Genetic mapping of a second locus predisposing to hereditary non–polyposis colon cancer

Lindblom, Annika; Tannergård, Pia; Werelius, Barbro; Nordenskjöld, Magnus

doi:10.1038/ng1193-279

Cited by 366 publications

(150 citation statements)

References 18 publications

Supporting

Mentioning

146

Contrasting

Unclassified

Order By: Relevance

“…Microsatellites are simple repeats, often a dinucleotide, on non-coding regions of DNA, which could be located within genes or in between genes (Weber and May, 1989). MSI was first described in a set of unselected CRC (Ionov et al, 1993;Thibodeau et al, 1993) and in hereditary non-polyposis colorectal cancer (HNPCC) Lindblom et al, 1993). HNPCC is caused by germ-line mutations in genes involved in DNA mismatch repair (MMR) (Kinzler and Vogelstein, 1996).…”

mentioning

confidence: 99%

Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor

et al. 1999

View full text Add to dashboard Cite

Summary Hereditary non-polyposis colorectal cancer (HNPCC) is linked to an inherited defect in the DNA mismatch repair system. DNA from HNPCC tumours shows microsatellite instability (MSI). It has been reported that HNPCC patients have a better prognosis than patients with sporadic colorectal cancer. We examined whether the presence of MSI in a series of unselected colorectal tumours carries prognostic information. In a series of 181 unselected colorectal tumours, 22 tumours (12%) showed MSI. Survival analysis at 5-10 years follow-up showed no statistically significant difference in prognosis between MSI-positive and -negative tumours. Our results suggest that the MSI phenotype as such is not an independent prognostic factor.

show abstract

mentioning

confidence: 99%

Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor

et al. 1999

View full text Add to dashboard Cite

show abstract

“…The nature of the second mutation can only be a matter for speculation at present. The simple explanation, that it is a somatically acquired defect in the second allele leading to loss of function of the HNPCC gene, has been questioned because loss of heterozygosity (LOH) of linked markers for the relevant chromosome loci is not a frequent finding in HNPCC tumours Lindblom et al, 1993). However, somatic point mutation of the second (wildtype) allele has been descnbed in two CRCs in HNPCC patients with germline mutations of either mutL or mutS homologues Nicolaides et al, 1994), indicating that this could still be an important route for acquiring the mutator phenotype.…”

Section: Methodsmentioning

confidence: 99%

“…HNPCC patients might therefore be expected to show an increased frequency of somatic mutation in a wide range of other genes. Loss of heterozygosity for chromosomes 2 or 3 is not common in HNPCC tumours Lindblom et al, 1993) and it is not certain whether the gene is acting dominantly, conferring increased mutation in the normal colon as well as in tumours, or whether its action is confined to tumours. Evidence suggesting-the latter is derived from the fact that a lymphoblastoid cell line from an HNPCC-affected individual was proficient in mismatch repair and that normal tissue (of unspecified type) from HNPCC patients was not found to show microsatellite instability .…”

mentioning

confidence: 99%

“…The gene for FAP (APC) has been identified on chromosome 5q21 (KinzAer et al, 1991), and inheritance of a mutated allele is associated with the development during the second or third decade of life of very many colorectal adenomas, a small number of which are highly likely to progress to adenocarcinoma in early to mid adult life. HNPCC appears to be a more genetically heterogeneous condition, in that inherited abnormalities of at least four genes on chromosomes 2p , 2q (Nicolaides et al, 1994), 3p (Lindblom et al, 1993) and 7p (Nicolaides et al, 1994) appear to be involved in different kindreds. CRC in HNPCC usually presents later in life than in FAP, and is more often right-sided, more frequently diploid or near-diploid and possibly more often of mucinous or signet ring cell type than sporadic CRC .…”

