Limits...
Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families.

Kanter-Smoler G, Fritzell K, Rohlin A, Engwall Y, Hallberg B, Bergman A, Meuller J, Grönberg H, Karlsson P, Björk J, Nordling M - BMC Med (2008)

Bottom Line: Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017).Using a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP.Probands with APC mutations outside codon 1250-1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer morbidity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. gunilla.kantersmoler@astrazeneca.com

ABSTRACT

Background: The dominantly inherited condition familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. Finding the causative mutations has great implications for the families. Correlating the genotypes to the phenotypes could help to improve the diagnosis and follow-up of patients.

Methods: Mutation screening of APC and the clinical characterization of 96 unrelated FAP patients from the Swedish Polyposis Registry was performed. In addition to generally used mutation screening methods, analyses of splicing-affecting mutations and investigations of the presence of low-frequency mutation alleles, indicating mosaics, have been performed, as well as quantitative real-time polymerase chain reaction to detect lowered expression of APC.

Results: Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity in colorectal cancer among probands was 25% at a mean age of 37.5 years and 29% at a mean age of 46.6 years.

Conclusion: Using a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP. Probands with APC mutations outside codon 1250-1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer morbidity.

Show MeSH

Related in: MedlinePlus

Pedigree presenting a part of family 1 of the Swedish Polyposis Registry. Family members where positive linkage to APC has been confirmed are indicated with asterisks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2386495&req=5

Figure 6: Pedigree presenting a part of family 1 of the Swedish Polyposis Registry. Family members where positive linkage to APC has been confirmed are indicated with asterisks.

Mentions: Lowered APC expression was observed in samples from two affected individuals from family 1 in the Swedish Polyposis Registry (index case, C152). The level of APC mRNA expression in peripheral blood cells from these two individuals where investigated by TaqMan quantitative RT-PCR analysis. In total, 29 patients including all 9 mutation-negative cases were analyzed. APC- and MUTYH-mutation positive patients as well as healthy individuals where included as controls. Reduced APC expression was only observed in two samples from affected individuals and both of those where from family 1 (Figure 5A). The APC-mutation positive samples used as controls did not show reduced expression of APC. To verify the expression data, cDNA from the individuals was sequenced over an informative heterozygous cSNP position (c.5465A > T). By sequencing cDNA and monitoring the level of expression of each allele as shown by the sequence diagram (Figure 5B), the level of the T-allele was found to be lowered in the two FAP-affected members of the family, compared with control individuals who had displayed normal APC expression in the quantitative RT-PCR experiment (Figure 5A). Linkage to the APC locus on chromosome 5 has also been investigated in this family. Positive linkage in two different branches of the family was determined. Individuals who have shown positive linkage to APC are indicated in Figure 6, which shows a pedigree presenting only a part of the complete pedigree of the large family 1. In total, this family includes 150 individuals of whom 57 are affected by the disease.


Clinical characterization and the mutation spectrum in Swedish adenomatous polyposis families.

Kanter-Smoler G, Fritzell K, Rohlin A, Engwall Y, Hallberg B, Bergman A, Meuller J, Grönberg H, Karlsson P, Björk J, Nordling M - BMC Med (2008)

Pedigree presenting a part of family 1 of the Swedish Polyposis Registry. Family members where positive linkage to APC has been confirmed are indicated with asterisks.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2386495&req=5

Figure 6: Pedigree presenting a part of family 1 of the Swedish Polyposis Registry. Family members where positive linkage to APC has been confirmed are indicated with asterisks.
Mentions: Lowered APC expression was observed in samples from two affected individuals from family 1 in the Swedish Polyposis Registry (index case, C152). The level of APC mRNA expression in peripheral blood cells from these two individuals where investigated by TaqMan quantitative RT-PCR analysis. In total, 29 patients including all 9 mutation-negative cases were analyzed. APC- and MUTYH-mutation positive patients as well as healthy individuals where included as controls. Reduced APC expression was only observed in two samples from affected individuals and both of those where from family 1 (Figure 5A). The APC-mutation positive samples used as controls did not show reduced expression of APC. To verify the expression data, cDNA from the individuals was sequenced over an informative heterozygous cSNP position (c.5465A > T). By sequencing cDNA and monitoring the level of expression of each allele as shown by the sequence diagram (Figure 5B), the level of the T-allele was found to be lowered in the two FAP-affected members of the family, compared with control individuals who had displayed normal APC expression in the quantitative RT-PCR experiment (Figure 5A). Linkage to the APC locus on chromosome 5 has also been investigated in this family. Positive linkage in two different branches of the family was determined. Individuals who have shown positive linkage to APC are indicated in Figure 6, which shows a pedigree presenting only a part of the complete pedigree of the large family 1. In total, this family includes 150 individuals of whom 57 are affected by the disease.

Bottom Line: Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017).Using a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP.Probands with APC mutations outside codon 1250-1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer morbidity.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular and Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. gunilla.kantersmoler@astrazeneca.com

ABSTRACT

Background: The dominantly inherited condition familial adenomatous polyposis (FAP) is caused by germline mutations in the APC gene. Finding the causative mutations has great implications for the families. Correlating the genotypes to the phenotypes could help to improve the diagnosis and follow-up of patients.

Methods: Mutation screening of APC and the clinical characterization of 96 unrelated FAP patients from the Swedish Polyposis Registry was performed. In addition to generally used mutation screening methods, analyses of splicing-affecting mutations and investigations of the presence of low-frequency mutation alleles, indicating mosaics, have been performed, as well as quantitative real-time polymerase chain reaction to detect lowered expression of APC.

Results: Sixty-one different APC mutations in 81 of the 96 families were identified and 27 of those are novel. We have previously shown that 6 of the 96 patients carried biallelic MUTYH mutations. The 9 mutation-negative cases all display an attenuated or atypical phenotype. Probands with a genotype (codon 1250-1464) predicting a severe phenotype had a median age at diagnosis of 21.8 (range, 11-49) years compared with 34.4 (range, 14-57) years among those with mutations outside this region (P < 0.017). Dense polyposis (> 1000) occurred in 75% of the probands with a severe phenotype compared with 30% in those with mutations outside this region. The morbidity in colorectal cancer among probands was 25% at a mean age of 37.5 years and 29% at a mean age of 46.6 years.

Conclusion: Using a variety of mutation-detection techniques, we have achieved a 100% detection frequency in classical FAP. Probands with APC mutations outside codon 1250-1464, although exhibiting a less-severe phenotype, are at high risk of having a colorectal cancer at diagnosis indicating that age at diagnosis is as important as the severity of the disease for colorectal cancer morbidity.

Show MeSH
Related in: MedlinePlus