Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363490.03055020 — This a preprint and has not been peer reviewed. Data may be preliminary. o-eei atr nw ob soitdwt eaolsoars r anyrltdt eylwbirth low very to related mainly are risk hepatoblastoma with includ- associated syndromes, be congenital to tumors specific known pediatric with population factors of association Non-genetic pediatric prevalence 1% in worldwide the only reported Beckwith-Wiedemann the in ing for been with liver accounting has concordant development are of disease, hepatoblastoma hepatoblastomas tumor ultrarare on an malignant data considered common collected is most it of the though spectrum is broad (HB) a Hepatoblastoma in variants pathogenic germline robust carry is patients the genes susceptibility of cancer 10% approximately unknown largely that is shown cancer pediatric of and etiology The cancer can to results hepatoblastoma. related These with already association pathways abnormalities. its INTRODUCTION for and congenital impor- enriched disease and Hirschsprung most are cancer of the that in biology encodes the genes role understand broader of gene to throughout a set This studies demonstrated have future a been could help patients. out has they pointed both activity suggesting last inducible data biology, in The relevant developmental our significance which CYP1A1. uncertain for Conclusion: and placenta of CEP164 the pregnancy. variants namely, of patients, presenting be enzyme these genes might gene xenobiotic-metabolizing of genes predisposition tant that only candidate phenotype cancer two genes the the known disclosed was 28 to data eight hepa- our contributing one in in Additionally, developed potentially MCC). detected disclosed variants and who were were germline SERPINA6, disease VUS we ODC1, (VUS) with Hirschsprung germline HRAS, Here significance ERCC2, importantly, with ERBB2, clinical More Procedures: patients BRCA1, uncertain (APC, syndromic phenotypes. development. of two patients’ hepatoblastoma variants to of of Germline related analysis risk exome Results: high germline long-standing a recognized toblastoma. of confer a results is syndromes cancer the few pediatric describe with very alterations although developmental and observation, defects global birth of association The Background: Abstract 2020 1, July 5 4 3 2 1 Valadares Oliveira Scliar Aguiar* Talita DEVELOPMENT? HEPATOBLASTOMA AND DISEASE HIRSCHSPRUNG SHARED PATHWAY FOR A BIOLOGICAL CANCER: CHILDHOOD AND DEFECTS BIRTH eeD’OR-S˜ao Luiz Rede Concei¸c˜ao Hospitalar Grupo Guimar˜aes Foundation Benjamim Paulo S˜ao Paulo Sao of of University University Biosciences, of Institute 2 eaaHall-Nielsen Renata , 4 6–8 raeBackes Ariane , 3 oee,teeilg fms fteeascain ean underexplored. remains associations these of most of etiology the however, , aulPinto Raquel , 1 neCrln Teixeira Caroline Anne , 15,16 2–5 4 4 sad Artigal´as Osvaldo , h vdneo h ikbtenpdarccne n ogntlanomalies congenital and cancer pediatric between link the of evidence The . n n Krepischi Ana and , aiilaeoaosplpss(FAP) polyposis adenomatous familial , 3 n eiaRamos Regina Ana , 1 uin Sobral Juliana , 1 eetsuiso ag oot fpdarccne have cancer pediatric of cohorts large of studies Recent . 4 1 sbl Cunha Isabela , 1 4 eti o Santos dos Beatriz , 1 ivaSuaCosta Souza Silvia , 17 5 n rsm fcrmsm 18 chromosome of trisomy and , al Rosenberg Carla , 4 12–14 Valentina , nrae ikfor risk Increased . 10,11 1 Mar´ılia, 1 Eugˆenia, nBrazil, In . 9 al- , 18 . Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363490.03055020 — This a preprint and has not been peer reviewed. Data may be preliminary. ldn l emievrat.Floig ainswr lee ae nSqec nooyb eSq and RefSeq, ex- by obtained Ontology of were Sequence models sample on dominant tumor based filtered the and were in recessive variants mutations Following, for somatic variants. 