Two high-risk susceptibility loci at 6p25.3 and 14q32.13 for Waldenström macroglobulinemia

Waldenström macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL) is a rare, chronic B-cell lymphoma with high heritability. We conduct a two-stage genome-wide association study of WM/LPL in 530 unrelated cases and 4362 controls of European ancestry and identify two high-risk loci associated with WM/LPL at 6p25.3 (rs116446171, near EXOC2 and IRF4; OR = 21.14, 95% CI: 14.40–31.03, P = 1.36 × 10−54) and 14q32.13 (rs117410836, near TCL1; OR = 4.90, 95% CI: 3.45–6.96, P = 8.75 × 10−19). Both risk alleles are observed at a low frequency among controls (~2–3%) and occur in excess in affected cases within families. In silico data suggest that rs116446171 may have functional importance, and in functional studies, we demonstrate increased reporter transcription and proliferation in cells transduced with the 6p25.3 risk allele. Although further studies are needed to fully elucidate underlying biological mechanisms, together these loci explain 4% of the familial risk and provide insights into genetic susceptibility to this malignancy

Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10-15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10-9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10-8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 (NR5A2), chr8q24.21 (MYC) and chr5p15.33 (CLPTM1L-TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal (n = 10) and tumor (n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10-8). This finding was validated in a second set of paired (n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10-4-2.0x10-3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology

Neurokognition des Alterns im Arbeitskontext

Aging is accompanied by changes in sensory, motor and cognitive functions. Particularly, a high status of so-called fluid cognitive functions is crucial for the employability at an older age. This status, which can be assessed by psychometric and neuroimaging methods, depends on a number of factors like physical constitution, nutrition, education and work demands. This paper systematically analyses factors affecting cognitive functions in aging and reviews current neuroscientific findings regarding training induced neuronal plasticity and compensation of cognitive declines in aging. In the second part the relationship between cognitive functions and the type of work will be discussed and the project PFIFF presented as an example for transfer of neuroscientific basic research to an applied context that aimed at ameliorating and evaluating age- and job-related cognitive deficits. The results of the first project period showed that cognitive decline, as revealed in behavior and brain wave data, may be accelerated by long-lasting unchallenging work and, hence, may occur already in middle age. In the second part of PFIFF a 3-month program consisting of a supervised cognitive training was implemented in a group of 120 assembly-line employees. Before and after the training a comprehensive battery of psychometric and EEG-based tests was administered. The results provide evidence that training in older employees with repetitive work improves impaired cognitive abilities and brain processes found in the first part of the project. These beneficial effects are apparently mediated by preserved brain plasticity in middle-aged and older individuals. This training approach appears to be suitable in order to improve mental fitness of elderly employees. The PFIFF project can be seen as a part of a comprehensive program for promoting mental fitness in older employees