Abstract
To determine prevalence, spectrum and genotype–phenotype correlations of MUTYH variants in Italian patients with suspected MAP (MUTYH-associated polyposis), a retrospective analysis was conducted to identify patients who had undergone MUTYH genetic testing from September 2002 to February 2014. Results of genetic testing and patient clinical characteristics were collected (gender, number of polyps, age at polyp diagnosis, presence of colorectal cancer (CRC) and/or other cancers, family data). The presence of large rearrangements of the MUTYH gene was evaluated by Multiplex Ligation-dependent Probe Amplification analysis. In all, 299 patients with colorectal neoplasia were evaluated: 61.2% were males, the median age at polyps or cancer diagnosis was 50 years (16–80 years), 65.2% had <100 polyps and 51.8% had CRC. A total of 36 different MUTYH variants were identified: 13 (36.1%) were classified as pathogenetic, whereas 23 (63.9%) were variants of unknown significance (VUS). Two pathogenetic variants were observed in 78 patients (26.1%). A large homozygous deletion of exon 15 was found in one patient (<1.0%). MAP patients were younger than those with negative MUTYH testing at polyps diagnosis (P<0.0001) and at first cancer diagnosis (P=0.007). MAP patients carrying the p.Glu480del variant presented with a younger age at polyp diagnosis as compared to patients carrying p.Gly396Asp and p.Tyr179Cys variants. A high heterogeneity of MUTYH variants and a high rate of VUS were identified in a cohort of Italian patients with suspected MAP. Genotype–phenotype analysis suggests that the p.Glu480del variant is associated with a severe phenotype.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Al-Tassan, N., Chmiel, N. H., Maynard, J., Fleming, N., Livingston, A. L., Williams, G. T. et al. Inherited variants of MYH associated with somatic G:C—>T:A mutations in colorectal tumors. Nat. Genet. 30, 227–232 (2002).
Nielsen, M., Hes, F. J., Nagengast, F. M., Weiss, M. M., Mathus-Vliegen, E. M., Morreau, H. et al. Germline mutations in APC and MUTYH are responsible for the majority of families with attenuated familial adenomatous polyposis. Clin. Genet. 71, 427–433 (2007).
Grover, S., Kastrinos, F., Steyerberg, E. W., Cook, E. F., Dewanwala, A., Burbidge, L. A. et al. Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas. JAMA 308, 485–492 (2012).
Aretz, S., Genuardi, M. & Hes, F. J. Clinical utility gene card for: MUTYH-associated polyposis (MAP), autosomal recessive colorectal adenomatous polyposis, multiple colorectal adenomas, multiple adenomatous polyps (MAP)—update 2012. Eur. J. Hum. Genet. 21, 1 (2013).
Nielsen, M., Joerink-van de Beld, M. C., Jones, N., Vogt, S., Tops, C. M., Vasen, H. F. et al. Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis. Gastroenterology 136, 471–476 (2009).
Nielsen, M., Morreau, H., Vasen, H. F. & Hes, F. J. MUTYH-associated polyposis (MAP). Crit. Rev. Oncol. Hematol. 79, 1–16 (2011).
Vogt, S., Jones, N., Christian, D., Engel, C., Nielsen, M., Kaufmann, A. et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 137, 1976–1985 (2009).
Win, A. K., Cleary, S. P., Dowty, J. G., Baron, J. A., Young, J. P., Buchanan, D. D. et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int. J. Cancer 129, 2256–2262 (2011).
Mazzei, F., Viel, A. & Bignami, M. Role of MUTYH in human cancer. Mutat. Res. 743-744, 33–43 (2013).
Markkanen, E., Dorn, J. & Hübscher, U. MUTYH DNA glycosylase: the rationale for removing undamaged bases from the DNA. Front. Genet. 28, 4 18 (2013).
Out, A. A., Tops, C. M., Nielsen, M., Weiss, M. M., van Minderhout, I. J., Fokkema, I. F. et al. Leiden Open Variation Database of the MUTYH gene. Hum. Mutat. 31, 1205–1215 (2010).
Grandval, P., Fabre, A. J., Gaildrat, P., Baert-Desurmont, S., Blayau, M., Buisine, M. P. et al. Genomic variations integrated database for MUTYH-associated adenomatous polyposis. J. Med. Genet. 52, 25–27 (2015).
Rouleau, E., Zattara, H., Lefol, C., Noguchi, T., Briaux, A., Buecher, B. et al. First large rearrangement in the MUTYH gene and attenuated familial adenomatous polyposis syndrome. Clin. Genet. 80, 301–303 (2011).
Torrezan, G. T., da Silva, F. C., Krepischi, A. C., Santos, E. M., Ferreira Fde, O., Rossi, B. M. et al. Breakpoint characterization of a novel large intragenic deletion of MUTYH detected in a MAP patient: case report. BMC Med. Genet 12, 128 (2011).
Poulsen, M. L. & Bisgaard, M. L. MUTYH associated polyposis (MAP). Curr. Genomics 9, 420–435 (2008).
