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APC is often cited as a prime example of a tumor suppressor gene. Truncating germline and somatic mutations (or, infrequently, allelic loss) occur in tumors in FAP (familial adenomatous polyposis). Most sporadic colorectal cancers also have two APC mutations. Clues from attenuated polyposis, missense germline variants with mild disease and the somatic mutation cluster region (codons 1,250-1,450) indicate, however, that APC mutations might not result in simple loss of protein function. We have found that FAP patients with germline APC mutations within a small region (codons 1,194-1,392 at most) mainly show allelic loss in their colorectal adenomas, in contrast to other FAP patients, whose 'second hits' tend to occur by truncating mutations in the mutation cluster region. Our results indicate that different APC mutations provide cells with different selective advantages, with mutations close to codon 1,300 providing the greatest advantage. Allelic loss is selected strongly in cells with one mutation near codon 1,300. A different germline-somatic APC mutation association exists in FAP desmoids. APC is not, therefore, a classical tumor suppressor. Our findings also indicate a new mechanism for disease severity: if a broader spectrum of mutations is selected in tumors, the somatic mutation rate is effectively higher and more tumors grow.

Original publication

DOI

10.1038/12511

Type

Journal article

Journal

Nat med

Publication Date

09/1999

Volume

5

Pages

1071 - 1075

Keywords

Adenoma, Adenomatous Polyposis Coli, Alleles, Base Sequence, Codon, Colorectal Neoplasms, DNA Mutational Analysis, Exons, Family Health, Fibromatosis, Aggressive, Frameshift Mutation, Gene Deletion, Gene Frequency, Genes, APC, Germ-Line Mutation, Humans, Models, Genetic, Mutation