The TP53 p.R337H Germline Variant and Breast Cancer: Prevalence from a Cohort Study and Structured Literature Review R337H in Breast Cancer
Abstract
BACKGROUND: The TP53 p.R337H germline variant is a Brazilian founder variant associated with Li-Fraumeni syndrome and increased cancer susceptibility. Its prevalence among breast cancer (BC) patients remains incompletely characterized. The objective of this study is to evaluate the prevalence of the TP53 p.R337H germline variant among breast cancer (BC) patients through a cohort study and structured literature review. METHODS: One hundred BC patients from Hospital Universitário Antonio Pedro were interviewed and tested for the p.R337H variant using Sanger sequencing. A structured literature review was also conducted following PRISMA 2020 recommendations, searching PubMed, LILACS and SciELO for studies published between 1997 and 2025. Studies reporting zero detected cases were included to reduce selection bias. Due to heterogeneity among studies, no formal meta-analysis was performed and prevalence was reported descriptively. RESULTS: Of the 100 patients tested in our study, none had the variant (0.0%; 95% CI: 0.00-3.62%). Of 46 identified records, 17 studies met the inclusion criteria. A total of 173 carriers were identified among 8,221 patients in the reviewed literature. Including our cohort, the combined sample totaled 8,321 patients, with a crude aggregated prevalence of 2.08% (95% CI 1.79-2.41%). Higher prevalence was observed in patients diagnosed at ≤ 45 years and in malignant phyllodes tumors, while lower or absent prevalence was observed in unselected populations. CONCLUSION: The prevalence of the p.R337H variant among breast cancer patients varied across studies, according to age at diagnosis, patient selection criteria and geographic region. Larger multicenter studies are needed to better define its role in breast cancer risk assessment.
References
Frebourg T, Bajalica Lagercrantz S, Oliveira C, Magenheim R, Evans DG, GENTURIS ERN. Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes. Eur J Hum Genet. Oct 2020;28(10):1379-1386. doi:10.1038/s41431-020-0638-4
Achatz MI, Olivier M, Le Calvez F, et al. The TP53 mutation, R337H, is associated with Li-Fraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett. Jan 8 2007;245(1-2):96-102. doi:10.1016/j.canlet.2005.12.039
Guindalini RSC, Viana DV, Kitajima JPFW, et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci Rep. Mar 09 2022;12(1):4190. doi:10.1038/s41598-022-07383-1
Oliveira LJC, Rodrigues AM, Fernandes CB, et al. A portrait of germline pathogenic variants in high and moderate penetrance breast cancer genes in Brazil. Front Oncol. 2024;14:1495605. doi:10.3389/fonc.2024.1495605
McBride O, Merry D, Givol D. The gene for human p53 cellular tumor antigen is located on chromosome 17 short arm (17p13). Proceedings of the National Academy of Sciences. 1986;83(1):130-134. doi:10.1073/pnas.83.1.130
Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. Jan 2022;12(1):31-46. doi:10.1158/2159-8290.CD-21-1059
Li FP, Fraumeni JF. Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst. Dec 1969;43(6):1365-73.
Pinto EM, Figueiredo BC, Chen W, et al. XAF1 as a modifier of p53 function and cancer susceptibility. Sci Adv. Jun 2020;6(26):eaba3231. doi:10.1126/sciadv.aba3231
Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358:15-16. doi:10.1038/358015a0
Kaiser AM, Attardi LD. Deconstructing networks of p53-mediated tumor suppression in vivo. Cell Death Differ. Jan 2018;25(1):93-103. doi:10.1038/cdd.2017.171
Joerger AC, Fersht AR. The p53 Pathway: Origins, Inactivation in Cancer, and Emerging Therapeutic Approaches. Annu Rev Biochem. Jun 02 2016;85:375-404. doi:10.1146/annurev-biochem-060815-014710
Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. May 2014;14(5):359-70. doi:10.1038/nrc3711
Tanaka T, Watanabe M, Yamashita K. Potential therapeutic targets of TP53 gene in the context of its classically canonical functions and its latest non-canonical functions in human cancer. Oncotarget. Mar 23 2018;9(22):16234-16247. doi:10.18632/oncotarget.24611
Jiang L, Sheikh MS, Huang Y. Decision making by p53: life versus death. Molecular and cellular pharmacology. 2010;2(2):69.