1% The germline or all out. 0.5% cluding filtered above were frequencies respectively, inheritance, populational with indel variants and Germline SNV databases. variants. functional the and filter ( clinical, and populational, depth annotate read to and by Helix) germline, (Golden filtered 1.5.0 were version variants software VarSeq used We analysis split data script WES the 3.7) using (GATK lines Toolkit different Analysis into Genome Atlas2 split The from were reference duplicates. variants PCR genome multiallelic Finally, mark human 2500 (VQSR). to GRCh37/hg19 and HiSeq the BAM Illumina into to file the aligned SAM 31 on were the DNA convert sequenced sequences Integrated to were The - BWA libraries (IDT Panel reads. the Enriched v1.0 Research with end Panel Constitutional paired kits. Research OneSeq Exome in sample) V6 mother), xGen platform tumor QXT 1’s and FFPE Sureselect Patient father), the - and 2’s and Technologies Patient 2, DNA genomic - and Technologies of 1 ug (Agilent Patients 1 - using Technologies constructed were (Agilent whole-exome of libraries Genomic sequencing and preparation Library tissue tumor (FFPE) followed parents extraction paraffin-embedded available phenol-chloroform formalin-fixed using their isolated and 29 and was precipitation 2), blood patients Ethanol da Patient peripheral both by from of Hospital DNA of 1. father from Patient blood and from referred (biopsy) peripheral 1 was Patient from 2 of extracted Patient (mother were and samples referred Brazil, DNA was 1 Genomic - Patient Baleia patients. da studied two Hospital the Pediatrics Crian¸ca of Concei¸c˜ao parents of Brazil. the - Department from from obtained was consent informed Written tumors. the of one samples in DNA mutations somatic one of of spectrum and the documented, investigated was METHODOLOGY also hepatoblastomas We and disease patient. ascertained Hirschsprung each we of of cancer, association parent (2016) case childhood the first with whom the al. individuals in besides et patients Brazilian hepatoblastoma, Pinto of and disease by cohort Hirschsprung a reported presenting in patient affected syndromic studies first additional genomic the one of of sex course the the to and In disease bowel aganglionic Hirschsprung the for of risk length the the both sibling increase to trisomy, according BBS1-BBS11 21 varies KIF1BP, rate chromosome recurrence L1CAM, including as DHCR7, such genes, ECE1, conditions, several SHH, Some Predispos- SOX10, in PHOX2B, heterogeneity. recognized genetic ZEB2, chronic been extensive EDN3, severe by have causing characterized mutations severity, development, and cell ing crest penetrance failure variable neural growth with defective and disorder of vomiting, consequence distension, a abdominal as constipation, bowel aganglionic newborns the 10,000 in in 1-5 about affecting 20 pregnancies ( weight iseebde nprffi,drc u (10 cut direct paraffin, in embedded tissue ; bowel, the of end the at neurons enteric of absence the from resulting anomaly congenital rare a is which , eeue orainidl,rclbaetebss n ocl Uie eoye)adrclbaevariants recalibrate and Genotyper) (Unified call to and bases, the recalibrate indels, realign to used were 26,27 < 50g,icuigpeembrh( birth preterm including g), 1500 9,19 napteno utfcoilihrtnewt ieetlaiiytrsodfrsex. for threshold liability different with inheritance multifactorial of pattern a in 32 > odt,teei igerpr faptetwt eaolsoaadHrcsrn disease Hirschsprung and hepatoblastoma with patient a of report single a is there date, To . ooti h C lsue o analysis. for used files VCF the obtain to E algorithm MEM .0frsmtcvrat) ain noainwspromdbsdo ulcdtbssof databases public on based performed was annotation Variant variants). somatic for 0.10 28 N rmFP uo apewsotie nteA aag uo Bank Tumor Camargo AC the in obtained was sample tumor FFPE from DNA . 30 20 iadtos(..,ht:/raisiuegtu.opcr/ eeused were http://broadinstitute.github.io/picard/) (v.1.8, tools Picard . nti eot epromdagrln xm nlsso hs two these of analysis exome germline a performed we report, this In . 21,22 > 0,Prdsoe( score Phred 10), eae yposaiebcueteei opousv motility propulsive no is there because arise symptoms Related . < 3wes,salsz o ettoa g,admlil birth multiple and age, gestational for size small weeks), 33 μ )adpeo-hooometato eeused. were extraction phenol-chloroform and g) 2 > 0,advratall rqec ( frequency allele variant and 20), 22,23 E,GN,GR1 RN EDNRB, NRTN, GFRA1, GDNF, RET, ishpugdsaei multigenic a is disease Hirschsprung . multiallelic and 25 h sibling The . RMRP > .5for 0.35 rows.rb 22,24 . Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363490.03055020 — This a preprint and has not been peer reviewed. Data may be preliminary. iue1;mtra aeilwsntaalbefrsgeainaayi.Ti N atal ulctsthe duplicates partially CNV This analysis. segregation for available not was inherited material not 14q23.2, maternal at The 1); kb 14q23.2(64374657 ˜364 patients. Figure of (arr[GRCh37] both segment father total in a his CNVs encompassing from germline duplication interrupted pathogenic an of carries presence 2 Patient the excluded analysis microarray Chromosome variants Germline published were details clinical RESULTS Further partial He by (2016) follow-up. followed risk. al. post-treatment low ifosfamide, et in II, and Pinto PRETEXT is doxorubicin by Subtype, cisplatin, patient Epithelial with the Fetal Currently, protocol hepatoblastoma as chemotherapy hepatectomy. rectum The classified the disconnected age, the surgically. to of corrected in a submitted months was cells and was 25 that ganglion at ileum disease diagnosed of abdominal Hirschsprung terminal was absence developed with tumor the revealed patient consistent in also the colon, examination age, sigmoid atresia and Histopathological of intestinal atresia, hours laparotomy, identified. ileal 48 congenital were During first of cecum was composed the vomiting. phenotype, and In syndromic and ventilation a deafness. mechanical distension with on sensorineural underwent born hemorrhage during and was intracranial patient cataract died He II premature the bilateral bilateral grade preeclampsia), sepsis. birth, born encephalomalacia, and congenital and periventricular At seizures was for with defect right, unit patient the failure. (cardiac born care intensive heart risk was The the congestive gestational sister to admitted to presented his ileus. due who couple; atresia-terminal birth mother, consanguineous intestinal his his a exhibited and of weeks) brother child (28 his third while male, a cataract, is chemotherapy procedure. the 2 surgical a to with the Patient old, submitted Subtype before was years Epithelial patient died 5 as The She at classified and high-risk. SIOPEL6. evaluation being (hypoplastic), IV, four, protocol clinical PRETEXT dysplasia of cells, the age nail embryonal In the of dysmorphisms, at predominance facial made. two diagnosed delay, was was her Hepatoblastoma neuropsychomotor section; disease hours clinodactyly. 24 global cesarean Hirschsprung first by with of the in term presented diagnosis detected at were she the evacuation born no and parents, and birth, distension non-consanguineous Abdominal after CNVs of phenotype. child Common normal third a have female, siblings Mb). a is 10 1 of Patient length LOH minimum REPORTS MEDICAL losses; disregarded. PATIENTS‘S were homozygous http://dgv.tcag.ca/dgv/app/home) and Variants, with Genomic (Biodiscovery), gains 9 of number Number (Database Copy copy Nexus log high software (threshold the for algorithm using sample segmentation SNP-FASST2 FFPE the the (Agilent from platform 180K obtained a data using exome 2 and reported 1 previously Patients for as Technologies), performed was analysis microarray chromosome Germline (CNAs) alterations number Copy ( genes candidate from of variants germline visual classified prioritized by were analysis. validated Two variants data were WES germline variants for prioritized The approach The the guidelines patients. (IGV). summarizes ACMG vari- the Viewer Varelect the LoF of using Genomics the to annotated phenotype Integrated All according was the specific variants prioritized. using the were filtered of tools to inspection list different associated five final genes least The ranking at damaging prioritized. by potential (https://www.ensembl.org/), also The pathogenic Ensembl were from as 2.4). ants package predicted software (version variants script dbNSFP VEP32 only database the and the using by assessed provided also algorithms was (loss effect six stop-codons analysis. on of further based gain/loss for were and maintained ants were frameshift, LoF) site, - splice function essential of and missense non-synonymous coding only TERT rmtrwr netgtdb agrsqecn pie ar r vial ne request). under available are pairs (primer sequencing Sanger by investigated were promoter 20 . 