mentioning

confidence: 99%

See 1 more Smart Citation

Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

Williams

Geraghty²,

Campbell³

et al. 1995

Br J Cancer

View full text Add to dashboard Cite

S_mmimary Hereditary non-polyposis colorectal cancer (HNPCC) has recently been linked to germline defects of DNA repair genes. Colorectal tumours in HNPCC frequently show DNA microsatellite instability, but it is not certain whether this mutator phenotype occurs throughout the morphologically normal colonic mucosa. We have previously used the mPAS histochemical technique in human colorectal mucosa to identify a polymorphism for O-acetyltransferase activity that shows monogenic inheritance and to show that cryptrestricted loss of O-acetyltransferase activity in heterozygotes is due to somatic mutation. We have now used this histochemical technique to measure the somatic mutation frequency in the uninvolved colon of 12 heterozygous patients with HNPCC, 15 with ileocaecal Crohn's disease and 16 with sporadic colorectal cancer (CRC). HNPCC patients showed a significant increase in mutation frequency with age (Mann-Whitney U. P=0.02). In HNPCC patients aged <49 years the mean stem cell mutation frequency was significantly lower than in the slightly younger group of patients with Crohn's disease (0.8 ± 0.9 x 10-' vs 3.5 ± 3.3 x 10-4, P<0.01), probably reflecting an increased mutation rate relating to chronic mucosal damage in Crohn's disease. Although not statistically significant, the stem cell mutation frequency was slightly less in HNPCC patients >50 years than in sporadic CRC cases (4.9 ± 3.4 x 10-4vs 5.9 ± 3.6 x 10-4, P>0.5 al., 1993).The APC gene is thought to act as a tumour-suppressor gene and, although the function of its product is not established, there is evidence to suggest that it is involved in cell adhesion (Su et al., 1993). The four putative HNPCC genes so far identified, on the other hand, appear to be involved in DNA repair. Colorectal adenomas and carcinomas, and extracolonic carcinomas, of HNPCC patients show a high frequency of DNA microsatellite instability (Aaltonen et al., 1994), and human homologues of the prokaryotic DNA mismatch repair genes mutS and mutL map to the regions of chromosomes 2, 3 and 7 that have been shown by linkage studies to bear the HNPCC loci. Moreover, germline mutations of these repair genes occur in affected patients (Fishel et al., 1993;Leach et al., 1993;Bronner et al., 1994;Nicolaides et al., 1994). HNPCC patients might therefore be expected to show an increased frequency of somatic mutation in a wide range of other genes. Loss of heterozygosity for chromosomes 2 or 3 is not common in HNPCC tumours Lindblom et al., 1993) and it is not certain whether the gene is acting dominantly, conferring increased mutation in the normal colon as well as in tumours, or whether its action is confined to tumours. Evidence suggesting-the latter is derived from the fact that a lymphoblastoid cell line from an HNPCC-affected individual was proficient in mismatch repair and that normal tissue (of unspecified type) from HNPCC patients was not found to show microsatellite instability . However, the possibility that the inherited DNA defect is confined to tissues with an increased inci...

show abstract

“…But one hypothesis for the initiation of abnormal mutation rates in tumors is the loss of mismatch repair (MMR). For instance, this phenomenon may follow from the inactivation of the genes hMSH2 and hMLH1 involved in hereditary nonpolyposis colorectal cancers (HNPCC) (Fishel et al 1993;Leach et al 1993;Lindblom et al 1993). In normal conditions, the MMR repair system involves a complex interaction among the protein products of hMSH2 and hMLH1 genes.…”

Section: Introductionmentioning

confidence: 99%

Conditional Coalescent Trees With Two Mutation Rates and Their Application to Genomic Instability

Emily¹,

Ochsenbein²

2006

Genetics

View full text Add to dashboard Cite

Humans have invested several genes in DNA repair and fidelity replication. To account for the disparity between the rarity of mutations in normal cells and the large number of mutations present in cancer, an hypothesis is that cancer cells must exhibit a mutator phenotype (genomic instability) during tumor progression, with the initiation of abnormal mutation rates caused by the loss of mismatch repair. In this study we introduce a stochastic model of mutation in tumor cells with the aim of estimating the amount of genomic instability due to the alteration of DNA repair genes. Our approach took into account the difficulties generated by sampling within tumoral clones and the fact that these clones must be difficult to isolate. We provide corrections to two classical statistics to obtain unbiased estimators of the raised mutation rate, and we show that large statistical errors may be associated with such estimators. The power of these new statistics to reject genomic instability is assessed and proved to increase with the intensity of mutation rates. In addition, we show that genomic instability cannot be detected unless the raised mutation rates exceed the normal rates by a factor of at least 1000. D NA replication in normal human cells is an extremely accurate process. During the cell division cycle, copy errors occur with probabilities ,10 ÿ9 -10 ÿ10 per nucleotide. In contrast, the malignant cells that constitute cancer tissues are markedly heterogeneous and exhibit alterations in the nucleotide sequence of DNA (e.g., Bielas and Loeb 2005). To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, Loeb et al. (1974) hypothesized that during tumor progression, cancer cells must exhibit a mutator phenotype (see the review by Loeb et al. 2003). It is still a matter of debate to know exactly which event initiates tumorigenesis. But one hypothesis for the initiation of abnormal mutation rates in tumors is the loss of mismatch repair (MMR). For instance, this phenomenon may follow from the inactivation of the genes hMSH2 and hMLH1 involved in hereditary nonpolyposis colorectal cancers (HNPCC) (Fishel et al. 1993;Leach et al. 1993;Lindblom et al. 1993). In normal conditions, the MMR repair system involves a complex interaction among the protein products of hMSH2 and hMLH1 genes. The result is to eliminate $99.9% of the errors in DNA replication, reducing errors to a rate of $1/10 12 bp in genes that regulate the apoptosis or the cell cycle duration. HNPCC is inherited in an autosomal dominant fashion. One copy of the mutant allele is defective and is inherited in the germline. The loss of MMR may start when the second mutation occurs somatically as a consequence of the two-hits theory (Moolgavkar and Knudson 1981).Widespread genomic instability seems associated with MMR-defective genes. For example, microsatellite instability is associated with HNPCC (Ionov et al. 1993;Peltomaki et al. 1993;Thibodeau et al. 1993). Detection of DNA insta...

show abstract

Genetic mapping of a second locus predisposing to hereditary non–polyposis colon cancer

Cited by 366 publications

References 18 publications

Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor

Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor

Normal colonic mucosa in hereditary non-polyposis colorectal cancer shows no generalised increase in somatic mutation

Conditional Coalescent Trees With Two Mutation Rates and Their Application to Genomic Instability

Contact Info

Product

Resources

About