Ann Lab Med.  2025 Jan;45(1):77-84. 10.3343/alm.2024.0242.

Carrier Frequency and Incidence of MUTYH-Associated Polyposis Based on Database Analysis in East Asians and Koreans

• Park JE
• Lee T
• Cho EH
• Jang MA
• Won D
• Park B
• Ki CS
• Kong SY

• KMID: 2563858
• DOI: http://doi.org/10.3343/alm.2024.0242

Abstract

Background
MUTYH-associated polyposis is an autosomal recessive disorder associated with an increased lifetime risk of colorectal cancer and a moderately increased risk of ovarian, bladder, breast, and endometrial cancers. We analyzed the carrier frequency and estimated the incidence of MUTYH-associated polyposis in East Asian and Korean populations, for which limited data were previously available.
Methods
We examined 125,748 exomes from the gnomAD database, including 9,197 East Asians, and additional data from 5,305 individuals in the Korean Variant Archive and 1,722 in the Korean Reference Genome Database. All MUTYH variants were interpreted according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines and the Sequence Variant Interpretation guidelines from ClinGen.
Results
The global carrier frequency of MUTYH-associated polyposis was 1.29%, with Europeans (non-Finnish) having the highest frequency of 1.86% and Ashkenazi Jews the lowest at 0.06%. East Asians and Koreans had a carrier frequency of 0.35% and 0.37% and an estimated incidence of 1 in 330,409 and 1 in 293,304 in Koreans, respectively, which were substantially lower than the global average of 1 in 24,160 and the European (nonFinnish) incidence of 1 in 11,520.
Conclusions
This was the first study to investigate the frequency of carriers of MUTYH-associated polyposis in East Asians, including specific subgroups, utilizing gnomAD and a Korean genome database. Our data provide valuable reference information for future investigations of MUTYH-associated polyposis to understand the genetic diversity and specific variants associated with this condition in East Asian populations.

Keyword

MUTYH-associated polyposis; Carrier frequency; Incidence; East Asian

Figure

• 

  Fig. 1 Carrier frequency and estimated incidence of MUTYH-associated polyposis in gnomAD (v2.1.1) according to population. Circle size corresponds to the carrier frequency of MUTYH-associated polyposis.

Reference

References

1. Nielsen M, Infante E, Brand R. Adam MP, Feldman J, editors. 2012. MUTYH polyposis. GeneReviews. University of Washington;Seattle (WA): DOI: 10.1007/978-1-4020-6754-9_6624.

2. Sieber OM, Lipton L, Crabtree M, Heinimann K, Fidalgo P, Phillips RK, et al. 2003; Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med. 348:791–9. DOI: 10.1056/NEJMoa025283. PMID: 12606733.

3. Ryu KH, Kang MC, Jung YR, Jang MA, Park JE, Kim N, et al. 2023; Clinical significance of MUTYH germline variant. Lab Med Online. 13:301–7. DOI: 10.47429/lmo.2023.13.4.301.

4. Win AK, Jenkins MA, Dowty JG, Antoniou AC, Lee A, Giles GG, et al. 2017; Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol Biomarkers Prev. 26:404–12. DOI: 10.1158/1055-9965.EPI-16-0693. PMID: 27799157. PMCID: PMC5336409.

5. Yurgelun MB, Kulke MH, Fuchs CS, Allen BA, Uno H, Hornick JL, et al. 2017; Cancer susceptibility gene mutations in individuals with colorectal cancer. J Clin Oncol. 35:1086–95. DOI: 10.1200/JCO.2016.71.0012. PMID: 28135145. PMCID: PMC5455355.

6. Wallace SS, Murphy DL, Sweasy JB. 2012; Base excision repair and cancer. Cancer Lett. 327:73–89. DOI: 10.1016/j.canlet.2011.12.038. PMID: 22252118. PMCID: PMC3361536.

7. Ruggieri V, Pin E, Russo MT, Barone F, Degan P, Sanchez M, et al. 2013; Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. Oncogene. 32:4500–8. DOI: 10.1038/onc.2012.479. PMID: 23108399.

8. Nielsen M, Morreau H, Vasen HF, Hes FJ. 2011; MUTYH-associated polyposis (MAP). Crit Rev Oncol Hematol. 79:1–16. DOI: 10.1016/j.critrevonc.2010.05.011. PMID: 20663686.

9. Win AK, Hopper JL, Jenkins MA. 2011; Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis. Fam Cancer. 10:1–9. DOI: 10.1007/s10689-010-9399-5. PMID: 21061173. PMCID: PMC3228836.

10. Thompson AB, Sutcliffe EG, Arvai K, Roberts ME, Susswein LR, Marshall ML, 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. 21:415–22. DOI: 10.1007/s10689-021-00285-7. PMID: 34981295.

11. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, et al. 2002; Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat Genet. 30:227–32. DOI: 10.1038/ng828. PMID: 11818965.

12. Cleary SP, Cotterchio M, Jenkins MA, Kim H, Bristow R, Green R, et al. 2009; Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology. 136:1251–60. DOI: 10.1053/j.gastro.2008.12.050. PMID: 19245865. PMCID: PMC2739726.

13. Aretz S, Genuardi M, Hes FJ. 2013; 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:DOI: 10.1038/ejhg.2012.163. PMID: 22872101. PMCID: PMC3533318.

14. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. 2020; The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581:434–43. DOI: 10.1038/s41586-020-2308-7. PMID: 32461654. PMCID: PMC7334197.

15. Lee J, Lee J, Jeon S, Lee J, Jang I, Yang JO, et al. 2022; A database of 5305 healthy Korean individuals reveals genetic and clinical implications for an East Asian population. Exp Mol Med. 54:1862–71. DOI: 10.1038/s12276-022-00871-4. PMID: 36323850. PMCID: PMC9628380.

16. Jung KS, Hong KW, Jo HY, Choi J, Ban HJ, Cho SB, et al. 2020; KRGDB: the large-scale variant database of 1722 Koreans based on whole genome sequencing. Database (Oxford). 2020:baz146. DOI: 10.1093/database/baz146. PMID: 32133509. PMCID: PMC7056612.

17. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 2015; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 17:405–24. DOI: 10.1038/gim.2015.30. PMID: 25741868. PMCID: PMC4544753.

18. Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, et al. 2016; REVEL: an Ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet. 99:877–85. DOI: 10.1016/j.ajhg.2016.08.016. PMID: 27666373. PMCID: PMC5065685.

19. Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, Darbandi SF, Knowles D, Li YI, et al. 2019; Predicting splicing from primary sequence with deep learning. Cell. 176:535–48.e24. DOI: 10.1016/j.cell.2018.12.015. PMID: 30661751.

20. Miller DT, Lee K, Abul-Husn NS, Amendola LM, Brothers K, Chung WK, et al. 2023; ACMG SF v3.2 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 25:100866. DOI: 10.1016/j.gim.2023.100866. PMID: 37347242. PMCID: PMC10524344.

21. Ceyhan-Birsoy O, Machini K, Lebo MS, Yu TW, Agrawal PB, Parad RB, et al. 2017; A curated gene list for reporting results of newborn genomic sequencing. Genet Med. 19:809–18. DOI: 10.1038/gim.2016.193. PMID: 28079900. PMCID: PMC5507765.

22. 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. 146:1208–11.e1-5. DOI: 10.1053/j.gastro.2014.01.022. PMID: 24444654. PMCID: PMC3992182.

23. Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS. 2009; Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol. 27:3975–80. DOI: 10.1200/JCO.2008.21.6853. PMID: 19620482.

24. Kim IJ, Ku JL, Kang HC, Park JH, Yoon KA, Shin Y, et al. 2004; Mutational analysis of OGG1, MYH, MTH1 in FAP, HNPCC and sporadic colorectal cancer patients: R154H OGG1 polymorphism is associated with sporadic colorectal cancer patients. Hum Genet. 115:498–503. DOI: 10.1007/s00439-004-1186-7. PMID: 15449173.

25. Kim H, Kim HJ, Chi SG, Lee SK, Joo GR, Dong SH, et al. 2006; Absence of MutY homologue mutation in patients with multiple sporadic adenomatous polyps in Korea. World J Gastroenterol. 12:951–5. DOI: 10.3748/wjg.v12.i6.951. PMID: 16521226. PMCID: PMC4066163.

26. Kim JC, Ka IH, Lee YM, Koo KH, Kim HC, Yu CS, et al. 2007; MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas. Virchows Arch. 450:311–9. DOI: 10.1007/s00428-006-0363-6. PMID: 17252231.

27. Kim DW, Kim IJ, Kang HC, Jang SG, Kim K, Yoon HJ, et al. 2007; Germline mutations of the MYH gene in Korean patients with multiple colorectal adenomas. Int J Colorectal Dis. 22:1173–8. DOI: 10.1007/s00384-007-0289-8. PMID: 17703316.

28. Castillejo A, Vargas G, Castillejo MI, Navarro M, Barberá VM, González S, et al. 2014; Prevalence of germline MUTYH mutations among Lynch-like syndrome patients. Eur J Cancer. 50:2241–50. DOI: 10.1016/j.ejca.2014.05.022. PMID: 24953332.

29. Ricci MT, Miccoli S, Turchetti D, Bondavalli D, Viel A, Quaia M, et al. 2017; Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study. J Hum Genet. 62:309–15. DOI: 10.1038/jhg.2016.132. PMID: 27829682.