title: Colorectal tumors from APC*I1307K carriers principally harbor somatic APC mutations outside the A8 tract.
abstract: OBJECTIVE
  APC*I1307K (c.3920T>A) is an inherited variant associated with colorectal tumour risk found almost exclusively in those of Ashkenazi Jewish ancestry. A single nucleotide substitution creates an oligo-adenine tract (A8) that appears to be inherently prone to further mis-pairing and slippage. The reported multiple tumor phenotype of carriers is not easily reconciled with molecular and population genetics data. We postulated that some c.3920T>A carriers with multiple adenomas have other unidentified APC germ line or somatic mutations.
  
  
  METHODS
  DNA from 82 colonic tumours and accompanying normal tissue collected from 29 carriers with multiple colorectal tumors was directly sequenced between codons 716 and 1604. We also assessed APC gene loss of heterozygosity.
  
  
  RESULTS
  One patient (3.4%) was found to have an additional APC germ line mutation. Twenty-five of the tumours showed no significant somatic molecular change, 36 showed one change, 20 showed two, and one tumour showed more than 2 changes. Our data suggest a correlation between advancing histology and fewer beta-catenin binding sites remaining in the mutant proteins.
  
  
  CONCLUSIONS
  There were no other common germ line variants identified within the region of the APC gene examined, suggesting that any effect from this region on tumour production is attributable to the c.3920T>A allele. Our findings further suggest the only somatic genetic change clearly attributable to the c.3920T>A mutation is the c.3924_3925insA.
authors.affiliation: Department of Medicine, Saint Barnabas Medical Center, Livingston, New Jersey, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Zauber
authors.affiliation: Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Timothy
authors.initials: T
authors.lastname: Bishop
authors.affiliation: Cancer Research UK Genomics Facility, Leeds Institute of Molecular Medicine, University of Leeds, Leeds, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Taylor
authors.affiliation: Department of Pathology, Saint Barnabas Medical Center, Livingston, New Jersey, United States of America.
authors.forename: Marlene
authors.initials: M
authors.lastname: Sabbath-Solitare
authors.affiliation: Department of Pathology, Saint Barnabas Medical Center, Livingston, New Jersey, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Marotta
authors.affiliation: Molecular and Population Genetics, Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Tomlinson
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000483:Alleles; D003062:Codon / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009838:Oligodeoxyribonucleotides
chemical_list: C555337:APC protein, human; D025601:Adenomatous Polyposis Coli Protein; D003062:Codon; D009838:Oligodeoxyribonucleotides; C030570:oligodeoxyadenylic acid