{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:21:20Z","timestamp":1760059280827,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T00:00:00Z","timestamp":1749168000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRONII\u2014CONACYT (Paraguay)"},{"name":"CAPES (Brazil)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Adrenal cortex carcinoma (ACC) in children is a rare tumor that is probably of multifactorial origin and is mainly associated with genetic and environmental alterations. In the south and part of the southeast of Brazil, as well as in the Paraguayan region bordering the Brazilian State of Paran\u00e1, ACC prevalence is higher than in any other country, which is associated with the high prevalence of the TP53 p.R337H variant in Paran\u00e1 (0.30%), Santa Catarina (0.249%), cities around Campinas-SP (0.21%), and the Paraguayan cities on the border with Paran\u00e1 (0.05%). Recent research suggests that the co-segregation of XAF1-E134* and TP53-R337H mutations leads to a more aggressive cancer phenotype than TP53-R337H alone. Breast cancer may be mildly influenced by co-segregation with XAF1 p.E134*, and this variant can also confer risk for sarcoma. Objectives: The objectives of this study were to (1) estimate the prevalence of the germline TP53 p.R337H and XAF1 p.E134* variants in Paraguay (excluding cities on the border with Paran\u00e1 State, Brazil) and (2) estimate whether the ethnic origin of TP53 p.R337H carriers in Paraguay is similar to that of ethnic groups in Paran\u00e1 (possible Portuguese\/Spanish origin). Materials and methods: DNA tests for the identification of TP53 p.R337H were carried out from 2016 to 2019 at the Bio-Materials Laboratory of Facultad Politecnica, UNA, and at the Research Center in Biotechnology and Informatics (CEBIOTEC), Asunci\u00f3n, Paraguay. Polymerase chain reaction followed by restriction enzyme digestion (PCR-RFLP) was used to identify TP53 p.R337H, and real-time PCR (RT-PCR) was employed for XAF1 p.E134*. Peripheral blood samples from 40,000 Paraguayan newborns (NBs) were used for the TP53 p.R337H tests. The XAF1 p.E134* tests (RT-PCR) were performed on samples from 2000 Paraguayan newborns at the Pel\u00e9 Pequeno Principe Research Institute, Curitiba, PR, Brazil. Results: The TP53 p.R337H variant was not found in any of the 14 Paraguayan departments investigated. A total of 12 of the 2000 Paraguayan NBs were positive for one XAF1 p.E134* allele. Conclusions: The hypothesis of Spanish immigrants carrying p.R337H to Paraguay was disproved. TP53 p.R337H neonatal testing in Paraguay is not recommended, except when there are families with Brazilian ancestry presenting cancer cases. Additional epidemiological studies are required to determine the likelihood of the identified prevalence of the XAF1 p.E134* allele (1\/153) in NBs from Paraguay without TP53 p.R337H to present cancer risk. This study complements the first national initiative for the DNA screening of newborns aimed at mapping the TP53 p.R337H and XAF1 p.E134* variants in Paraguay (based on the regions of residence of the newborns).<\/jats:p>","DOI":"10.3390\/curroncol32060333","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T09:02:03Z","timestamp":1749200523000},"page":"333","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Germline TP53 p.R337H and XAF1 p.E134* Variants: Prevalence in Paraguay and Comparison with Rates in Brazilian State of Paran\u00e1 and Previous Findings at the Paraguayan\u2013Brazilian Border"],"prefix":"10.3390","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8045-8202","authenticated-orcid":false,"given":"Edith","family":"Falcon-de Legal","sequence":"first","affiliation":[{"name":"Laboratorio de Bio y Materiales, NIDTEC-N\u00facleo de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Facultad Polit\u00e9cnica, Universidad Nacional de Asunci\u00f3n, Campus UNA, San Lorenzo 111421, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Ascurra","sequence":"additional","affiliation":[{"name":"Programa de Prevenci\u00f3n de la Fibrosis Qu\u00edstica y del Retardo Mental, Centro de Salud No. 9, Ministerio de Salud P\u00fablica y Bienestar Social, Asunci\u00f3n 001222, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Vega-Paredes","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Universidad del Norte, Asunci\u00f3n 001218, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elis","family":"Sade","sequence":"additional","affiliation":[{"name":"Hospital de Clinicas, Universidade Federal do Paran\u00e1, Curitiba 80060-000, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5078-7214","authenticated-orcid":false,"given":"Magna","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Laboratorio de Bio y Materiales, NIDTEC-N\u00facleo de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Facultad Polit\u00e9cnica, Universidad Nacional de Asunci\u00f3n, Campus UNA, San Lorenzo 111421, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariana","family":"Para\u00edzo","sequence":"additional","affiliation":[{"name":"Instituto de Pesquisa Pel\u00e9 Pequeno Pr\u00edncipe, Curitiba 80250-060, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magali","family":"Colman","sequence":"additional","affiliation":[{"name":"CEBIOTEC-Centro de Investigaci\u00f3n en Biotecnolog\u00eda e Inform\u00e1tica, Asunci\u00f3n 001226, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angeles Gutierrez","family":"Florentin","sequence":"additional","affiliation":[{"name":"CEBIOTEC-Centro de Investigaci\u00f3n en Biotecnolog\u00eda e Inform\u00e1tica, Asunci\u00f3n 001226, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cesar","family":"Ojeda","sequence":"additional","affiliation":[{"name":"CEBIOTEC-Centro