35,36 38 oai N vnsi h uo rmPtet1wr eie from derived were 1 Patient from tumor the in events CNA Somatic . sn h asm tool Varsome the using , 4304x;arGC3]14q23.2(64474837 arr[GRCh37] 64435014)x3; 3 nsilico In 2 CYP1A1 y/y ai of ratio Cy3/Cy5 rdcino ahgnct fmses vari- missense of pathogenicity of prediction 37 h uprigIfrainFgr S1 Figure Information Supporting The . and CEP164 | 0.2 | n uainlhotspots mutational and ) o an n losses; and gains for 33 n HPO and 64738458)x3; 34 | 1.2 for | Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363490.03055020 — This a preprint and has not been peer reviewed. Data may be preliminary. nPtet1 ult otoso h xm aarvae 7 f1xmda oeaeo agt ih98.03% with target, on coverage median 10x of 97% revealed data exome (DGV Variants the Q of Genomic of controls of quality Database 1, Patient the In in reported were region http://dgv.tcag.ca) this - ( overlapping genes duplications OMIM Rare Morbid VUS. two of sequence genomic o hs ains lvnoto h 2vrat eeLFaetn h genes the variants genes affecting heterozygous predisposition LoF rare cancer were 72 variants the TMPRSS7 in 72 of SPAG8, the P2RX6, total KIR2DL4,LHX8, of A HAO2, out GGCT, Eleven filtering. variants. after non- these 1 coding for (see rare Patient criteria 333 in analysis of the detected total fulfilled was a (Supporting variant patients, disease genes. homozygous both 317 No Hirschsprung sequences of exonic to data and the mapping the that hepatoblastoma detected, Considering confirm were to for covered. variants files properly BAM synonymous genes were the known of genes analysis these of visual of by set Supporting performed was and a S2) consanguinity. Table S1 of parental Information Table evaluation reported Information the active (Supporting with An data accordance exome in result using S2), 2 Figure Patient Information in homozygosity of regions eotda ahgnci oeta v ahgnct aaae.Too h eetdmttoswere mutations detected the of Two databases. pathogenicity five than mapped more which sample, in the tumor pathogenic in the LoF, in as two disclosed comprising reported were mutations genes, non-synonymous different coding 36 somatic to 1 36 of Patient total from signaling A sample Wnt hepatoblastoma family, FFPE proteins in and FGFR mutations modification, Somatic cancer, Re- protein to 71 post-translational Version related system, pathways immune - the biology. for (https://reactome.org/ developmental in enriched Database signaling was Pathway cytokine involved set metabolism, Reactome are pathway variants gene used non-synonymous The we coding germline roles, leased). rare with biological genes their the which and in pathways the 2). explore affecting (Figure To sequencing 2 samples Sanger Patient HB by the in validated reported in were previously genes detected were gene was this variant in mutations one MCC, additionally, SLC6A6, VUS; as SLC25A47, SERPINA6, Different PLCD4, to ODC1, predispose that KMT2D, syndromes HRAS, ZNF215 or HGS, cancer, FASN, functions/structure, ( the ERCC2, liver hepatoblastoma to ( with cancer, submitted disease associated liver development) was Hirschsprung hepatoblastoma with patients to (related related both indirectly directly from or 2). variants gene Patient non-synonymous one for revealed coding 62 ysis rare and VarElect 1 with Patient tool detected genes for the prioritization 317 and (57 of algorithms S3 five Table list least Information The at Supporting for damaging in as shown classified are variants variants missense LoF the of Details SON, 2. SLC16A12, Patient RPGRIP1, PCDH15, genes HGSNAT, cancer-predisposing COL4A4, het- the in in detected ERBB2 them were of Variants 243 MCC father. gene 2, the the Patient SBK2, in in LoF ity in RFPL1, one PCDHGA1, analysis including LSM14A, homozygosity, further FAM3A, in genes for GCA, the prioritized FRG1B, affecting ELMOD3, were LoF variants thirteen rare comprising erozygosity, the 261 in filtering, disease Hirschsprung After to related variant one and identified, > (c.862G 0 nPtet2 8 f1xmda oeaeo agt ih7.8 fQ of 71.28% with target, on coverage median 10x of 98% 2, Patient in 30; (c.170A .Tbe1peet h emieVSascae ihteseicpeoye fec patient. each of phenotypes specific