Genes on chromosome 22 involved in the pathogenesis of central nervous system tumors

It is nowadays generally accepted that cancer can be considered as a genetic disease. However, there are two clear differences between cancer and most other genetic diseases. First, most cancers are caused essentially by somatic mutations, whereas all other genetic diseases are caused solely by germline mutations. Second, for most cancer types at least two mutations are required before a tumor may arise. For most pediatric and some adult tumors only a limited number of mutations are supposed to be sufficient for tumor development (Knudson, 1971, 1986; Haber and Housman, 1992). In contrast, most adult cancers appear to require more than two genetic changes. This 'multiple-hit' concept of tumorigenesis stems from several lines of evidence. First, most adult cancers show an exponential increase in incidence with age, suggesting that the accumulation of different hits is involved in tumor development (Vogelstein and Kinzler, 1993). Second, a dramatically increased incidence of cancer has been observed in individuals with chromosome instability syndromes such as Bloom's syndrome (Vijayalaxmi et aI., 1983; Seshadri et aI., 1987). Third, repeated administration of mutagen to test animals is generally required before a tumor arises (Saffhill et aI., 1985). Fourth, increasing evidence becomes available for the involvement of multiple genetic alterations in common human tumors. The most extensively studied example is the accumulation of genetic alterations observed in human colon tumors, in which mutations in APe and ras found in adenomatous polyps have been classified as early events and mutations in p53 and Dee as later events that may contribute to tumor progression (Fearon and Vogelstein, 1990; section 3.3). In a specific human cancer, mutations in one particular gene appear to precede those in others (Vogelstein and Kinzler, 1993), although after this first hit the accumulation of changes rather than their specific order seems to be important for tumor progression (Marx, 1989)

Next-generation sequencing-based genome diagnostics across clinical genetics centers: Implementation choices and their effects

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care

Increased cardiac workload by closure of the ductus arteriosus leads to hypertrophy and apoptosis rather than to hyperplasia in the late fetal period

It is generally thought that adult mammalian cardiomyocytes compensate for an increased workload by hypertrophy, whereas fetal myocardium grows by cellular proliferation. We analyzed the response of late-fetal rat hearts upon an increased workload imposed by premature constriction of the ductus arteriosus with indomethacin. Initially the fetal heart responds by proliferative growth, as both wet weight and labeling index (bromodeoxyuridine incorporation) of the ventricles increased, whereas neither a change in the fibroblast fraction, ploidy and nucleation in the ventricles is observed. However, this hyperplastic growth is abrogated by a subsequent burst in apoptosis and followed by a hypertrophic response as based on a decrease in DNA and increase in both RNA and protein concentration. This hypertrophic growth was accompanied by a 1.4-fold increase in the volume of the cardiomyocytes. Changes in the molecular phenotype characteristic of pressure-overload hypertrophic growth accompany the process. Thus, the levels of expression of beta-myosin heavy chain and atrial natriuretic factor mRNA increased, of sarcoplasmic/endoplasmic reticulum ATPase (SERCA2) mRNA decreased, and of alpha-myosin heavy chain, phospholamban, and calsequestrin mRNA did not change. In situ hybridization showed that the pattern of mRNA expression changed first in the right ventricular wall and subsequently in the left ventricular free wall as well. It is concluded that pressure-overload imposed on the late-fetal heart induces limited proliferative growth complemented by extensive hypertrophic growth

Recurrent and founder mutations in the Netherlands: mutation p.K217del in troponin T2, causing dilated cardiomyopathy

Background. About 30% of dilated cardiomyopathy (DCM) cases are familial. Mutations are mostly found in the genes encoding lamin A/C, beta-myosin heavy chain and the sarcomeric protein cardiac troponin-T (TNNT2). Mutations in TNNT2 are reported in approximately 3% of DCM patients. The overall phenotype caused by TNNT2 mutations is thought to be a fully penetrant, severe disease. This also seems to be true for a recurrent deletion in the TNNT2 gene; p.K217del (also known as p.K210del)