Cancer risk assessment and genetics at the Helen F. Graham Cancer Center: model for personalized medicine and early intervention.

This article discusses cancer risk assessment, screening options, referral guidelines, and the experience of the Familial Risk Assessment Program at the Helen F. Graham Cancer Center. Two clinical situations are described that illustrate the impact of genetics in the multidisciplinary approach to managing cancer. Identifying risk level in patients will impact mortality in those at high risk, as well as psychosocial well-being in those at low risk.

A reciprocal translocation 46,XY,t(8;9)(p11.2;q13) in a bladder exstrophy patient disrupts CNTNAP3 and presents evidence of a pericentromeric duplication on chromosome 9.

A patient with sporadic bladder exstrophy and de novo apparently balanced chromosomal translocation 46,XY,t(8;9)(p11.2;q13) was analyzed by fluorescence in situ hybridization (FISH) and molecular methods. We were able to map both translocation breakpoints to single genomic clones. The chromosome 8p11.2 breakpoint was mapped to BAC clone RP4-547J18, predicted to contain several hypothetical genes. Characterization of the chromosome 9q13 breakpoint indicated a disruption in the 5' region of CNTNAP3 within BAC RP11-292B8. This observation suggests possible involvement of CNTNAP3 in the etiology of bladder exstrophy. Additionally, FISH analysis identified several genomic copies of CNTNAP3 on both sides of the chromosome 9 centromere flanking the polymorphic heterochromatin. Northern blot analysis of lymphoblast and bladder RNA confirmed CNTNAP3 transcripts in these tissues and did not show abnormal CNTNAP3 expression in the proband and two unrelated patients with bladder exstrophy. The identification of multiple copies of three BAC clones in the proband, his parents, and unrelated controls suggests that duplications of CNTNAP3 and the surrounding genomic region have occurred as a result of repeated events of unequal crossing over and pericentric inversions during chromosome 9 evolution.

Clinical and molecular characterization of the bladder exstrophy-epispadias complex: analysis of 232 families.

OBJECTIVE: To identify genetic and nongenetic factors contributing to the risk of bladder exstrophy-epispadias complex (BEEC). PATIENTS AND METHODS: In all, 285 families with BEEC were invited to participate in the study, and 232 of them were recruited. Epidemiological information was obtained from 151 of the consenting families, with a detailed clinical genetic examination of 94 probands. In all, 440 DNA samples were collected from 163 families for molecular analysis. RESULTS: Most of the cases were sporadic and had no family history of BEEC. Among patients, 95% were Caucasian, and males were more common in both the epispadias group (M/F, 2.2, 29 patients) and the classic bladder-exstrophy group (M/F 1.8, 164), but in the cloacal exstrophy group the sex ratio was close to unity (1.1, 15). There was a statistically significant association with advanced parental age (P < 0.001). Birth weight, gestational age and maternal reproductive history did not appear to be significantly different from those in the general population. Information on exposures to tobacco, alcohol and drugs was collected but none appeared to act as a risk factor. Karyotype analysis on 37 cases detected two chromosomal abnormalities, i.e. 46XY t(8;9)(p11.2; q13) and 47XYY. Molecular analysis of the HLXB9 gene, which causes Currarino syndrome, did not detect mutations in the blood or bladder DNA of 10 patients with bladder or cloacal exstrophy. CONCLUSIONS: BEEC most commonly occurs as an isolated sporadic birth defect with a recurrence risk of << 1%. There was no evidence of a single-gene effect or common environmental factor in this study population. In addition to race and advanced parental age, birth order may be a risk factor for BEEC. We suggest somatic mutations in a gene(s) within the pathway regulating bladder development may be the cause of BEEC.