Adenomatous Polyposis Syndromes: Unexplained Colorectal Adenomatous Polyposis

Chapter

Abstract

In a considerable number of patients with clinically confirmed colorectal adenomatous polyposis, no germline mutation in known genes can be identified, although a genetic etiology is likely. The phenotype of these cases is characterized by a more attenuated course, no evident extracolonic manifestations, and an unsuspicious or unclear family history in at least half of the patients. Diagnostic and technical difficulties to identify mutations in established genes might be relevant, in particular low-level APC mutational mosaicism seems to be the underlying cause in a large fraction of unexplained cases. During the last decades, several efforts had been made to uncover further genetic causes. Using different approaches including exome sequencing, however, only few and very rare novel genetic subtypes could be delineated pointing to extreme genetic heterogeneity. Consequently, large cohorts provided by international collaborations and novel analytic strategies are required to uncover the genetic basis in those patients.

Keywords

Etiology Mutation negative polyposis Colorectal cancer Classification Multiple adenomas 

References

  1. 1.
    Hes FJ, Ruano D, Nieuwenhuis M, et al. Colorectal cancer risk variants on 11q23 and 15q13 are associated with unexplained adenomatous polyposis. J Med Genet. 2014;51:55–60.CrossRefGoogle Scholar
  2. 2.
    Thirlwell C, Howarth KM, Segditsas S, et al. Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations. Br J Cancer. 2007;96:1729–34.CrossRefGoogle Scholar
  3. 3.
    Mongin C, Coulet F, Lefevre JH, et al. Unexplained polyposis: a challenge for geneticists, pathologists and gastroenterologists. Clin Genet. 2012;81:38–46.CrossRefGoogle Scholar
  4. 4.
    Adam R, Spier I, Zhao B, Kloth M, Marquez J, Hinrichsen I, Kirfel J, Tafazzoli A, Horpaopan S, Uhlhaas S, Stienen D, Friedrichs N, Altmüller J, Laner A, Holzapfel S, Peters S, Kayser K, Thiele H, Holinski-Feder E, Marra G, Kristiansen G, Nöthen MM, Büttner R, Möslein G, Betz RC, Brieger A, Lifton RP, Aretz S. Exome sequencing identifies biallelic MSH3 germline mutations as a recessive subtype of colorectal adenomatous polyposis. Am J Hum Genet. 2016;99:337–51.CrossRefGoogle Scholar
  5. 5.
    Ngeow J, Heald B, Rybicki LA, Orloff MS, Chen JL, Liu X, Yerian L, Willis J, Lehtonen HJ, Lehtonen R, Mester JL, Moline J, Burke CA, Church J, Aaltonen LA, Eng C. Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps. Gastroenterology. 2013;144:1402–9.CrossRefGoogle Scholar
  6. 6.
    Azzopardi D, Dallosso AR, Eliason K, Hendrickson BC, Jones N, Rawstorne E, Colley J, Moskvina V, Frye C, Sampson JR, Wenstrup R, Scholl T, Cheadle JP. Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. Cancer Res. 2008;68:358–63.CrossRefGoogle Scholar
  7. 7.
    Spier I, Horpaopan S, Vogt S, Uhlhaas S, Morak M, Stienen D, Draaken M, Ludwig M, Holinski-Feder E, Nöthen MM, Hoffmann P, Aretz S. Deep intronic APC mutations explain a substantial proportion of patients with familial or early-onset adenomatous polyposis. Hum Mutat. 2012;33:1045–50.CrossRefGoogle Scholar
  8. 8.
    Nieminen TT, Pavicic W, Porkka N, Kankainen M, Järvinen HJ, Lepistö A, Peltomäki P. Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis. Oncotarget. 2016;7(43):70685–98.CrossRefGoogle Scholar
  9. 9.
    Spier I, Drichel D, Kerick M, Kirfel J, Horpaopan S, Laner A, Holzapfel S, Peters S, Adam R, Zhao B, Becker T, Lifton RP, Perner S, Hoffmann P, Kristiansen G, Timmermann B, Nöthen MM, Holinski-Feder E, Schweiger MR, Aretz S. Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases. J Med Genet. 2016;53:172–9.CrossRefGoogle Scholar
  10. 10.
    Jansen AM, Crobach S, Geurts-Giele WR, van den Akker BE, Garcia MV, Ruano D, Nielsen M, Tops CM, Wijnen JT, Hes FJ, van Wezel T, Dinjens WN, Morreau H. Distinct patterns of somatic mosaicism in the APC gene in neoplasms from patients with unexplained adenomatous polyposis. Gastroenterology. 2017;152:546–9.CrossRefGoogle Scholar
