Inherited predisposition to colorectal adenomas caused by multiple rare alleles of MUTYH but not OGG1, NUDT1, NTH1 or NEIL 1, 2 or 3

Dallosso, A. A.; Dolwani, S.; Jones, N.; Jones, S.; Colley, J.; Maynard, J.; Idziaszczyk, S.; Humphreys, V.; Arnold, J.; Donaldson, A.; Eccles, D.; Ellis, A.; Evans, D. G.; M.^Frayling, I.; Hes, F. J.; Houlston, R. S.; Maher, E. R.; Nielsen, M.; Parry, S.; Tyler, E.
September 2008
Gut;Sep2008, Vol. 57 Issue 9, p1252
Academic Journal
Background: MUTYH-associated polyposis (MAP) is a recessive trait characterised by multiple colorectal adenomas and a high risk of colorectal cancer. MUTYH functions in the DNA base excision repair pathway and has a key role in the repair of oxidative DNA damage. Objectives: To assess the contribution of inherited variants in genes involved in base excision repair and oxidative DNA damage including MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 to the multiple colorectal adenoma phenotype. Methods: Inherited variants of MUTYH, OGG1, NEIL1, NEIL2, NEIL3, NUBT1 and NTH1 were sought in 167 unrelated patients with multiple colorectal adenomas whose family histories were consistent with recessive inheritance. These variants were also characterised in ~300 population controls. Results: Thirty-three patients (20%) and no controls were MUTYH homozygotes or compound heterozygotes (ie, carried two mutations) and therefore had MAP. Eight different pathogenic MUTYH mutations were identified, of which four were novel. MAP cases had significantly more adenomas than non-MAP cases (p = 0.0009; exact test for trends in proportions) and presented earlier (p = 0.013; analysis of variance). Twenty-four protein-altering variants were identified upon screening of OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1. However, all combinations of two (or more) variants that were identified at an individual locus in patients were also seen in controls, and no variants were significantly over-represented (or under-represented) in cases. Conclusion: Multiple rare alleles of MUTYH are associated with autosomal recessive MAP, while OGG1, NEIL1, NEIL2, NEIL3, NUDT1 and NTH1 do not contribute significantly to autosomal recessive polyposis.


Related Articles

  • Characterization of promoter regulatory elements involved in downexpression of the DNA polymerase κ in colorectal cancer. Lemée, F.; Bavoux, C.; Pillaire, M. J.; Bieth, A.; Machado, C. R.; Pena, S. D.; Guimbaud, R.; Selves, J.; Hoffmann, J. S.; Cazaux, C. // Oncogene;5/17/2007, Vol. 26 Issue 23, p3387 

    The low-fidelity DNA polymerases thought to be specialized in DNA damage processing are frequently misregulated in cancers. We show here that DNA polymerase kappa (polκ), prone to replicate across oxidative and aromatic adducts and known to function in nucleotide excision repair (NER), is...

  • New insights into p53 activation. Brooks, Christopher L.; Wei.Gu // Cell Research;Jun2010, Vol. 20 Issue 6, p614 

    The tumor suppressor p53 is a multifunctional, highly regulated, and promoter-specific transcriptional factor that is uniquely sensitive to DNA damage and cellular stress signaling. The mechanisms by which p53 directs a damaged cell down either a cell growth arrest or an apoptotic pathway remain...

  • Grading of distal colorectal adenomas as predictors for proximal colonic neoplasia and choice of endoscope in population screening: experience from the Norwegian Colorectal Cancer Prevention study (NORCCAP). Gondal, G.; Grotmol, T.; Hofstad, B.; Bretthauer, M.; Eide, T.J.; Hoff, G. // Gut;Mar2003, Vol. 52 Issue 3, p398 

    Background and aims: The purpose of this study was to evaluate the utility of easily measured clinical variables at flexible sigmoidoscopy (FS) screening that might predict a proximal advanced neoplasm (PAN). Methods: We studied 1833 subjects with biopsy verified adenomas at FS who subsequently...

  • Low folate conditions may enhance the interaction of trifluorothymidine with antifolates in colon cancer cells. Temmink, Olaf H.; Hoogeland, Marco F. M.; Fukushima, Masakazu; Peters, Godefridus J. // Cancer Chemotherapy & Pharmacology;Feb2006, Vol. 57 Issue 2, p171 

    Purpose: Trifluorothymidine (TFT) is a fluoropyrimidine that is part of the novel combination metabolite TAS-102, in which TFT is combined with a potent thymidine phosphorylase inhibitor (TPI). TAS-102 is currently tested as an orally chemotherapeutic agent in different schedules in a phase I...

  • Base-excision repair of oxidative DNA damage. David, Sheila S.; O'Shea, Valerie L.; Kundu, Sucharita // Nature;6/21/2007, Vol. 447 Issue 7147, p941 

    Maintaining the chemical integrity of DNA in the face of assault by oxidizing agents is a constant challenge for living organisms. Base-excision repair has an important role in preventing mutations associated with a common product of oxidative damage to DNA, 8-oxoguanine. Recent structural...

  • Complete regression of colonic adenomas after treatment with sulindac in Gardner's syndrome: a 4-year follow-up. Okai, Takashi; Yamaguchi, Yasushi; Sakai, Junta; Ohtsubo, Koushiro; Mouri, Hisatsugu; Sawabu, Norio // Journal of Gastroenterology;2001, Vol. 36 Issue 11, p778 

    A 22-year-old woman with Gardner's syndrome in whom long-term sulindac therapy, without surgical treatment, was effective in inducing complete regression of colonic adenomas is reported. One hundred milligrams of sulindac was administered twice daily after endoscopic polypectomy. Follow-up...

  • The causes of ordinary colorectal adenomas: the key to the control of colorectal cancer? Kune, Gabriel A.; Vitetta, Luis // Journal of the Royal Society of Medicine;Nov1995, Vol. 88 Issue 11, p625 

    The article discusses the possibility of control to colorectal cancer. This paper explores the causes of ordinary colorectal adenomas as a key for controlling colorectal cancer as the incidence of the disease is increasing in developing countries. Researches are well under way for the pathology...

  • DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Bartkova, Jirina; Horejší, Zuzana; Koed, Karen; Krämer, Alwin; Tort, Frederic; Zieger, Karsten; Guldberg, Per; Sehested, Maxwell; Nesland, Jahn M.; Lukas, Claudia; Ømtoft, Torben; Lukas, Jiri; Bartek, Jiri // Nature;4/14/2005, Vol. 434 Issue 7035, p864 

    During the evolution of cancer, the incipient tumour experiences‘oncogenic stress’, which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell...

  • The PI3K inhibitor LY294002 prevents p53 induction by DNA damage and attenuates chemotherapy-induced apoptosis. Bar, J.; Lukaschuk, N.; Zalcenstein, A.; Wilder, S.; Seger, R.; Oren, M.; Melino, G. // Cell Death & Differentiation;Dec2005, Vol. 12 Issue 12, p1578 

    The p53 tumor suppressor plays a key role in the natural protection against cancer. Activation of p53 by DNA-damaging agents can contribute to successful elimination of cancer cells via chemotherapy-induced apoptosis. The phosphatidylinositol-3 kinase (PI3K) pathway, triggered in normal cells...


Read the Article


Sign out of this library

Other Topics