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

Lamlum, Hanan, Ilyas, Mohammad, Rowan, Andrew, Clark, Susan, Johnson, Victoria, Bell, Jennie, Frayling, Ian Martin, Efstathiou, Jason, Pack, Kevin, Payne, Stewart, Roylance, Rebecca, Gorman, Patricia, Sheer, Denise, Neale, Kay, Phillips, Robin, Talbot, Ian, Bodmer, Walter and Tomlinson, Ian 1999. 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. Nature Medicine 5 (9) , pp. 1071-1075. 10.1038/12511

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Abstract

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 mutations1. Clues from attenuated polyposis2, 3, 4, missense germline variants with mild disease5, 6 and the somatic mutation cluster region (codons 1,250−1,450)1, 7, 8 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	Nature Publishing Group
ISSN:	1078-8956
Last Modified:	04 Jun 2017 07:56
URI:	https://orca.cardiff.ac.uk/id/eprint/70129

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