Varley JM, McGown G, Thorncroft M, et al. Are there low-penetrance TP53 Alleles? evidence from childhood adrenocortical tumors. Am J Hum Genet. Oct 1999;65(4):995-1006. doi:10.1086/302575
Garritano S, Gemignani F, Palmero EI, et al. Detailed haplotype analysis at the TP53 locus in p. R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect. Human mutation. 2010;31(2):143-150. doi:10.1002/humu.2117217. Pinto EM, Billerbeck AE, Villares MC, Domenice S, Mendonça BB, Latronico AC. Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors. Arq Bras Endocrinol Metabol. Oct 2004;48(5):647-50. doi:10.1590/s0004-27302004000500009
Lwin TZ, Durant JJ, Bashford D. A fluid salt-bridging cluster and the stabilization of p53. J Mol Biol. Nov 09 2007;373(5):1334-47. doi:10.1016/j.jmb.2007.07.080
DiGiammarino EL, Lee AS, Cadwell C, et al. A novel mechanism of tumorigenesis involving pH-dependent destabilization of a mutant p53 tetramer. Nat Struct Biol. Jan 2002;9(1):12-6. doi:10.1038/nsb730
Institute NC. TP53 Database. https://tp53.isb-cgc.org
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. PLoS Med. Mar 2021;18(3):e1003583. doi:10.1371/journal.pmed.1003583
Giacomazzi J, Graudenz MS, Osorio CA, et al. Prevalence of the TP53 p.R337H mutation in breast cancer patients in Brazil. PLoS One. 2014;9(6):e99893. doi:10.1371/journal.pone.0099893
Hahn EC, Bittar CM, Vianna FSL, et al. TP53 p. Arg337His germline mutation prevalence in Southern Brazil: Further evidence for mutation testing in young breast cancer patients. PloS one. 2018;13(12) doi:10.1371/journal.pone.0209934
Giacomazzi J, Koehler-Santos P, Palmero EI, et al. A TP53 founder mutation, p.R337H, is associated with phyllodes breast tumors in Brazil. Virchows Arch. Jul 2013;463(1):17-22. doi:10.1007/s00428-013-1439-8
Assumpção JG, Seidinger AL, Mastellaro MJ, et al. Association of the germline TP53 R337H mutation with breast cancer in southern Brazil. BMC cancer. 2008;8(1):357. doi:10.1186/1471-2407-8-357
Giacomazzi J, Correia RL, Palmero EI, et al. The Brazilian founder mutation TP53 p.R337H is uncommon in Portuguese women diagnosed with breast cancer. Breast J. Sep-Oct 2014;20(5):534-6. doi:10.1111/tbj.12308
Mathias C, Bortoletto S, Centa A, et al. Frequency of the TP53 R337H variant in sporadic breast cancer and its impact on genomic instability. Sci Rep. Oct 06 2020;10(1):16614. doi:10.1038/s41598-020-73282-y
Gomes MC, Kotsopoulos J, de Almeida GL, et al. The R337H mutation in TP53 and breast cancer in Brazil. Hered Cancer Clin Pract. Mar 28 2012;10(1):3. doi:10.1186/1897-4287-10-3
Cury NM, Ferraz VE, Silva WA, Jr. TP53 p.R337H prevalence in a series of Brazilian hereditary breast cancer families. Hereditary cancer in clinical practice. 2014;12(1):8-8. doi:10.1186/1897-4287-12-8
Silva FC, Lisboa BC, Figueiredo MC, et al. Hereditary breast and ovarian cancer: assessment of point mutations and copy number variations in Brazilian patients. BMC medical genetics. 2014;15:55-55. doi:10.1186/1471-2350-15-55
Felix GE, Abe-Sandes C, Machado-Lopes TM, et al. Germline mutations in BRCA1, BRCA2, CHEK2 and TP53 in patients at high-risk for HBOC: characterizing a Northeast Brazilian Population. Hum Genome Var. 2014;1:14012. doi:10.1038/hgv.2014.12
Cipriano NM, Jr., de Brito AM, de Oliveira ES, et al. Mutation screening of TP53, CHEK2 and BRCA genes in patients at high risk for hereditary breast and ovarian cancer (HBOC) in Brazil. Breast Cancer. May 2019;26(3):397-405. doi:10.1007/s12282-018-00938-z
Sandoval RL, Leite ACR, Barbalho DM, et al. Germline molecular data in hereditary breast cancer in Brazil: Lessons from a large single-center analysis. PLoS One. 2021;16(2):e0247363. doi:10.1371/journal.pone.0247363
Matta BP, Gomes R, Mattos D, et al. Familial history and prevalence of BRCA1, BRCA2 and TP53 pathogenic variants in HBOC Brazilian patients from a public healthcare service. Sci Rep. Nov 03 2022;12(1):18629. doi:10.1038/s41598-022-23012-3
da Silva PFF, Goveia RM, Teixeira TB, et al. Pathogenic Variants in Early-Onset Breast Cancer Patients Fulfilling Hereditary Breast and Ovary Cancer and Li-Fraumeni-like Syndromes. Biomolecules. Apr 27 2022;12(5)doi:10.3390/biom12050640
Corrêa TS, Asprino PF, de Oliveira ESC, et al. p.R337H Germline Variant among Women at Risk of Hereditary Breast Cancer in a Public Health System of Midwest Brazil. Genes (Basel). Jul 16 2024;15(7)doi:10.3390/genes15070928
Authors
Copyright (c) 2026 Archives of Breast Cancer
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright©. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International License, which permits copy and redistribution of the material in any medium or format or adapt, remix, transform, and build upon the material for any purpose, except for commercial purposes.