Kim, D. W., Kim, I. J., Kang, H. C., Jang, S. G., Kim, K., Yoon, H. J. et al. Germline mutations of the MYH gene in Korean patients with multiple colorectal adenomas. Int. J. Colorectal Dis. 22, 1173–1178 (2007).
Sampson, J. R., Dolwani, S., Jones, S., Eccles, D., Ellis, A., Evans, D. G. et al. Autosomal recessive colorectal adenomatous polyposis due to inherited mutations of MYH. Lancet 362, 39–41 (2003).
Miyaki, M., Iijima, T., Yamaguchi, T., Hishima, T., Tamura, K., Utsunomiya, J. et al. Germline mutations of the MYH gene in Japanese patients with multiple colorectal adenomas. Mutat. Res. 578, 430–433 (2005).
Taki, K., Sato, Y., Nomura, S., Ashihara, Y., Kita, M., Tajima, I. et al. Mutation analysis of MUTYH in Japanese colorectal adenomatous polyposis patients. Fam. Cancer. 15, 261–265 (2016).
Lefevre, J. H., Colas, C., Coulet, F., Baert-Desurmont, S., Mongin, C., Tiret, E. et al. Frequent mutation in North African patients with MUTYH-associated polyposis. Clin. Genet. 80, 389–393 (2011).
Grasso, F., Giacomini, E., Sanchez, M., Degan, P., Gismondi, V., Mazzei, F. et al. Genetic instability in lymphoblastoid cell lines expressing biallelic and monoallelic variants in the human MUTYH gene. Hum. Mol. Genet. 23, 3843–3852 (2014).
D’Agostino, V. G., Minoprio, A., Torreri, P., Marinoni, I., Bossa, C., Petrucci, T. C. et al. Functional analysis of MUTYH mutated proteins associated with familial adenomatous polyposis. DNA Repair (Amst) 9, 700–707 (2010).
Gismondi, V., Meta, M., Bonelli, L., Radice, P., Sala, P., Bertario, L. et al. Prevalence of the Y165C, G382D and 1395delGGA germline mutations of the MYH gene in Italian patients with adenomatous polyposis coli and colorectal adenomas. Int. J. Cancer 109, 680–684 (2004).
Venesio, T., Molatore, S., Cattaneo, F., Arrigoni, A., Risio, M. & Ranzani, G. N. High frequency of MYH gene mutations in a subset of patients with familial adenomatous polyposis. Gastroenterology 126, 1681–1685 (2004).
Aceto, G., Curia, M. C., Veschi, S., De Lellis, L., Mammarella, S., Catalano, T. et al. Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli. Hum. Mutat. 26, 394 (2005).
de Leon, M. P., Urso, E. D., Pucciarelli, S., Agostini, M., Nitti, D., Roncucci, L. et al. Clinical and molecular features of attenuated adenomatous polyposis in northern Italy. Tech. Coloproctol 17, 79–87 (2013).
Pin, E., Pastrello, C., Tricarico, R., Papi, L., Quaia, M., Fornasarig, M. et al. MUTYH c.933+3A>C, associated with a severely impaired gene expression, is the first Italian founder mutation in MUTYH-associated polyposis. Int. J. Cancer 132, 1060–1069 (2013).
Isidro, G., Laranjeira, F., Pires, A., Leite, J., Regateiro, F., Castro e Sousa, F. et al. Germline MUTYH (MYH) mutations in Portuguese individuals with multiple colorectal adenomas. Hum. Mutat. 24, 353–354 (2004).
Filipe, B., Baltazar, C., Albuquerque, C., Fragoso, S., Lage, P., Vitoriano, I. et al. 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 (2009).
Goto, M., Shinmura, K., Nakabeppu, Y., Tao, H., Yamada, H., Tsuneyoshi, T. et al. Adenine DNA glycosylase activity of 14 human MutY homolog (MUTYH) variant proteins found in patients with colorectal polyposis and cancer. Hum. Mutat. 31, E1861–E1874 (2010).
Molatore, S., Russo, M. T., D’Agostino, V. G., Barone, F., Matsumoto, Y., Albertini, A. M. et al. MUTYH mutations associated with familial adenomatous polyposis: functional characterization by a mammalian cell-based assay. Hum. Mutat. 31, 159–166 (2010).
Ruggieri, V., Pin, E., Russo, M. T., Barone, F., Degan, P., Sanchez, M. et al. Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. Oncogene 32, 4500–4508 (2013).
Thompson, B. A., Spurdle, A. B., Plazzer, J. P., Greenblatt, M. S., Akagi, K., Al-Mulla, F. et al. InSiGHT. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat. Genet. 46, 107–115 (2014).
Acknowledgements
This work was supported by Ministry of Health, Project ‘Malattie Rare’ (MB) and by ‘Fondi 5 per mille’ to IRCCS AOU San Martino-IST, Genoa (LV).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Ricci, M., Miccoli, S., Turchetti, D. et al. Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study. J Hum Genet 62, 309–315 (2017). https://doi.org/10.1038/jhg.2016.132
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2016.132
