Translational research in cancer genetics: the road less traveled.

Gene discoveries in cancer have the potential for clinical and public health applications. To take advantage of such discoveries, a translational research agenda is needed to take discoveries from the bench to population health impact. To assess the current status of translational research in cancer genetics, we analyzed the extramural grant portfolio of the National Cancer Institute (NCI) from Fiscal Year 2007, as well as the cancer genetic research articles published in 2007. We classified both funded grants and publications as follows: T0 as discovery research; T1 as research to develop a candidate health application (e.g., test or therapy); T2 as research that evaluates a candidate application and develops evidence-based recommendations; T3 as research that assesses how to integrate an evidence-based recommendation into cancer care and prevention; and T4 as research that assesses health outcomes and population impact. We found that 1.8% of the grant portfolio and 0.6% of the published literature was T2 research or beyond. In addition to discovery research in cancer genetics, a translational research infrastructure is urgently needed to methodically evaluate and translate gene discoveries for cancer care and prevention.

The value of molecular haplotypes in a family-based linkage study.

Novel methods that could improve the power of conventional methods of gene discovery for complex diseases should be investigated. In a simulation study, we aimed to investigate the value of molecular haplotypes in the context of a family-based linkage study. The term "haplotype" (or "haploid genotype") refers to syntenic alleles inherited on a single chromosome, and we use the term "molecular haplotype" to refer to haplotypes that have been determined directly by use of a molecular technique such as long-range allele-specific polymerase chain reaction. In our study, we simulated genotype and phenotype data and then compared the powers of analyzing these data under the assumptions that various levels of information from molecular haplotypes were available. (This information was available because of the simulation procedure.) Several conclusions can be drawn. First, as expected, when genetic homogeneity is expected or when marker data are complete, it is not efficient to generate molecular haplotyping information. However, with levels of heterogeneity and missing data patterns typical of complex diseases, we observed a 23%-77% relative increase in the power to detect linkage in the presence of heterogeneity with heterogeneity LOD scores >3.0 when all individuals are molecularly haplotyped (compared with the power when only standard genotypes are used). Furthermore, our simulations indicate that most of the increase in power can be achieved by molecularly haplotyping a single individual in each family, thereby making molecular haplotyping a valuable strategy for increasing the power of gene mapping studies of complex diseases. Maximization of power, given an existing family set, can be particularly important for late-onset, often-fatal diseases such as cancer, for which informative families are difficult to collect.

HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome.

We report here the identification of a gene associated with the hyperparathyroidism-jaw tumor (HPT-JT) syndrome. A single locus associated with HPT-JT (HRPT2) was previously mapped to chromosomal region 1q25-q32. We refined this region to a critical interval of 12 cM by genotyping in 26 affected kindreds. Using a positional candidate approach, we identified thirteen different heterozygous, germline, inactivating mutations in a single gene in fourteen families with HPT-JT. The proposed role of HRPT2 as a tumor suppressor was supported by mutation screening in 48 parathyroid adenomas with cystic features, which identified three somatic inactivating mutations, all located in exon 1. None of these mutations were detected in normal controls, and all were predicted to cause deficient or impaired protein function. HRPT2 is a ubiquitously expressed, evolutionarily conserved gene encoding a predicted protein of 531 amino acids, for which we propose the name parafibromin. Our findings suggest that HRPT2 is a tumor-suppressor gene, the inactivation of which is directly involved in predisposition to HPT-JT and in development of some sporadic parathyroid tumors.

Novel mutations in collagen VI genes: expansion of the Bethlem myopathy phenotype.

OBJECTIVE: To investigate the molecular basis of autosomal dominant limb-girdle muscular dystrophy (AD-LGMD) in three large new families. METHODS AND RESULTS: Genome-wide linkage was performed to show that the causative gene in all three families localized to chromosome 21q22.3 (Zmax = 10.3; theta = 0). This region contained the collagen VI alpha1 and alpha2 genes, which have been previously shown to harbor mutations causing a relatively mild congenital myopathy with contractures (Bethlem myopathy). Screening of the collagen VI alpha1 and alpha2 genes revealed novel, causative mutations in each family (COL6A1-K121R, G341D; COL6A2-D620N); two of these mutations were in novel regions of the proteins not previously associated with disease. Collagen VI is a ubiquitously expressed component of connective tissue; however, both limb-girdle muscular dystrophy and Bethlem myopathy patients show symptoms restricted to skeletal muscle. To address the muscle-specific symptoms resulting from collagen VI mutations, the authors studied three patient muscle biopsies at the molecular level (protein expression). A marked reduction of laminin beta1 protein in the myofiber basal lamina in all biopsies was found, although this protein was expressed normally in the neighboring capillary basal laminae. CONCLUSIONS: The authors' studies widen the clinical spectrum of Bethlem myopathy and suggest collagen VI etiology should be investigated in dominant limb-girdle muscular dystrophy. The authors hypothesize that collagen VI mutations lead to muscle-specific defects of the basal lamina, and may explain the muscle-specific symptoms of Bethlem and limb-girdle muscular dystrophy patients with collagen VI mutations.

Plasma gamma-hexachlorocyclohexane concentrations in forestry workers exposed to lindane.

Plasma gamma-hexachlorocyclohexane (gamma-HCH) and three urinary trichlorophenols were measured in forestry workers who were engaged in planting seedlings treated with gamma-HCH. These two procedures were assessed as potential biological monitoring methods and the data were compared with reported clinical symptoms. The measurement of plasma gamma-HCH was considered to be a feasible and valid monitoring method for use in routine practice and is a useful indicator of gamma-HCH absorption. The data were used to illustrate the need to be vigilant about personal hygiene and the efficacy of protective clothing. Plasma gamma-HCH concentrations above 70 nmol/l were measured in two workers which coincided with persistent non-specific clinical symptoms. Trichlorophenols were identified in urine but the extensive and variable metabolism of gamma-HCH makes this approach less suitable for biological monitoring.

Platelet functions in relation to diet and serum lipids in British farmers.

Coagulation and platelet aggregation induced by thrombin, ADP, adrenaline, and collagen were studied in three contrasted groups, each of 20 to 22 middle-aged male farmers. Serum lipids were similar in the three groups. In the west of Scotland group, however, platelet reactivity was significantly greater than in the east of Scotland. This was associated with a dietary intake, evaluated by three different techniques, higher in saturated fat but also lower in polyunsaturated fat and alcohol. Platelet function in the southern England group also correlated with dietary fats and in addition inversely with calcium intake. On an individual basis in the 63 farmers, all the platelet function tests were significantly correlated with the intake of saturated fat regulated by that of calcium and alcohol. The dietary effects on platelets appear to be mediated by the fatty acid composition of plasma lipids and of platelet phospholipids. In that fraction, the fatty acids 20:3 omega 9, 22:3 omega 9 and 20:4 were the most closely related to the platelet function tests. the trienoic acid 20:3 omega 9, identified with essential fatty acid deficiency, was also correlated with the intake of saturated fat and calcium. In this study, platelet functions were more dependent upon the dietary factors associated with coronary heart disease such as saturated fats, calcium, and alcohol than upon serum lipids.