title: Increased MUTYH mutation frequency among Dutch families with breast cancer and colorectal cancer.
abstract: Homozygous and compound heterozygous MUTYH mutations predispose for MUTYH-associated polyposis (MAP). The clinical phenotype of MAP is characterised by the multiple colorectal adenomas and colorectal carcinoma. We previously found that female MAP patients may also have an increased risk for breast cancer. Yet, the involvement of MUTYH mutations in families with both breast cancer and colorectal cancer is unclear. Here, we have genotyped the MUTYH p.Tyr179Cys, p.Gly396Asp and p.Pro405Leu founder mutations in 153 Dutch families with breast cancer patients and colorectal cancer patients. Families were classified as polyposis, revised Amsterdam criteria positive (FCRC-AMS positive), revised Amsterdam criteria negative (FCRC-AMS negative), hereditary breast and colorectal cancer (HBCC) and non-HBCC breast cancer families. As anticipated, biallelic MUTYH mutations were identified among 13% of 15 polyposis families, which was significantly increased compared to the absence of biallelic MUTYH mutations in the population (P = 0.0001). Importantly, six heterozygous MUTYH mutations were identified among non-polyposis families with breast and colorectal cancer. These mutations were identified specifically in FCRC-AMS negative and in HBCC breast cancer families (11% of 28 families and 4% of 74 families, respectively; P = 0.02 for both groups combined vs. controls). Importantly, the 11% MUTYH frequency among FCRC-AMS negative families was almost fivefold higher than the reported frequencies for FCRC-AMS negative families unselected for the presence of breast cancer patients (P = 0.03). Together, our results indicate that heterozygous MUTYH mutations are associated with families that include both breast cancer patients and colorectal cancer patients, independent of which tumour type is more prevalent in the family.
authors.affiliation: Department of Medical Oncology, Josephine Nefkens Institute, Erasmus University Medical Centre, Be414, Erasmus MC, CA, Rotterdam, The Netherlands.
authors.forename: Marijke
authors.initials: M
authors.lastname: Wasielewski
authors.forename: Astrid A
authors.initials: AA
authors.lastname: Out
authors.forename: Joyce
authors.initials: J
authors.lastname: Vermeulen
authors.forename: Maartje
authors.initials: M
authors.lastname: Nielsen
authors.forename: Ans
authors.initials: A
authors.lastname: van den Ouweland
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Mieke
authors.initials: M
authors.lastname: Schutte
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D016017:Odds Ratio; D010375:Pedigree; D010641:Phenotype; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase