The characterization of somatic APC mutations in colonic adenomas and carcinomas in Ashkenazi Jews with the APC I1307K variant using linkage disequilibrium

J Pathol. 2003 Feb;199(2):146-51. doi: 10.1002/path.1226.


Mutations of the adenomatous polyposis coli (APC) gene play a critical role in the development of colorectal neoplasms. A novel mechanism involves a germline variant, at codon 1307 of the APC gene. The mutation is thought to create an unstable segment of DNA, which facilitates the development of somatic mutations. I1307K has been shown to be ancestral in Middle Eastern populations. The aim of the present study was to confirm this observation for a Western population and to utilize this information in the characterization of the somatic changes in colorectal neoplasia in carriers of I1307K. DNA from 182 US Ashkenazim was screened for the I1307K variant, which was found in 22 (12.1%), and the ancestral nature of this variant was confirmed in this population by showing that all of those with the I1307K variant carried a specific allele at the D5S346 locus, while the majority shared a D5S1385 allele. Subsequently, 79 neoplasms were analysed from 15 I1307K carriers for loss of heterozygosity (LOH) at the D5S346 locus. LOH was detected in 18 neoplasms (23%). Of these 18, four neoplasms showed loss of the I1307K-associated allele, while 14 neoplasms had retained the I1307K-associated allele and, by implication, the I1307K variant. PCR products were also cloned into a plasmid vector to isolate individual APC alleles. For those neoplasms with LOH, 13 of the 18 neoplasms (72%) had a somatic mutation, of which 12 involved the I307K-bearing chromosome. This study is consistent with two previous studies in showing that additional somatic mutations close to codon 1307 are almost always on the I1307K-bearing chromosome, but either allele may demonstrate LOH. Further evidence for the interpretation of the action of I1307K as producing DNA instability is provided by analysing multiple neoplasms from the same person and by showing that these neoplasms have differing patterns of LOH and associated somatic mutations.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics*
  • Adenoma / pathology
  • Aged
  • Alleles
  • Carcinoma / genetics
  • Carcinoma / pathology
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology
  • DNA, Neoplasm / analysis
  • Genes, APC*
  • Genetic Markers / genetics
  • Genotype
  • Humans
  • Jews / genetics*
  • Linkage Disequilibrium / genetics*
  • Loss of Heterozygosity / genetics
  • Male
  • Microsatellite Repeats / genetics
  • Mutation / genetics
  • Polymerase Chain Reaction


  • DNA, Neoplasm
  • Genetic Markers