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      TP53 p.Arg337His geographic distribution correlates with adrenocortical tumor occurrence

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          Abstract

          Background

          The p.Arg337His mutation of the TP53 is the most frequent germline missense variant associated with cancer described so far in this gene. It is mainly found in the South and Southeastern regions of Brazil, where it has been associated with a high incidence of pediatric adrenocortical (ACT) and choroid plexus tumors. The frequency and geographic distribution of this mutation is largely unknown, except for the Parana State, where a mean prevalence of 0.27% was reported. In the present study, we developed a high‐throughput method for p.Arg337His genotyping, what allowed us to determine the frequency and geographic distribution of this mutation in a cohort from the most populous state in Brazil.

          Methods

          Consecutive samples from 31,612 newborns from São Paulo State were screened for p.Arg337His. The allelic discrimination was done by real‐time polymerase chain reaction (PCR) and the presence of haplotype A3 in carriers was examined by using allele‐specific oligonucleotide PCR, followed by nested‐PCR to detect the SNP rs9894946.

          Results

          We found 67 (0.21%) samples positive for this mutation. The highest p.Arg337His frequencies were found in the cities close to the boundary between São Paulo and Minas Gerais State. No association could be found between p.Arg337His and gender, ethnicity, premature birth or twinning. Remarkably, a trend was found between the geographic distribution of p.Arg337His carriers and occurrence of ACT.

          Conclusion

          We presented for the first time the p.Arg337His frequency among individuals unselected for any disease from a subset of the São Paulo State, the most populous in Brazil. The allele discrimination assay we presented here has proven to be a reliable and efficient method for high‐throughput genotyping. ACT was found to be a good sentinel cancer to suppose p.Arg337His presence in our region.

          Abstract

          The study presents a reliable and efficient method for high‐throughput TP53 p.Arg337His genotyping, what allowed authors to determine the frequency and geographic distribution of this mutation in a cohort from the most populous state in Brazil. In addition, adrenocortical tumor was found to be a good sentinel cancer to suppose p.Arg337His presence in the region analyzed.

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          Most cited references28

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          Cancer. p53, guardian of the genome.

          D P Lane (1992)
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            Combination chemotherapy in advanced adrenocortical carcinoma.

            Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).
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              Pathologic features of prognostic significance in adrenocortical carcinoma.

              There are currently no well-established pathologic prognostic factors helpful in distinguishing low versus high grade adrenocortical carcinomas. The effect of 11 pathologic parameters on survival was investigated in 42 cases of adrenocortical carcinoma. Only one variable, mitotic rate, had a strong statistical association with patient outcome. The 21 patients with carcinomas with greater than 20 mitoses per 50 high power fields (hpf) had a median survival of 14 months, whereas the 21 patients with carcinomas with less than or equal to 20 mitoses had a median survival of 58 months (p less than 0.02). The presence of atypical mitoses, capsular invasion, tumor weight greater than 250 g, and size greater than 10 cm each showed a marginal statistical association with poor survival (p less than 0.06), whereas other features assessed, such as nuclear grade, presence of necrosis or of venous or sinusoidal invasion, character of the tumor cell cytoplasm, or architectural pattern, showed no statistical significance in predicting survival. It is proposed that adrenal cortical carcinomas with greater than 20 mitoses be designated high grade, whereas tumors with less than or equal to 20 mitoses be designated low grade.
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                Author and article information

                Contributors
                analuseidinger@gmail.com
                andres@boldrini.org.br
                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                10.1002/(ISSN)2324-9269
                MGG3
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                2324-9269
                27 June 2020
                September 2020
                : 8
                : 9 ( doiID: 10.1002/mgg3.v8.9 )
                : e1168
                Affiliations
                [ 1 ] Molecular Biology Laboratory Centro Infantil Boldrini Campinas São Paulo Brazil
                [ 2 ] Medical Genetics Department Faculty of Medical Sciences State University of Campinas Campinas São Paulo Brazil
                [ 3 ] Integrated Center of Oncohematology Research in Childhood State University of Campinas Campinas São Paulo Brazil
                [ 4 ] Pediatric Oncology Centro Infantil Boldrini Campinas São Paulo Brazil
                Author notes
                [*] [* ] Correspondence

                José A. Yunes, Molecular Biology Laboratory, Centro Infantil Boldrini, R. Dr. Gabriel Porto, 1270, CEP 13083‐210, Campinas, SP, Brazil.

                Email: andres@ 123456boldrini.org.br

                Ana L. Seidinger, Molecular Biology Laboratory, Centro Infantil Boldrini, Campinas, São Paulo, Brazil.

                Email: analuseidinger@ 123456gmail.com

                Author information
                https://orcid.org/0000-0002-9023-4649
                https://orcid.org/0000-0002-1316-3525
                Article
                MGG31168
                10.1002/mgg3.1168
                7503091
                32592449
                dcef8544-a147-45e0-bf23-0f1bfbefcdf2
                © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 08 August 2019
                : 20 January 2020
                : 27 January 2020
                Page count
                Figures: 3, Tables: 2, Pages: 9, Words: 13406
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo , open-funder-registry 10.13039/501100001807;
                Award ID: 2011/05657‐2
                Funded by: Conselho Nacional de Desenvolvimento Científico e Tecnológico , open-funder-registry 10.13039/501100003593;
                Award ID: 401991/2010
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                September 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.1 mode:remove_FC converted:22.09.2020

                genetic counseling,high‐throughput genotyping,p.arg337his,pediatric oncology,tp53

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