Advertisement

Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis

  • Erin G. Sutcliffe
  • Amanda Bartenbaker Thompson
  • Amy R. Stettner
  • Megan L. Marshall
  • Maegan E. Roberts
  • Lisa R. Susswein
  • Ying Wang
  • Rachel T. Klein
  • Kathleen S. Hruska
  • Benjamin D. Solomon
Original Article

Abstract

Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.

Keywords

Inherited cancer Genetic testing MAP MUTYH FAP 

Notes

Compliance with ethical standards

Conflict of interest

Erin G. Sutcliffe, Amanda Bartenbaker Thompson, Megan L. Marshall, Maegan E. Roberts, Lisa R. Susswein, Ying Wang are employed by GeneDx/BioReference Laboratories, Inc./OPKO Health, and have salary as the only disclosure. Kathleen S. Hruska, Benjamin D. Solomon are employed by and have stock ownership or options in GeneDx/BioReference Laboratories, Inc./OPKO Health. Amy R. Stettner and Rachel T. Klein have no conflicts of interest to disclose.

Supplementary material

10689_2018_116_MOESM1_ESM.docx (28 kb)
Supplementary material 1 (DOCX 27 KB)

References

  1. 1.
    Jenkins MA, Croitoru ME, Monga N et al (2006) Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol 15:312–314.  https://doi.org/10.1158/1055-9965.EPI-05-0793 CrossRefGoogle Scholar
  2. 2.
    Goodenberger M, Lindor NM (2011) Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol 45:488–500.  https://doi.org/10.1097/MCG.0b013e318206489c CrossRefGoogle Scholar
  3. 3.
    Farrington SM, Tenesa A, Barnetson R et al (2005) Germline susceptibility to colorectal cancer due to base-excision repair gene defects. Am J Hum Genet 77:112–119.  https://doi.org/10.1086/431213 CrossRefGoogle Scholar
  4. 4.
    Balaguer F, Castellví-Bel S, Castells A et al (2007) Identification of MYH mutation carriers in colorectal cancer: a multicenter, case-control, population-based study. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc 5:379–387.  https://doi.org/10.1016/j.cgh.2006.12.025 Google Scholar
  5. 5.
    Morak M, Laner A, Bacher U et al (2010) MUTYH-associated polyposis—variability of the clinical phenotype in patients with biallelic and monoallelic MUTYH mutations and report on novel mutations. Clin Genet 78:353–363.  https://doi.org/10.1111/j.1399-0004.2010.01478.x CrossRefGoogle Scholar
  6. 6.
    Leoz ML, Carballal S, Moreira L et al (2015) The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management. Appl Clin Genet 8:95–107.  https://doi.org/10.2147/TACG.S51484 Google Scholar
  7. 7.
    Barnetson RA, Devlin L, Miller J et al (2007) Germline mutation prevalence in the base excision repair gene, MYH, in patients with endometrial cancer. Clin Genet 72:551–555.  https://doi.org/10.1111/j.1399-0004.2007.00900.x CrossRefGoogle Scholar
  8. 8.
    Tricarico R, Bet P, Ciambotti B et al (2009) Endometrial cancer and somatic G> T KRAS transversion in patients with constitutional MUTYH biallelic mutations. Cancer Lett 274:266–270.  https://doi.org/10.1016/j.canlet.2008.09.022 CrossRefGoogle Scholar
  9. 9.
    Vogt S, Jones N, Christian D et al (2009) Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology 137:1976–1985.e1.  https://doi.org/10.1053/j.gastro.2009.08.052 CrossRefGoogle Scholar
  10. 10.
    Win AK, Reece JC, Dowty JG et al (2016) Risk of extracolonic cancers for people with biallelic and monoallelic mutations in MUTYH. Int J Cancer 139:1557–1563.  https://doi.org/10.1002/ijc.30197 CrossRefGoogle Scholar
  11. 11.
    Castillejo A, Vargas G, Castillejo MI et al (2014) Prevalence of germline MUTYH mutations among Lynch-like syndrome patients. Eur J Cancer Oxf Engl 1990 50:2241–2250.  https://doi.org/10.1016/j.ejca.2014.05.022 Google Scholar
  12. 12.
    NCCN Guidelines. Genetic/Familial High-Risk Assessment: Colorectal (Version 3.2017). http://www.nccn.org/clinical.asp. Accessed 19 Jun 2017
  13. 13.
    Nielsen M, Lynch H, Infante E, Brand R (2015) MUTYH-associated polyposis. In: Adam MP, Ardinger HH, Pagon RA et al (eds) GeneReviews®. University of Washington, SeattleGoogle Scholar
  14. 14.
    Wallis YL, Macdonald F, Hultén M et al (1994) Genotype-phenotype correlation between position of constitutional APC gene mutation and CHRPE expression in familial adenomatous polyposis. Hum Genet 94:543–548CrossRefGoogle Scholar
  15. 15.
    Coleman P, Barnard NAS (2007) Congenital hypertrophy of the retinal pigment epithelium: prevalence and ocular features in the optometric population. Ophthalmic Physiol Opt J Br Coll Ophthalmic Opt Optom 27:547–555.  https://doi.org/10.1111/j.1475-1313.2007.00513.x CrossRefGoogle Scholar
  16. 16.
    Sieber OM, Lipton L, Crabtree M et al (2003) Multiple colorectal adenomas, classic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med 348:791–799.  https://doi.org/10.1056/NEJMoa025283 CrossRefGoogle Scholar
