentioningthatfourof thefivepatientsdiedin12monthsafternephrecto-myandthetumorprogressedinallofthemdespite treatmentwithnephrectomy,radiotherapyandchemotherapy [7].Limitationtotherenalparenchyma andepithelialtypeofnephroblastomaofa47-yearold woman were related to favorable prognosis: no tumor progression for 5 years before surgery and 2-year-long disease-free survival afterwards without anyfollow-uptherapy [6].Thatiswhyitisimportanttoincludesuchdetailsashistopathologicaltypingwithpresenceofeventualanaplasiaandstaging e.g.…”