de Investigaci\u00f3n en Biotecnolog\u00eda e Inform\u00e1tica, Asunci\u00f3n 001226, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1790-2559","authenticated-orcid":false,"given":"Horacio","family":"Legal-Ayala","sequence":"additional","affiliation":[{"name":"NIDTEC-N\u00facleo de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Facultad Polit\u00e9cnica, Universidad Nacional de Asunci\u00f3n, Campus UNA, San Lorenzo 111421, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2976-7964","authenticated-orcid":false,"given":"Andreas","family":"Ries","sequence":"additional","affiliation":[{"name":"NIDTEC-N\u00facleo de Investigaci\u00f3n y Desarrollo Tecnol\u00f3gico, Facultad Polit\u00e9cnica, Universidad Nacional de Asunci\u00f3n, Campus UNA, San Lorenzo 111421, Paraguay"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/pbc.20318","article-title":"Biology, clinical characteristics, and management of adrenocortical tumors in children","volume":"45","author":"Figueiredo","year":"2005","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_2","first-page":"817","article-title":"The p53 tumor suppressor gene","volume":"123","author":"Levine","year":"1994","journal-title":"J. Lab. Clin. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/356215a0","article-title":"Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours","volume":"356","author":"Donehower","year":"1992","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1126\/science.1978757","article-title":"Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms","volume":"250","author":"Malkin","year":"1990","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0960-9822(00)00002-6","article-title":"Tumor spectrum analysis in p53-mutant mice","volume":"4","author":"Jacks","year":"1994","journal-title":"Curr. Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9330","DOI":"10.1073\/pnas.161479898","article-title":"An inherited p53 mutation that contributes in a tissue-specific manner to pediatric adrenal cortical carcinoma","volume":"98","author":"Ribeiro","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4970","DOI":"10.1210\/jcem.86.10.7957","article-title":"An inherited mutation outside the highly conserved DNA-binding domain of the p53 tumor suppressor protein in children and adults with sporadic adrenocortical tumors","volume":"86","author":"Latronico","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1016\/j.ejca.2004.01.031","article-title":"Childhood adrenocortical tumours","volume":"40","author":"Ribeiro","year":"2004","journal-title":"Eur. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1002\/pbc.20624","article-title":"Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil","volume":"47","author":"Pianovski","year":"2006","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Costa, T.E.J., Gerber, V.K.Q., Iba\u00f1ez, H.C., Melanda, V.S., Parise, I.Z.S., Watanabe, F.M., Pianovski, M.A.D., Fiori, C.M.C.M., Fabro, A.L.M.R., and da Silva, D.B. (2019). Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil. Cancers, 11.","DOI":"10.3390\/cancers11111804"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2228","DOI":"10.1002\/cncr.25826","article-title":"Association of the highly prevalent TP53 R337H mutation with pediatric choroid plexus carcinoma and osteosarcoma in southeast Brazil","volume":"117","author":"Seidinger","year":"2011","journal-title":"Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.canep.2015.01.005","article-title":"Prevalence of an inherited cancer predisposition syndrome associated with the germ line TP53 R337H mutation in Paraguay","volume":"39","author":"Legal","year":"2015","journal-title":"Cancer Epidemiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"8921","DOI":"10.18632\/oncotarget.13475","article-title":"The role of p53 in cancer drug resistance and targeted chemotherapy","volume":"8","author":"Hientz","year":"2017","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1200\/JCO.2004.08.085","article-title":"Clinical and outcome characteristics of children with adrenocortical tumors: A report from the International Pediatric Adrenocortical Tumor Registry","volume":"22","author":"Michalkiewicz","year":"2004","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/278261a0","article-title":"T antigen is bound to a host protein in SV40-transformed cells","volume":"278","author":"Lane","year":"1979","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0092-8674(79)90293-9","article-title":"Characterization of a 54K Dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells","volume":"17","author":"Linzer","year":"1979","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/nrc864","article-title":"Live or let die: The cell\u2019s response to p53","volume":"2","author":"Vousden","year":"2002","journal-title":"Nat. Rev. Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1038\/35042675","article-title":"Surfing the p53 network","volume":"408","author":"Vogelstein","year":"2000","journal-title":"Nature"},{"key":"ref_19","first-page":"4855","article-title":"Mutations in the p53 tumor suppressor gene: Clues to cancer etiology and molecular pathogenesis","volume":"54","author":"Greenblatt","year":"1994","journal-title":"Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<105::AID-HUMU19>3.0.CO;2-G","article-title":"p53 website and analysis of p53 gene mutations in human cancer: Forging a link between epidemiology and cancerogenesis","volume":"15","author":"Soussi","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/348747a0","article-title":"Transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome","volume":"348","author":"Srivastava","year":"1990","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1590\/S0004-27302004000500009","article-title":"Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors","volume":"48","author":"Pinto","year":"2004","journal-title":"Arq. Bras. De Endocrinol. Metabol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Paskulin, D.D., Giacomazzi, J., Achatz, M.I., Costa, S., Reis, R.M., Hainaut, P., Dos Santos, S.E.B., and Ashton-Prolla, P. (2015). Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0143262"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1002\/mc.20807","article-title":"XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification","volume":"51","author":"Zou","year":"2012","journal-title":"Mol. Carcinog."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1111\/j.0022-202X.2004.23467.x","article-title":"XAF1 expression is significantly reduced in human melanoma","volume":"123","author":"Ng","year":"2004","journal-title":"J. Investig. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"100244","DOI":"10.1016\/j.xhgg.2023.100244","article-title":"Multiple TP53 p.R337H haplotypes and implications for tumor susceptibility","volume":"5","author":"Pinto","year":"2024","journal-title":"Hum. Genet. Genom. Adv."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gerber, V.K.Q., Paraizo, M.M., Iba\u00f1ez, H.C., Casali-da-Rocha, J.C., Pinto, E.M., Andrade, D.P., Iba\u00f1ez, M.V.C., Komechen, H., Figueiredo, M.M.O., and Cust\u00f3dio, G. (2022). Environmental Contaminants Modulate Breast Cancer Development and Outcome in TP53 p.R337H Carriers and Noncarriers. Cancers, 14.","DOI":"10.3390\/cancers14123014"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.mce.2011.10.019","article-title":"Molecular epidemiology of adrenocortical tumors in southern Brazil","volume":"351","author":"Komechen","year":"2012","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_29","unstructured":"(2025, January 18). Instituto Nacional de Estad\u00edstica, Paraguay, Available online: https:\/\/www.ine.gov.py\/."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/j.1744-313X.2010.00959.x","article-title":"HLA polymorphism in a guarani-indian population from Paraguay and its usefulness for the hispano-indian admixture study in Paraguay","volume":"38","author":"Benitez","year":"2011","journal-title":"Int. J. Immunogenet."},{"key":"ref_31","unstructured":"(2025, January 18). Comunidades Brasileiras No Exterior, Available online: https:\/\/www.gov.br\/mre\/pt-br\/assuntos\/portal-consular\/BrasileirosnoExterior2023.pdf."},{"key":"ref_32","unstructured":"(2022, February 02). ABraOM: Brazilian Genomic Variants. Available online: https:\/\/abraom.ib.usp.br\/index.php."},{"key":"ref_33","unstructured":"(2022, February 02). NCBI\u2014National Center for Biotechnology Information, Available online: https:\/\/www.ncbi.nlm.nih.gov\/."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Custodio, G., Taques, G.R., Figueiredo, B.C., Gugelmin, E.S., Oliveira Figueiredo, M.M., Watanabe, F., Pontarolo, R., Lalli, E., and Bleggi Torres, L.F. (2011). Increased incidence of choroid plexus carcinoma due to the germline TP53 R337H mutation in southern Brazil. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018015"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2619","DOI":"10.1200\/JCO.2012.46.3711","article-title":"Impact of neonatal screening and surveillance for the TP53 R337H mutation on early detection of childhood adrenocortical tumors","volume":"31","author":"Parise","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"747","DOI":"10.7326\/0003-4819-71-4-747","article-title":"Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?","volume":"71","author":"Li","year":"1969","journal-title":"Ann. Intern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2442","DOI":"10.1158\/0008-5472.CAN-20-1750","article-title":"The Common Germline TP53-R337H Mutation Is Hypomorphic and Confers Incomplete Penetrance and Late Tumor Onset in a Mouse Model","volume":"81","author":"Jeffers","year":"2021","journal-title":"Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1177\/1947601911409745","article-title":"TP53-Associated Pediatric Malignancies","volume":"2","author":"Pinto","year":"2011","journal-title":"Genes. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1038\/nsb730","article-title":"A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer","volume":"9","author":"DiGiammarino","year":"2002","journal-title":"Nat. Struct. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.7150\/jca.19036","article-title":"Identification of transcription factor YY1 as a regulator of a prostate cancer specific pathway using proteomic analysis","volume":"8","author":"Park","year":"2017","journal-title":"J. Cancer"},{"key":"ref_41","first-page":"1298","article-title":"Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families","volume":"54","author":"Birch","year":"1994","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/s13045-022-01332-1","article-title":"Genotype-phenotype associations within the Li-Fraumeni spectrum: A report from the German Registry","volume":"15","author":"Penkert","year":"2022","journal-title":"J. Hematol. Oncol."}],"container-title":["Current Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1718-7729\/32\/6\/333\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:47:40Z","timestamp":1760032060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1718-7729\/32\/6\/333"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,6]]},"references-count":42,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["curroncol32060333"],"URL":"https:\/\/doi.org\/10.3390\/curroncol32060333","relation":{},"ISSN":["1718-7729"],"issn-type":[{"type":"electronic","value":"1718-7729"}],"subject":[],"published":{"date-parts":[[2025,6,6]]}}}