  17. 17.
    Gismondi V, Meta M, Bonelli L et al (2004) 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.  https://doi.org/10.1002/ijc.20054 CrossRefGoogle Scholar
  18. 18.
    Eliason K, Hendrickson BC, Judkins T et al (2005) The potential for increased clinical sensitivity in genetic testing for polyposis colorectal cancer through the analysis of MYH mutations in North American patients. J Med Genet 42:95–96.  https://doi.org/10.1136/jmg.2004.025973 CrossRefGoogle Scholar
  19. 19.
    Riegert-Johnson DL, Johnson RA, Rabe KG et al (2007) The value of MUTYH testing in patients with early onset microsatellite stable colorectal cancer referred for hereditary nonpolyposis colon cancer syndrome testing. Genet Test 11:361–365.  https://doi.org/10.1089/gte.2007.0014 CrossRefGoogle Scholar
  20. 20.
    Pearlman R, Frankel WL, Swanson B et al (2017) Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol 3:464–471.  https://doi.org/10.1001/jamaoncol.2016.5194 CrossRefGoogle Scholar
  21. 21.
    Morak M, Heidenreich B, Keller G et al (2014) Biallelic MUTYH mutations can mimic Lynch syndrome. Eur J Hum Genet EJHG 22:1334–1337.  https://doi.org/10.1038/ejhg.2014.15 CrossRefGoogle Scholar
  22. 22.
    Seguí N, Navarro M, Pineda M et al (2015) Exome sequencing identifies MUTYH mutations in a family with colorectal cancer and an atypical phenotype. Gut 64:355–356.  https://doi.org/10.1136/gutjnl-2014-307084 CrossRefGoogle Scholar
  23. 23.
    Kacerovska D, Drlik L, Slezakova L et al (2016) Cutaneous sebaceous lesions in a patient with MUTYH-associated polyposis mimicking Muir-Torre syndrome. Am J Dermatopathol 38:915–923.  https://doi.org/10.1097/DAD.0000000000000649 CrossRefGoogle Scholar
  24. 24.
    Roberts ME, Riegert-Johnson DL, Thomas BC et al (2013) Screening for Muir-Torre syndrome using mismatch repair protein immunohistochemistry of sebaceous neoplasms. J Genet Couns 22:393–405.  https://doi.org/10.1007/s10897-012-9552-4 CrossRefGoogle Scholar
  25. 25.
    Landon M, Ceulemans S, Saraiya DS et al (2015) Analysis of current testing practices for biallelic MUTYH mutations in MUTYH-associated polyposis. Clin Genet 87:368–372.  https://doi.org/10.1111/cge.12375 CrossRefGoogle Scholar
  26. 26.
    Susswein LR, Marshall ML, Nusbaum R et al (2016) Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med Off J Am Coll Med Genet 18:823–832.  https://doi.org/10.1038/gim.2015.166 Google Scholar
  27. 27.
    Roberts ME, Jackson SA, Susswein LR et al (2018) MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med Off J Am Coll Med Genet.  https://doi.org/10.1038/gim.2017.254 Google Scholar
  28. 28.
    SEER 9 Regs Research Data Surveillance, Epidemiology, and End Results (SEER) Program (http://www.seer.cancer.gov) SEER*Stat Database: Incidence—SEER 9 Regs Research Data, Nov 2017 Sub (1973-2015) <Katrina/Rita Population Adjustment>—Linked To County Attributes—Total U.S., 1969-2016 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, released April 2018, based on the November 2017 submission.
  29. 29.
    Cleary SP, Cotterchio M, Jenkins MA et al (2009) Germline MutY human homologue mutations and colorectal cancer: a multisite case-control study. Gastroenterology 136:1251–1260.  https://doi.org/10.1053/j.gastro.2008.12.050 CrossRefGoogle Scholar
  30. 30.
    Lek M, Karczewski KJ, Minikel EV et al (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536:285–291.  https://doi.org/10.1038/nature19057 CrossRefGoogle Scholar
  31. 31.
    Win AK, Dowty JG, Cleary SP et al (2014) Risk of colorectal cancer for carriers of mutations in MUTYH, with and without a family history of cancer. Gastroenterology 146:1208–1211.e1–e5.  https://doi.org/10.1053/j.gastro.2014.01.022.CrossRefGoogle Scholar
  32. 32.
    Elsaid A, Elshazli R, El-Tarapely F et al (2017) Association of monoallelic MUTYH mutation among Egyptian patients with colorectal cancer. Fam Cancer 16:83–90.  https://doi.org/10.1007/s10689-016-9927-z CrossRefGoogle Scholar
  33. 33.
    Lubbe SJ, Di Bernardo MC, Chandler IP, Houlston RS (2009) Clinical implications of the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol Off J Am Soc Clin Oncol 27:3975–3980.  https://doi.org/10.1200/JCO.2008.21.6853 CrossRefGoogle Scholar
  34. 34.
    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.  https://doi.org/10.1007/s10689-010-9399-5 CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Erin G. Sutcliffe
    • 1
  • Amanda Bartenbaker Thompson
    • 1
  • Amy R. Stettner
    • 2
  • Megan L. Marshall
    • 1
  • Maegan E. Roberts
    • 1
  • Lisa R. Susswein
    • 1
  • Ying Wang
    • 1
  • Rachel T. Klein
    • 2
  • Kathleen S. Hruska
    • 1
  • Benjamin D. Solomon
    • 1
  1. 1.GeneDxGaithersburgUSA
  2. 2.My Gene TeamMiamiUSA

Personalised recommendations