title: Prevalence and phenotypes of APC and MUTYH mutations in patients with multiple colorectal adenomas.
abstract: BACKGROUND
  Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes.
  
  
  OBJECTIVE
  To determine the prevalence of pathogenic APC and MUTYH mutations in patients with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers.
  
  
  METHODS
  Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses.
  
  
  METHODS
  Prevalence of pathogenic mutations in APC and MUTYH genes.
  
  
  RESULTS
  Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% [95% CI, 71%-87%]) and 2 of 119 (2% [95% CI, 0.2%-6%]), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% [95% CI, 54%-59%]) and 94 of 1338 (7% [95% CI, 6%-8%]) among those with 100 to 999 adenomas, 326 of 3253 (10% [95% CI, 9%-11%]) and 233 of 3253 (7% [95% CI, 6%-8%]) among those with 20 to 99 adenomas, and 50 of 970 (5% [95% CI, 4%-7%]) and 37 of 970 (4% [95% CI, 3%-5%]) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses.
  
  
  CONCLUSIONS
  Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.|Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA.|Program in Cancer Outcomes Research Training, Massachusetts General Hospital, Boston, MA.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Grover
authors.affiliation: Columbia University Medical Center, New York, NY.|Herbert Irving Comprehensive Cancer Center, New York, NY.
authors.forename: Fay
authors.initials: F
authors.lastname: Kastrinos
authors.affiliation: Center for Medical Decision Making, Erasmus Medical Center, Rotterdam, Netherlands.
authors.forename: Ewout W
authors.initials: EW
authors.lastname: Steyerberg
authors.affiliation: Harvard School of Public Health, Boston, MA.
authors.forename: E Francis
authors.initials: EF
authors.lastname: Cook
authors.affiliation: Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Akriti
authors.initials: A
authors.lastname: Dewanwala
authors.affiliation: Myriad Genetic Laboratories Inc., Salt Lake City, UT.
authors.forename: Lynn Anne
authors.initials: LA
authors.lastname: Burbidge
authors.affiliation: Myriad Genetic Laboratories Inc., Salt Lake City, UT.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wenstrup
authors.affiliation: Division of Gastroenterology, Brigham and Women's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.|Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA.
authors.forename: Sapna
authors.initials: S
authors.lastname: Syngal
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000328:Adult; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D003430:Cross-Sectional Studies; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase