Abstract
MUTYH-Associated Polyposis (MAP) is caused by biallelic pathogenic germline variants in the MUTYH gene. However, individuals harboring monoallelic MUTYH pathogenic variants in the presence of a positive family history have been reported to have a twofold increased risk of colorectal cancer (CRC) and extra colonic cancers. Our aim was to characterize the spectrum of monoallelic and biallelic germline MUTYH pathogenic variants in Latin American patients and to describe their clinical and genetic characteristics. Patients were identified from eight high-risk genetic cancer centers of five Latin American countries. Statistical analysis was performed using the two-sided P test using the Vassarstats statistical tools. Statistical significance was set at a p value ≤ 0.05. Of the 105 unrelated patients with cancer or colorectal polyposis, 84.8% and 15.2% carried pathogenic monoallelic and biallelic MUTYH variants, respectively. The most common pathogenic variants were p.Gly396Asp and p.Tyr179Cys (55% and 23%, respectively). The mean age at first diagnosis was 48.29 years (range 31–71) and 49.90 years (range 27–87) in biallelic and monoallelic MUTYH patients, respectively. CRC was the only cancer diagnosed in patients with biallelic MUTYH pathogenic variants (75%), while breast cancer (46.1%) was more common than CRC (24.7%) in individuals with monoallelic MUTYH pathogenic variants. We reported a high frequency of European founder variants in our diverse population. Some phenotypic differences from current studies were identified, such as a higher breast cancer burden in monoallelic carriers and a complete absence of extra-colon tumors in biallelic patients.
Similar content being viewed by others
Data availability
No datasets were generated or analysed during the current study.
References
Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, Bray F (2021) Cancer statistics for the year 2020: an overview. Int J Cancer 149(4):778–789
Medina Pabón MA, Babiker HM (2022) A review of hereditary colorectal cancers. StatPearls Publishing, StatPearls
Cruz-Correa M, Pérez-Mayoral J, Dutil J, Echenique M, Mosquera R, Rivera-Román K et al (2017) Clinical Cancer Genetics Consortia. Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines. Hered Cancer Clin Pract 15:3
Hampel H (2018) Population screening for hereditary colorectal cancer. Surg Oncol Clin N Am 2:319–325
Sutcliffe EG, Bartenbaker Thompson A, Stettner AR, Marshall ML, Roberts ME et al (2019) Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis. Fam Cancer 18(2):203–209
Boparai KS, Dekker E, Van Eeden S, Polak MM, Bartelsman JF, Mathus-Vliegen EM et al (2008) Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 135(6):2014–2018
Pitroski C, Cossio S, Koehler-Santos P, Graudenz M, Prolla J, Ashton-Prolla P (2011) Frequency of the common germline MUTYH mutations p. G396D and p.Y179C in patients diagnosed with colorectal cancer in Southern Brazil. Int J Colorectal Dis 26:841–846
Nielsen M, de Joerink-van Beld MC, Jones N, Vogt S, Tops CM, Vasen HFA et al (2009) Analysis of MUTYH genotypes and colorectal phenotypes in patients with MUTYH-associated polyposis. Gastroenterology 136:471–476
Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, Haile R et al (2009) Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 136(4):1251–1260
Win AK, Hopper JL, Jenkins MA (2011) Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis. Fam Cancer 10(1):1–9
Wasielewski M, Out AA, Vermeulen J, Nielsen M, van den Ouweland A, Tops CM, Wijnen JT, Vasen HF, Weiss MM, Klijn JG, Devilee P, Hes FJ, Schutte M (2010) Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer. Breast Cancer Res Treat 124(3):635–641
Jones N, Vogt S, Nielsen M, Christian D, Wark PA, Eccles D, Edwards E, Evans DG, Maher ER, Vasen HF, Hes FJ, Aretz S et al (2009) Increased colorectal cancer incidence in obligate carriers of heterozygous mutations in MUTYH. Gastroenterology 137:489–494
Lowry R (2023). VassarStats: Website for Statistical Computation. http://vassarstats.net/. Accessed 7 Feb 2023
Rodriguez-Rojas LX, Candelo E, Pachajoa H, Garcia-Robledo JE, Nastasi-Catanese JA, Olave-Rodriguez JA, Zambrano AR (2023) The unique spectrum of MUTYH germline mutations in colombian patients with extracolonic carcinomas. Appl Clin Genet 16:53–62
Vaccaro CA, López-Kostner F, Adriana DV, Palmero EI, Rossi BM, Antelo M et al (2019) From colorectal cancer pattern to the characterization of individuals at risk: picture for genetic research in Latin America. Int J Cancer 145(2):318–326
Curia MC, Catalano T, Aceto GM (2020) MUTYH: not just polyposis. World J Clin Oncol 11(7):428–449
Filipe B, Baltazar C, Albuquerque C, Fragoso S, Lage P, Vitoriano I et al (2009) C. APC or MUTYH mutations account for the majority of clinically well-characterized families with FAP and AFAP phenotype and patients with more than 30 adenomas. Clin Genet 76:242–255
Cheadle JP, Sampson JR (2007) MUTYH-associated polyposis–from defect in base excision repair to clinical genetic testing. DNA Repair 6:274–279
Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS (2009) Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 27:3975–3980
Lipton L, Halford SE, Johnson V, Novelli MR, Jones A, Cummings C et al (2003) Carcinogenesis in MYH-associated polyposis follows a distinct genetic pathway. Cancer Res 63:7595–7599
National Comprehensive Cancer Network (2023) Colorectal (Version 2.2023). https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf
Nielsen M, Infante E, Brand R (1993-2024) MUTYH Polyposis. 2012 Oct 4 [Updated 2021 May 27]. In: Adam MP, Feldman J, Mirzaa GM et al (eds). GeneReviews®. University of Washington, Seattle
Gupta S, Weiss JM, Axell L, Burke CA, Chen LM, Chung DC, Clayback KM, Dallas S, Felder S, Giardiello FM et al (2024) NCCN genetic/familial high-risk assessment: colorectal version 2.2023. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Accessed 12 Mar 2024. https://www.nccn.org/home/
Magrin L, Fanale D, Brando C et al (2022) MUTYH-associated tumor syndrome: the other face of MAP. Oncogene 41:2531–2539
Win AK, Dowty JG, Cleary SP, Kim H, Buchanan DD, Young JP et al (2014) Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 146(5):1208–1211
Thompson AB, Sutcliffe EG, Arvai K, Roberts ME, Susswein LR et al (2022) Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer. Fam Cancer 21:415–422
Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY et al (2021) A population-based study of genes previously implicated in breast cancer. N Engl J Med 384(5):440–451
Author information
Authors and Affiliations
Contributions
Adriana Della Valle, Florencia Neffa and Patricia Esperon: Conception and Design. Patricia Esperon: Methodology and Data analysis, preparation fo Figures 1-3 and Table 1 Patricia Esperon, Karin Alvarez, María José Mullins, Benedito Mauro Rossi, Rodrigo Felipe Góngora e Silva, Carlos Vaccaro, Francisco Lopéz-Köstner, Jorge Rugeles, Florencia Spirandelli, and Walter Pavicic: Data adquisition. Mev Dominguez, Florencia Neffa and Patricia Esperon: Writing, review &editing, All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Esperon, P., Neffa, F., Pavicic, W. et al. A comprehensive characterization of the spectrum of MUTYH germline pathogenic variants in Latin America. Familial Cancer (2024). https://doi.org/10.1007/s10689-024-00382-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s10689-024-00382-3