the with associated VUS germline the presents 1 Table ). CYP1A1 > rs34696815), - T > s4412) ih ainswr apdi ee eae octrc ( cataract to related genes in mapped were variants Eight rs140441229). - G ainswr dnie nPtet (c.1390C 1 Patients in identified were variants 33 sn h hntpshptbatm n ogntlmgcln hsanal- This megacolon. congenital and hepatoblastoma phenotypes the using Methodology ODC1 ERCC2 r16242-c.568G - (rs116522452 (c.545C ,2 fte eeihrtdfo e ohr loheterozygous also mother, her from inherited were them of 24 ), FAM3A. SYNE2 ANKRD22 > s4969)and rs142936491) T 4 684 and #608442 it-i ainswr lopeeti heterozygos- in present also were variants Fifty-six PBPC4 E5L,CB2 DENND6A, CNBD2, CEP57L1, APOB/PLCD4, and > 14 and and , A), P,BC1 E14 Y11 ERBB2, CYP1A1, CEP164, BRCA1, APC, h ainsi the in variants The . ALDH1A2 FRY ALDH1A2 VAT1 BRCA1 > ZNF215. )ad2(c.877C 2 and A) ESR2 genes HRAS ,aohrciia odto fthe of condition clinical another ), APC CEP164 , (c.4039A ,adsvnengnsdirectly genes seventeen and ), (c.1100A 616)adwscasfidas classified was and #601663) and n hrenmses variants missense thirteen and atclry isnevariants missense Particularly, 5r4,CC2 FRMPD2, CWC22, C5orf47, (c.75G (c.3895G SLC19A1; > 0 twsietfidsix identified was It 30. > CYP1A1 > (c.1429C > s8969,and rs28897689), - G s4289)were rs142218590) A > )gene T) ) ohclassified both G), > n 8variants 18 and rs1801166), - C > . and ) somatic T), ABCA4, CEP164 and Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363490.03055020 — This a preprint and has not been peer reviewed. Data may be preliminary. nti td,w icoe oeptnilcniaegnsfrhptbatm n ishpugdisease. Hirschsprung and hepatoblastoma for genes candidate potential some disclosed we study, this In ( cataract VAT1 to related genes in observed HB to predisposes in genes that cancer-predisposing conditions the genetic in VUS pathway cell the four of abnormal revealed one also FAP, and 2 to overgrowth Patient the syndrome. cell of Beckwith-Wiedemann data from of Germline etiology result the probably in heart symptoms role and a and features, play signs facial the distinctive disability, of division intellectual the many as increases but which such syndrome problems, predisposition in dominant cancer identified rare besides was a syndrome development inheritance #218040), tumors maternal (OMIM of of syndrome variant risk Costello A with associated 1. genes been Patient predisposition of characteristic cancer clinical the tumor in solid DNA identified childhood damaged were variants repair helps missense development bilateral germline retinal congenital rare patient’s (c.545C proper 1, to for contribute Patient role might In gene important phenotypes. this an deafness in has sensorineural alterations in and gene that Alterations cataract indicate the formation). could migration defects, cilia evidence centrosome (primary retinal for This ciliogenesis and with required early population is associated during and control surface been progenitors the cell photoreceptor apical in retinal the individuals in to few migration a nuclear in in involved and documented VUS. cancer been as in have classified role was 14q23.2 broader segment post-translational a in system, have Duplication immune could the they in suggesting coding biology, abnormalities. signaling rare developmental congenital proteins cytokine with FGFR and cancer, set metabolism, to modification, gene related pathway protein pathways The for signaling enriched etiology. was Wnt patients disease family, two the these in to identified variants contributing several germline mechanisms with disease underlying expressivity, Hirschsprung mutated and of and cases when mutations investigated penetrance the pathology of disease variable this 50% cause Hirschsprung with only to condition and known multifactorial to hepatoblastoma already a genes between addition nail is association in study and disease an this hepatoblastoma, Hirschsprung cataract of of congenital tumor 2 report Patient delay, rare the developmental clinical to the as only corresponds developed such The anomalies, who other patients dysplasia. besides syndromic disease, two Hirschsprung here report abnor- We chromosomal to recognized unrelated abnormalities defects been congenital birth long in of syndromes variety also has genetic cancer cancer known in pediatric or of pediatric 17q malities risk and and increased an 8 anomalies evidenced 2q, congenital studies in between detected association were The Gains Information (Supporting considered. sample S4). were Table tumor DISCUSSION Mb Information the 3 (Supporting from 1 than profile Patient larger CNA from genomic alterations hepatoblastoma a only generate S3), to Figure used was data Exome and tomas, COSMIC: in reported already ERBB2 ) > 56 51–53 62–64 )and T) n addt uo upesrgene suppressor tumor candidate a and eearayascae ihtemgclnphenotype megacolon the with associated already gene a , RHBDL1 neetnl,aLFwsosre nthe in observed was LoF a Interestingly, . lnclcniino hspatient. this of condition clinical a , HRAS (c.1211G SYNE2 49 (c.75G hl n te ainsi hsgn aebe eae ohppatcnis a nails, hypoplastic to related been have gene this in variants other and while , 50 47,48 ti o nw how known not is It . nopse ntegrln ulcto t1q32dtce nPtet2 is 2, Patient in detected 14q23.2 at duplication germline the in encompassed , > CTNNB1 > ooyosvrat nti eeaeascae ihpeipsto to predisposition with associated are gene this in variants Homozygous . ) ohi heterozygosity in both A), OM74) eetdi noeru tumors. endometrium in detected COSM97348), - A 8,42,43 40,41 BA,CLA,HSA,PD1,RGI1 L1A2 SON, SLC16A12, RPGRIP1, PCDH15, HGSNAT, COL4A4, ABCA4, seilycaisnsoi n ea anomalies renal and craniosynostosis especially , (c.101G eaolsoa,i atclr cu nascainwt wide a with association in occur particular, in Hepatoblastomas, . 20 . > 57–59 OM60,vratarayrpre nhepatoblas- in reported already variant COSM5670), - T 5 HRAS ; ZNF215 ODC1 44 onigt h xsec fytukongenetic unknown yet of existence the to pointing , ERCC2 . uain as h te etrso Costello of features other the cause mutations 22,23 2,54,55 and , irpin nti eewr rpsdto proposed were gene this in disruptions , oee,grln uain con for account mutations germline however, , ; MCC, BRCA1 sivle ngn rncito and transcription gene in involved is 60,61 nadto,egtvrat were variants eight addition, In . euao fteWtsignaling Wnt the of regulator a n U eeas observed also were VUS One . APC HRAS 12 SYNE2 . eerelated gene a , hc has which , 39 Recent . aealso have ERCC2 45,46 . Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363490.03055020 — This a preprint and has not been peer reviewed. Data may be preliminary. it,adAaKeici h rtdato h aucitwswitnb aiaAua,An Teixeira Anne Aguiar, Talita by written was manuscript the of draft Raquel Eugˆenia first Valadares, Cunha, The Isabela Krepischi. Sobral, analysis Juliana Ana and Teixeira, and collection Anne data Pinto, Aguiar, preparation, Talita Material design. by and performed conception were study the obtained to contributed was authors All consent signed informed STATEMENT after AUTHOR research collected Crian¸caCREDIT this were da guardians. approved samples Hospital from legal Institutions from all referred or referred respective and parents was was the samples, from 1 2 biological of Patient Patient these Committee and institutions: using Brazil, Ethics - Brazilian Research Baleia two The da in Concei¸c˜ao Brazil. Hospital enrolled - Pediatrics patients to of Department from decision recovered analysis, were and Samples collection, data COMMITTEE design, ETHICAL study WITH the COMPLIANCE CNPq manuscript. in the and roles of 2019/17423-8) preparation no or 2016/04785-0, had Research publish, Cell funders 2018/05961-2, Stem The and Genome fellowships: Human (141625/2016-3). - 2018/21047-9; (CEPID FAPESP 2013/08028-1; from grants Center by supported was study present The study. this in enrolled who families FUNDING their and patients the thank We association results its These and disease study). Hirschsprung this of ACKNOWLEDGMENTS of biology the hepatoblastoma. findings the like understand main understand conditions, the to and other illustrates studies ( with identify 3 future genes to delineate (Figure candidate to tumorigenesis difficult novel contribute HB out it with pointed makes association data information, the Our clinical mutations. CYP1A1 number grouping germline the CEP164, of causal hepatoblastoma, as a lack such of