The genetic heterogeneity of colorectal cancer predisposition - guidelines for gene discovery.

BACKGROUND: Colorectal cancer (CRC) is a cumulative term applied to a clinically and genetically heterogeneous group of neoplasms that occur in the bowel. Based on twin studies, up to 45 % of the CRC cases may involve a heritable component. Yet, only in 5-10 % of these cases high-penetrant germline mutations are found (e.g. mutations in APC and DNA mismatch repair genes) that result in a familial aggregation and/or an early onset of the disease. Genome-wide association studies have revealed that another ~5 % of the CRC cases may be explained by a cumulative effect of low-penetrant risk factors. Recent attempts to identify novel genetic factors using whole exome and whole genome sequencing has proven to be difficult since the remaining, yet to be discovered, high penetrant CRC predisposing genes appear to be rare. In addition, most of the moderately penetrant candidate genes identified so far have not been confirmed in independent cohorts. Based on literature examples, we here discuss how careful patient and cohort selection, candidate gene and variant selection, and corroborative evidence may be employed to facilitate the discovery of novel CRC predisposing genes. CONCLUSIONS: The picture emerges that the genetic predisposition to CRC is heterogeneous, involving complex interplays between common and rare (inter)genic variants with different penetrances. It is anticipated, however, that the use of large clinically well-defined patient and control datasets, together with improved functional and technical possibilities, will yield enough power to unravel this complex interplay and to generate accurate individualized estimates for the risk to develop CRC.

Impaired antibody response to conjugated meningococcal serogroup C vaccine in asplenic patients.

The purpose of this study was to determine the quantity and quality of antibodies against the meningococcal serogroup C (MenC) conjugated vaccine in asplenic patients. In 116 asplenic patients, antibody concentrations (IgG) were measured against meningococcal serogroup C before and after immunisation. Of MenC-specific IgG, both antibody avidity and subclasses of IgG1 and IgG2 were determined. The mean MenC IgG concentration rose from 0.16 µg/mL prior to vaccination to 3.69 µg/mL 3 weeks post-vaccination, with 67% of patients reaching the threshold of ≥ 2.0 µg/mL. The mean IgG concentration at 35 weeks post-vaccination was 3.10 µg/mL. IgG2 concentrations increased more than IgG1. Marginal avidity maturation was seen. Hypo-responders to the first MenC vaccine (IgG anti-MenC ≤ 2.0 µg/mL) were offered a booster dose. After revaccination, 59% reached the chosen IgG threshold. The IgG concentration rose from 0.29 to 1.12 µg/mL, with an increase in the IgG1/IgG2 ratio. Avidity indices remained below 33%. In asplenic patients, the quantity and quality of antibodies produced after one dose of conjugated MenC vaccination is lower than that observed in previous studies in healthy adults. Booster vaccination does, indeed, lead to a rise in IgG geometric mean concentrations (GMCs), but does not lead to higher avidity of antibodies.