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 L.; Bell, Jennie; Frayling, Ian Martin; Efstathiou, Jason A.; Pack, Kevin; Payne, Stewart J.; Roylance, Rebecca; Gorman, Patricia; Sheer, Denise; Neale, Kay; Phillips, R. K. S.; Talbot, Ian C.; Bodmer, W F; Tomlinson, Ian

doi:10.1038/12511

Cited by 340 publications

(284 citation statements)

References 19 publications

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“…This finding corresponds with the published correlation between the presence of a germline mutation in the mutation cluster region (MCR) and the severity of polyposis (Ficari et al, 2000). It appears that the germline mutation in the MCR (codons 1250 -1500) could contribute to the occurrence of somatic MCR mutations and increase the likelihood of polyposis (Lamlum et al, 1999). In colorectal cancer it has been previously noted that the majority of the somatic APC mutations map to the MCR.…”

Section: Resultssupporting

confidence: 87%

APCgermline mutations identified in Czech patients with familial adenomatous polyposis

et al. 2002

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Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited predispositionto colorectal cancer, which is caused by germline mutations in the adenomatous polyposis coli (APC) gene. The APC mutations have been investigated in 46 Czech unrelated FAP families and 9 suspected FAP families using DGGE analysis and direct DNA sequencing. We found 25 germline APC mutations and identified 11 which were not previously reported. Of the identified mutations, 10 were 1 to 5 bp deletions, four were 1 bp insertions and six were nonsense, all leading to the formation of premature stop codon. In addition, we detected two mutations in the splice-donor region of APC intron 11, one missense and two samesense mutations. Phenotypes of patients with known and novel types of mutations are presented and discussed.

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Section: Resultssupporting

confidence: 87%

APCgermline mutations identified in Czech patients with familial adenomatous polyposis

et al. 2002

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“…The emerged discrepancy calls for an explanation. The opposite result obtained from the Spanish study could be explained by the phenomenon detected in the adenomatous polyposis coli tumor suppressor gene, in which the site of the germline mutation determines the type of the second hit (Lamlum et al, 1999). The genotypes involved could play a role, but because no significant correlation was seen in the studies (Sanchez de Abajo et al, 2006, this study) between LOH and the germline genotype, this is unlikely.…”

contrasting

confidence: 57%

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

et al. 2006

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Hereditary non-polyposis colorectal cancer (HNPCC) is caused by germline mutations in mismatch repair (MMR) genes, mostly MLH1 and MSH2. Somatic inactivation of the wild-type allele of the respective MMR gene is required for tumor development. Unexpectedly, a recent study utilizing DNA from paraffin-embedded tissue material detected frequent loss of the mutant MMR gene allele in HNPCC tumors. Dual role for loss of heterozygosity (LOH) was proposed. If somatic loss of the wild-type MMR gene allele had occurred through point mutation or promoter hypermethylation, frequent somatic deletions at the region of the MMR gene locus, perhaps targeting other relevant cancer genes, could quite commonly lead to loss of the mutant allele. To test this hypothesis, we studied a population-based series of 25 fresh-frozen HNPCC tumors with a germline mutation in MLH1 or MSH2 for LOH. Fourteen of the 25 tumors (56%) showed LOH at the respective locus, and all 14 losses targeted the wild-type allele (P ¼ 0.00006). These results strongly support the traditional two-hit model of HNPCC gene inactivation.

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“…21 and 23 occurred in a particular region of the APC gene, between the second and third 20 amino-acid repeats that are involved in b-catenin degradation. Such a spectrum of mutations might be expected in patients with a germline APC mutation before codon 1280 (Lamlum et al, 1999;Albuquerque et al, 2002;Crabtree et al, 2003) or with a deficiency in MMR that did not manifest as MSI in adenomas (Wu et al, 1999). For these reasons, we rescreened patient nos.…”

Section: No Definitive Mutational Signature In the Mcra Patients' Tummentioning

confidence: 99%

Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations

et al. 2007

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Patients with multiple (5 -100) colorectal adenomas (MCRAs) often have no germline mutation in known predisposition genes, but probably have a genetic origin. We collected a set of 25 MCRA patients with no detectable germline mutation in APC, MYH/MUTYH or the mismatch repair genes. Extracolonic tumours were absent in these cases. No vertical transmission of the MCRA phenotype was found. Based on the precedent of MYH-associated polyposis (MAP), we searched for a mutational signature in 241 adenomatous polyps from our MCRA cases. Somatic mutation frequencies and spectra at APC, K-ras and BRAF were, however, similar to those in sporadic colorectal adenomas. Our data suggest that the genetic pathway of tumorigenesis in the MCRA patients' tumours is very similar to the classical pathway in sporadic adenomas. In sharp contrast to MAP tumours, we did not find evidence of a specific mutational signature in any individual patient or in the overall set of MCRA cases. These results suggest that hypermutation of APC does not cause our patients' disease and strongly suggests that MAP is not a paradigm for the remaining MCRA patients. Our MCRA patients' colons showed no evidence of microadenomas, unlike in MAP and familial adenomatous polyposis (FAP). However, nuclear b-catenin expression was significantly greater in MCRA patients' tumours than in sporadic adenomas. We suggest that, at least in some cases, the MCRA phenotype results from germline variation that acts subsequent to tumour initiation, perhaps by causing more rapid or more likely progression from microadenoma to macroadenoma.

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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

Cited by 340 publications

References 19 publications

APCgermline mutations identified in Czech patients with familial adenomatous polyposis

APCgermline mutations identified in Czech patients with familial adenomatous polyposis

No evidence for dual role of loss of heterozygosity in hereditary non-polyposis colorectal cancer

Investigation of pathogenic mechanisms in multiple colorectal adenoma patients without germline APC or MYH/MUTYH mutations

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