tumors, the physiopathology pediatric infants and rare of for and cases proportion However, diagnosis considerable of in databases. a delay public in the some problems in period, available health mechanism neonatal other the genetic and even in or failure early idiopathic development genes diagnosed remain to 70 be underlying lead cases should of can many disease treatment existence The and the recognized. condition, indicating yet genetic not investigation, heterogeneous molecular highly extensive a after is disease enzyme this Hirschsprung acid that suggest retinoic gene of mouse development synthesis homologous organs a the later of catalyzes Studies cytochrome that tissues. the enzyme adult and and an developing is in gene functions that this of retinaldehyde product from The germline The pathogenicity. study. of this score response in adaptive disclosed was the in disease development of Hirschsprung variant embryonic mediator in and involved a physiology cytochrome as another normal role Interestingly, to important contributes an also plays and hepatoblastoma which xenobiotics enzymes congenital receptor, to gene of AhR of the the superfamily case in through P450 variants a regulated cytochrome germline in the patients, reported of both previously member in was detected, gene also We this hepatoblastomas 2. two Patient in the mutated somatically be to occurs damage mutations somatic DNA of when study exome HB an in genes in variants Particularly, ntesm a,agoignme fcne ucpiiiygnsaebigietfidadifrainis information and identified being are genes susceptibility cancer of number growing a way, same the In . ALDH1A2 68 and , CYP26A1 (c.1100A eiocai,teatv eiaieo iai ,i omnlsgaigmolecule signaling hormonal a is A, vitamin of derivative active the acid, Retinoic . 69 SYNE2 65 . hsgn sivle ntesaiiyo h eoeadwspeiul found previously was and genome the of stability the in involved is gene This . CEP164 > )i ecie nCSI n CCa oai uainwt high a with mutation somatic a as ICGC and COSMIC in described is T) ocretyetbihlclebyncrtni cdlvl,wihfacilitate which levels, acid retinoic embryonic local establish concurrently o ishpugdsaebooywt oeta ucinlrl in role functional potential a with biology disease Hirschsprung for ) and CYP1A1 14 . CEP164 14 eeitrsigbcuete eepeiul observed previously were they because interesting were 6 emievratwsietfidi the in identified was variant germline A . noe rti epnil o h earsignaling repair the for responsible protein a encodes 66 h xrsino hsgn stranscriptionally is gene this of expression the ; 14 . CYP1A1 CYP1A1 67 . noe protein a encodes n ain in variant One . ALDH1A2, CEP164 of Posted on Authorea 1 Jul 2020 — The copyright holder is the author/funder. All rights reserved. No reuse without permission. — https://doi.org/10.22541/au.159363490.03055020 — This a preprint and has not been peer reviewed. Data may be preliminary. 5 eanM,Tce A iko acrdrn h rtfu er flf ncide rmTeBeckwith- The from children in life of years four first the during cancer Hepatoblastomas Registry. of of Syndrome Risk Burden Wiedemann MA. Mutation Tucker Somatic MR, DeBaun the Into 15. Insights al. et S, Patients. Costa Brazilian MP, From Rivas TFM, Registros Aguiar Dos 14. Informacoes Mortalidade Brasil: de No Jovens Sistema 2016. Adultos INCA; Do Pombo- e e Adolescentes (INCA). M, Cancer Silva Criancas, Santos da de Em Gomes Oliveira Cancer Alencar de Por Jose S, Cancer Hospitalar de Ferman Nacional embryonic R, Instituto childhood Reis system 13. nervous Souza non-central de of incidence JM, Brazil. the Ferreira in and tumours Oliveira status de Socioeconomic B, MS. controversies. de-Oliveira Camargo and de advances, recent 12. understanding, current Hepatoblastoma: H. Garnier F1000Research project. of P, System risk Czauderna Information the 11. Cancer survival, and and Childhood characteristics incidence Automated birth children: doi:10.1016/j.ejca.2006.05.011 the European of in 2006;42(13):2115-2123. from cancer study Liver Report Case-control E. Steliarova-Foucher J, 1978-1997. Pritchard al. CA, et Pe- Stiller C, 10. of Lombardi Review TJ, Comprehensive Meyers A JE, hepatoblastoma. K. Heck Schneider Wolfe 9. JT, Syndromes. 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