title: Mutation and association analyses of the candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A in patients with unexplained MSH2-deficient tumors.
abstract: Lynch syndrome (Hereditary non-polyposis colorectal cancer/HNPCC) is a cancer susceptibility syndrome which is caused by germline mutations in DNA mismatch repair (MMR) genes, in particular MLH1 and MSH2. A pathogenic germline mutation in the respective MMR gene is suggested by the finding of a loss of a mismatch repair protein in tumor tissue on immunohistochemical staining combined with an early age of onset and/or the familial occurrence of colorectal cancer. Pathogenic germline mutations are identifiable in around 60% of patients suspected of Lynch syndrome, depending on the familial occurrence. The aim of the present study was to identify novel susceptibility genes for Lynch syndrome. 64 Healthy controls and 64 Lynch syndrome patients with no pathogenic MSH2 mutation but a loss of MSH2 expression in their tumor tissue were screened for rare and disease causing germline mutations in the functional candidate genes ESR1, ESR2, MAX, PCNA, and KAT2A. Thirty variants were identified, and these were then genotyped in an independent sample of 36 mutation negative Lynch syndrome patients and 234 controls. Since a trend towards association was observed for KAT2A, an additional set of 21 tagging SNPs was analyzed at this locus in a final case-control sample of 142 mutation negative Lynch syndrome patients and 298 controls. The mutation analysis failed to reveal any rare disease-causing mutations. No association was found at the single-marker or haplotypic level for any common disease-modifying variant. The present results suggest that neither rare nor common genetic variants in ESR1, ESR2, MAX, PCNA, or KAT2A contribute to the development of Lynch syndrome.
authors.affiliation: Institute of Human Genetics, BMZ, University of Bonn, Sigmund-Freud-Strasse 25, 53127, Bonn, Germany. nils.rahner@uni-duesseldorf.de
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Felix F
authors.initials: FF
authors.lastname: Brockschmidt
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.forename: Philip
authors.initials: P
authors.lastname: Kahl
authors.forename: Tim
authors.initials: T
authors.lastname: Becker
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Carli J M
authors.initials: CJ
authors.lastname: Tops
authors.forename: Elke
authors.initials: E
authors.lastname: Holinski-Feder
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Spruijt
authors.forename: Heike
authors.initials: H
authors.lastname: Görgens
authors.forename: Susanne
authors.initials: S
authors.lastname: Stemmler
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dietmaier
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D016022:Case-Control Studies; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D047628:Estrogen Receptor alpha / Q000235:genetics*; D047629:Estrogen Receptor beta / Q000235:genetics*; D005500:Follow-Up Studies; D051548:Histone Acetyltransferases / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics*; D000099224:p300-CBP-Associated Factor
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D051548:Histone Acetyltransferases; D051718:MutS Homolog 2 Protein; D018809:Proliferating Cell Nuclear Antigen; C506487:ESR1 protein, human; C499330:MAX protein, human; C501179:KAT2A protein, human; D000099224:p300-CBP-Associated Factor; C497172:MSH2 protein, human
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