PMID- 10470088
OWN - NLM
STAT- MEDLINE
DCOM- 19990924
LR  - 20220309
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 5
IP  - 9
DP  - 1999 Sep
TI  - The type of somatic mutation at APC in familial adenomatous polyposis is
      determined by the site of the germline mutation: a new facet to Knudson's
      'two-hit' hypothesis.
PG  - 1071-5
AB  - 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.
FAU - Lamlum, H
AU  - Lamlum H
AD  - Molecular and Population Genetics Laboratory, Imperial Cancer Research Fund, 44, 
      Lincoln's Inn Fields, London WC2A 3PX, UK.
FAU - Ilyas, M
AU  - Ilyas M
FAU - Rowan, A
AU  - Rowan A
FAU - Clark, S
AU  - Clark S
FAU - Johnson, V
AU  - Johnson V
FAU - Bell, J
AU  - Bell J
FAU - Frayling, I
AU  - Frayling I
FAU - Efstathiou, J
AU  - Efstathiou J
FAU - Pack, K
AU  - Pack K
FAU - Payne, S
AU  - Payne S
FAU - Roylance, R
AU  - Roylance R
FAU - Gorman, P
AU  - Gorman P
FAU - Sheer, D
AU  - Sheer D
FAU - Neale, K
AU  - Neale K
FAU - Phillips, R
AU  - Phillips R
FAU - Talbot, I
AU  - Talbot I
FAU - Bodmer, W
AU  - Bodmer W
FAU - Tomlinson, I
AU  - Tomlinson I
LA  - eng
GR  - A3585/CRUK_/Cancer Research UK/United Kingdom
PT  - Journal Article
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Codon)
SB  - IM
MH  - Adenoma/genetics/pathology
MH  - Adenomatous Polyposis Coli/*genetics/pathology
MH  - Alleles
MH  - Base Sequence
MH  - Codon/genetics
MH  - Colorectal Neoplasms/*genetics/pathology
MH  - DNA Mutational Analysis
MH  - Exons/genetics
MH  - Family Health
MH  - Fibromatosis, Aggressive/genetics/pathology
MH  - Frameshift Mutation/genetics
MH  - Gene Deletion
MH  - Gene Frequency
MH  - Genes, APC/*genetics
MH  - Germ-Line Mutation/*genetics
MH  - Humans
MH  - *Models, Genetic
MH  - Mutation/*genetics
EDAT- 1999/09/02 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/09/02 09:00
PHST- 1999/09/02 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/09/02 09:00 [entrez]
AID - 10.1038/12511 [doi]
PST - ppublish
SO  - Nat Med. 1999 Sep;5(9):1071-5. doi: 10.1038/12511.