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Germline EPHB2 receptor variants in familial colorectal cancer.

Zogopoulos G, Jorgensen C, Bacani J, Montpetit A, Lepage P, Ferretti V, Chad L, Selvarajah S, Zanke B, Hudson TJ, Pawson T, Gallinger S - PLoS ONE (2008)

Bottom Line: Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I).The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases.In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism.

View Article: PubMed Central - PubMed

Affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

ABSTRACT
Familial clustering of colorectal cancer occurs in 15-20% of cases, however recognized cancer syndromes explain only a small fraction of this disease. Thus, the genetic basis for the majority of hereditary colorectal cancer remains unknown. EPHB2 has recently been implicated as a candidate tumor suppressor gene in colorectal cancer. The aim of this study was to evaluate the contribution of EPHB2 to hereditary colorectal cancer. We screened for germline EPHB2 sequence variants in 116 population-based familial colorectal cancer cases by DNA sequencing. We then estimated the population frequencies and characterized the biological activities of the EPHB2 variants identified. Three novel nonsynonymous missense alterations were detected. Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I). The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases. Genotyping of additional patients with colorectal cancer and control subjects revealed that A438T and G787R represent rare EPHB2 alleles. In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism. Tumor tissue from the G787R variant case manifested loss of heterozygosity, with loss of the wild-type allele, supporting a tumor suppressor role for EPHB2 in rare colorectal cancer cases. Rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer.

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Pedigrees of colorectal cancer cases carrying the A438T (Family 1, Panel A) and G787R (Family 1, Panel B) variants.+/−, carrier; −/−, non-carrier; LOH+, Colorectal tumour tissue was found to manifest LOH, with loss of the wild-type allele; Ca, cancer.
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pone-0002885-g001: Pedigrees of colorectal cancer cases carrying the A438T (Family 1, Panel A) and G787R (Family 1, Panel B) variants.+/−, carrier; −/−, non-carrier; LOH+, Colorectal tumour tissue was found to manifest LOH, with loss of the wild-type allele; Ca, cancer.

Mentions: The A438T variant was found in a patient who had two primary cancers. He was diagnosed with prostate cancer and a microsatellite stable right-sided colon cancer at the ages of 61 and 64 years, respectively (Figure 1A, Family 1). The proband's father also carried the A438T variant and is the only other family member with colon cancer, he was diagnosed with a microsatellite stable sigmoid cancer at the age of 76 years. Of the 6 unaffected family members tested for this missense change, 3 were found to carry the A438T variant (Figure 1A). Sequencing analyses of paired tumor-normal genomic DNA samples revealed loss of the wild-type EPHB2 allele in the colon cancer from the proband, but not in the colon cancer from his father (data not shown). The father's tumor manifested LOH of the variant, rather than the wild-type, EPHB2 allele. This latter observation may reflect the frequent loss of the 1p36.1 chromosomal region during tumorigenesis [7], [8], and not the targeted inactivation of the EPHB2 locus by LOH.


Germline EPHB2 receptor variants in familial colorectal cancer.

Zogopoulos G, Jorgensen C, Bacani J, Montpetit A, Lepage P, Ferretti V, Chad L, Selvarajah S, Zanke B, Hudson TJ, Pawson T, Gallinger S - PLoS ONE (2008)

Pedigrees of colorectal cancer cases carrying the A438T (Family 1, Panel A) and G787R (Family 1, Panel B) variants.+/−, carrier; −/−, non-carrier; LOH+, Colorectal tumour tissue was found to manifest LOH, with loss of the wild-type allele; Ca, cancer.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2483346&req=5

pone-0002885-g001: Pedigrees of colorectal cancer cases carrying the A438T (Family 1, Panel A) and G787R (Family 1, Panel B) variants.+/−, carrier; −/−, non-carrier; LOH+, Colorectal tumour tissue was found to manifest LOH, with loss of the wild-type allele; Ca, cancer.
Mentions: The A438T variant was found in a patient who had two primary cancers. He was diagnosed with prostate cancer and a microsatellite stable right-sided colon cancer at the ages of 61 and 64 years, respectively (Figure 1A, Family 1). The proband's father also carried the A438T variant and is the only other family member with colon cancer, he was diagnosed with a microsatellite stable sigmoid cancer at the age of 76 years. Of the 6 unaffected family members tested for this missense change, 3 were found to carry the A438T variant (Figure 1A). Sequencing analyses of paired tumor-normal genomic DNA samples revealed loss of the wild-type EPHB2 allele in the colon cancer from the proband, but not in the colon cancer from his father (data not shown). The father's tumor manifested LOH of the variant, rather than the wild-type, EPHB2 allele. This latter observation may reflect the frequent loss of the 1p36.1 chromosomal region during tumorigenesis [7], [8], and not the targeted inactivation of the EPHB2 locus by LOH.

Bottom Line: Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I).The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases.In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism.

View Article: PubMed Central - PubMed

Affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.

ABSTRACT
Familial clustering of colorectal cancer occurs in 15-20% of cases, however recognized cancer syndromes explain only a small fraction of this disease. Thus, the genetic basis for the majority of hereditary colorectal cancer remains unknown. EPHB2 has recently been implicated as a candidate tumor suppressor gene in colorectal cancer. The aim of this study was to evaluate the contribution of EPHB2 to hereditary colorectal cancer. We screened for germline EPHB2 sequence variants in 116 population-based familial colorectal cancer cases by DNA sequencing. We then estimated the population frequencies and characterized the biological activities of the EPHB2 variants identified. Three novel nonsynonymous missense alterations were detected. Two of these variants (A438T and G787R) result in significant residue changes, while the third leads to a conservative substitution in the carboxy-terminal SAM domain (V945I). The former two variants were found once in the 116 cases, while the V945I variant was present in 2 cases. Genotyping of additional patients with colorectal cancer and control subjects revealed that A438T and G787R represent rare EPHB2 alleles. In vitro functional studies show that the G787R substitution, located in the kinase domain, causes impaired receptor kinase activity and is therefore pathogenic, whereas the A438T variant retains its receptor function and likely represents a neutral polymorphism. Tumor tissue from the G787R variant case manifested loss of heterozygosity, with loss of the wild-type allele, supporting a tumor suppressor role for EPHB2 in rare colorectal cancer cases. Rare germline EPHB2 variants may contribute to a small fraction of hereditary colorectal cancer.

Show MeSH
Related in: MedlinePlus