A common nonsense mutation in EphB2 is associated with prostate cancer risk in African American men with a positive family history

Abstract

Background: The EphB2 gene was recently implicated as a prostate cancer (PC) tumour suppressor gene, with somatic inactivating mutations occurring in ,10% of sporadic tumours. We evaluated the contribution of EphB2 to inherited PC susceptibility in African Americans (AA) by screening the gene for germline polymorphisms. Methods: Direct sequencing of the coding region of EphB2 was performed on 72 probands from the African American Hereditary Prostate Cancer Study (AAHPC). A case-control association analysis was then carried out using the AAHPC probands and an additional 183 cases of sporadic PC compared with 329 healthy AA male controls. In addition, we performed an ancestry adjusted association study where we adjusted for individual ancestry among all subjects, in order to rule out a spurious association due to population stratification. Results: Ten coding sequence variants were identified, including the K1019X (3055ART) nonsense mutation which was present in 15.3% of the AAHPC probands but only 1.7% of 231 European American (EA) control samples. We observed that the 3055ART mutation significantly increased risk for prostate cancer over twofold (Fisher's two sided test, p = 0.003). The T allele was significantly more common among AAHPC probands (15.3%) than among healthy AA male controls (5.2%) (odds ratio 3.31; 95% confidence interval 1.5 to 7.4; p = 0.008). The ancestry adjusted analyses confirmed the association. Conclusions: Our data show that the K1019X mutation in the EphB2 gene differs in frequency between AA and EA, is associated with increased risk for PC in AA men with a positive family history, and may be an important genetic risk factor for prostate cancer in AA.

A genome-wide map of human genetic interactions inferred from radiation hybrid genotypes

“…For example, the interaction between the ephrin receptor B2 gene (EPHB2) and fumarate hydratase (FH) in our network is undocumented. Mutations in EPHB2 have been linked to prostate cancer (Kittles et al 2006), and mutations in FH have been linked to renal cell cancer (Toro et al 2003). Together, these results suggest that genes in the RH network are functionally clustered in ways reminiscent of protein interaction networks and that RH interactions can be used to predict functions of uncharacterized genes.…”

NAT2 and NER genetic variants and sporadic prostate cancer susceptibility in African Americans

“…These markers show large allele frequency differences (delta, d) between the ancestral populations for African Americans (West Africans and Europeans), and were used to control for the presence of population stratification (PS) due to admixture. [19][20][21] The description of this marker set has been provided in previous papers. 19,22 AIM frequencies for West African (Central African Republic, Nigeria and Sierra Leone, N ¼ 480), and European (Spain, Germany, England and Ireland, N ¼ 243) populations were included in the analysis as representative of ancestral groups.…”

EPH-EPHRIN in human gastrointestinal cancers

“…Mao [58] reported EPHB2 as a therapeutic antibody drug target for EPHB2 over-expressing tumors. Mutation analyses in kinase genes have been very popular and somatic mutations of EPHB2 have also been reported in many cancers [59,60] , including GI tract cancers [61,62] . However, these mutations occur mostly in the microsatellite repeats of tumors with microsatellite instability or nonsense mutations causing RNA decay.…”