  11. 11.
    Aceto GM, Fantini F, De Iure S, Di Nicola M, Palka G, Valanzano R, Di Gregorio P, Stigliano V, Genuardi M, Battista P, Cama A, Curia MC. Correlation between mutations and mRNA expression of APC and MUTYH genes: new insight into hereditary colorectal polyposis predisposition. J Exp Clin Cancer Res. 2015;34:131.CrossRefGoogle Scholar
  12. 12.
    Rigter LS, Kallenberg FG, Bastiaansen B, van Os TA, van Leeuwen FE, van Leerdam ME, Dekker E. A case series of intestinal adenomatous polyposis of unidentified etiology; a late effect of irradiation? BMC Cancer. 2016;16:862.CrossRefGoogle Scholar
  13. 13.
    Knudsen AL, Bisgaard ML, Bülow S. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Familial Cancer. 2003;2:43–55.CrossRefGoogle Scholar
  14. 14.
    Fearnhead NS, Wilding JL, Winney B, et al. Multiple rare variants in different genes account for multifactorial inherited susceptibility to colorectal adenomas. Proc Natl Acad Sci USA. 2004;101:15992–7.CrossRefGoogle Scholar
  15. 15.
    Lefevre JH, Bonilla C, Colas C, et al. Role of rare variants in undetermined multiple adenomatous polyposis and early-onset colorectal cancer. J Hum Genet. 2012;57:709–16.CrossRefGoogle Scholar
  16. 16.
    Dallosso AR, Dolwani S, Jones N, et al. Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3. Gut. 2008;57:1252–5.CrossRefGoogle Scholar
  17. 17.
    Will O, Carvajal-Carmona LG, Gorman P, Howarth KM, Jones AM, Polanco-Echeverry GM, Chinaleong JA, Gunther T, Silver A, Clark SK, Tomlinson I. Homozygous PMS2 deletion causes a severe colorectal cancer and multiple adenoma phenotype without extraintestinal cancer. Gastroenterology. 2007;132:527–30.CrossRefGoogle Scholar
  18. 18.
    Rio Frio T, Lavoie J, Hamel N, et al. Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia. N Engl J Med. 2010;363:2628–37.CrossRefGoogle Scholar
  19. 19.
    de Voer RM, Geurts van Kessel A, Weren RD, Ligtenberg MJ, Smeets D, Fu L, Vreede L, Kamping EJ, Verwiel ET, Hahn MM, Ariaans M, Spruijt L, van Essen T, Houge G, Schackert HK, Sheng JQ, Venselaar H, van Ravenswaaij-Arts CM, van Krieken JH, Hoogerbrugge N, Kuiper RP. Germline mutations in the spindle assembly checkpoint genes BUB1 and BUB3 are risk factors for colorectal cancer. Gastroenterology. 2013;145:544–7.CrossRefGoogle Scholar
  20. 20.
    Horpaopan S, Spier I, Zink AM, Altmüller J, Holzapfel S, Laner A, Vogt S, Uhlhaas S, Heilmann S, Stienen D, Pasternack SM, Keppler K, Adam R, Kayser K, Moebus S, Draaken M, Degenhardt F, Engels H, Hofmann A, Nöthen MM, Steinke V, Perez-Bouza A, Herms S, Holinski-Feder E, Fröhlich H, Thiele H, Hoffmann P, Aretz S. Genome-wide CNV analysis in 221 unrelated patients and targeted high-throughput sequencing reveal novel causative candidate genes for colorectal adenomatous polyposis. Int J Cancer. 2015;136:E578–89.CrossRefGoogle Scholar
  21. 21.
    Gilissen C, Hoischen A, Brunner HG, Veltman JA. Disease gene identification strategies for exome sequencing. Eur J Hum Genet. 2012;20:490–7.CrossRefGoogle Scholar
  22. 22.
    Palles C, et al. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45(2):136–44.CrossRefGoogle Scholar
  23. 23.
    Weren RD, Ligtenberg MJ, Kets CM, de Voer RM, Verwiel ET, Spruijt L, van Zelst-Stams WA, Jongmans MC, Gilissen C, Hehir-Kwa JY, Hoischen A, Shendure J, Boyle EA, Kamping EJ, Nagtegaal ID, Tops BB, Nagengast FM, Geurts van Kessel A, van Krieken JH, Kuiper RP, Hoogerbrugge N. A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Nat Genet. 2015;47(6):668–71.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Institute of Human Genetics, Center for Hereditary Tumor Syndromes, University of BonnBonnGermany
  2. 2.Department of Clinical GeneticsLeiden University Medical CentreLeidenThe Netherlands

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