Small-cell lung cancer (SCLC) is an aggressive lung tumor subtype with poor survival1–3. We sequenced 29 SCLC exomes, two genomes and 15 transcriptomes and found an extremely high mutation rate of 7.4±1 protein-changing mutations per million basepairs. Therefore, we conducted integrated analyses of the various data sets to identify pathogenetically relevant mutated genes. In all cases we found evidence for inactivation of TP53 and RB1 and identified recurrent mutations in histone-modifying genes, CREBBP, EP300, and MLL. Furthermore, we observed mutations in PTEN, in SLIT2, and EPHA7, as well as focal amplifications of the FGFR1 tyrosine kinase gene. Finally, we detected many of the alterations found in humans in SCLC tumors from p53/Rb1-deficient mice4. Our study implicates histone modification as a major feature of SCLC, reveals potentially therapeutically tractable genome alterations, and provides a generalizable framework for identification of biologically relevant genes in the context of high mutational background.

A multicenter study has been carried out to characterize 13 polymorphic short tandem repeat (STR) systems located on the male specific part of the human Y chromosome (DYS19, DYS288, DYS385, DYS388, DYS389I/II, DYS390, DYS391, DYS392, DYS393, YCAI, YCAII, YCAIII, DXYS156Y). Amplification parameters and electrophoresis protocols including multiplex approaches were compiled. The typing of non-recombining Y loci with uniparental inheritance requires special attention to population substructuring due to prevalent male lineages. To assess the extent of these subheterogeneities up to 3825 unrelated males were typed in up to 48 population samples for the respective loci. A consistent repeat based nomenclature for most of the loci has been introduced. Moreover we have estimated the average mutation rate for DYS19 in 626 confirmed fatherson pairs as 3.2 x 10(-3) (95% confidence interval limits of 0.00041-0.00677), a value which can also be expected for other Y-STR loci with similar repeat structure. Recommendations are given for the forensic application of a basic set of 7 STRs (DYS19, DYS3891, DYS389II, DYS390, DYS391, DYS392, DYS393) for standard Y-haplotyping in forensic and paternity casework. We recommend further the inclusion of the highly polymorphic bilocal Y-STRs DYS385, YCAII, YCAIII for a nearly complete individualisation of almost any given unrelated male individual. Together, these results suggest that Y-STR loci are useful markers to identify males and male lineages in forensic practice.

The most important factor for predicting lymph-node metastasis in early esophageal cancer is the presence of submucosal infiltration. Early adenocarcinomas and SCCs do not differ with regard to their rate of lymphatic involvement. The rate of lymph-node metastasis increases with the depth of submucosal infiltration, but metastases can already occur in sm1 lesions. Submucosal infiltration is a contraindication for endoscopic mucosectomy. Limited surgical procedures without adequate lymphadenectomy do not appear to be appropriate in the treatment of patients with submucosal esophageal carcinomas.

Pulse oximetry screening (POS) has been proposed as an effective, noninvasive, inexpensive tool allowing earlier diagnosis of critical congenital heart disease (cCHD). Our aim was to test the hypothesis that POS can reduce the diagnostic gap in cCHD in daily clinical routine in the setting of tertiary, secondary and primary care centres. We conducted a prospective multicenter trial in Saxony, Germany. POS was performed in healthy term and post-term newborns at the age of 24–72 h. If an oxygen saturation (SpO2) of ≤95% was measured on lower extremities and confirmed after 1 h, complete clinical examination and echocardiography were performed. POS was defined as false-negative when a diagnosis of cCHD was made after POS in the participating hospitals/at our centre. From July 2006–June 2008, 42,240 newborns from 34 institutions have been included. Seventy-two children were excluded due to prenatal diagnosis (n = 54) or clinical signs of cCHD (n = 18) before POS. Seven hundred ninety-five newborns did not receive POS, mainly due to early discharge after birth (n = 727; 91%). In 41,445 newborns, POS was performed. POS was true positive in 14, false positive in 40, true negative in 41,384 and false negative in four children (three had been excluded for violation of study protocol). Sensitivity, specificity, positive and negative predictive value were 77.78%, 99.90%, 25.93% and 99.99%, respectively. With POS as an adjunct to prenatal diagnosis, physical examination and clinical observation, the percentage of newborns with late diagnosis of cCHD was 4.4%. POS can substantially reduce the postnatal diagnostic gap in cCHD, and false-positive results leading to unnecessary examinations of healthy newborns are rare. POS should be implemented in routine postnatal care.

Tumor necrosis factor-alpha is considered to be one of the important mediators in the pathogenesis of psoriasis. A strong association of juvenile onset psoriasis with the major histocompatibility complex encoded HLA-Cw6 antigen has been reported but it is unclear whether Cw6 itself or a closely linked gene is involved in the pathogenesis. This study has focused on the association of promoter polymorphisms of the major histocompatibility complex encoded tumor necrosis factor-alpha gene with psoriasis and psoriatic arthritis. Tumor necrosis factor-alpha promoter polymorphisms were sought by sequence-specific oligonucleotide hybridization and by direct sequencing in Caucasian patients with juvenile onset psoriasis and with psoriatic arthritis and in healthy controls. A mutation at position -238 of the tumor necrosis factor-alpha promoter was present in 23 of 60 patients (38%; p < 0.0001; p[corr] < 0.008) with juvenile onset psoriasis and in 20 of 62 patients (32%; p < 0.0003; p[corr] < 0.03) with psoriatic arthritis, compared with seven of 99 (7%) Caucasian controls. There was a marked increase of homozygotes for this mutation in the psoriasis group. Another mutation at position -308 was found in similar proportions of patients and controls. Our study shows a strong association of the tumor necrosis factor-alpha promoter polymorphism at position -238 with psoriasis and psoriatic arthritis. Our findings suggest that this promoter polymorphism itself or a gene in linkage disequilibrium with tumor necrosis factor-alpha predispose to the development of psoriasis.

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Several autoimmune disorders as well as congenital adrenal hyperplasia (CAH) are either associated or closely linked with genetic variants of the fourth component of complement (C4A and C4B) and the enzyme steroid 21-hydroxylase (21-OH). These proteins are encoded by genes that are located downstream from the genes for complement proteins, C2 and factor B (BF) between HLA-B and -DR in the major histocompatibility complex (MHC). Previous studies of variants and null alleles were based on electrophoretic mobility ofC4 protein and linkage with disease phenotypes. These data did not permit analysis of the basis for the observed null alleles and duplicated variants. We studied this region ofthe MHC in 126 haplotypes for a structural analysis of the four adjacent loci, C4A, 21-OHA, C4B, and 21-OHB. About half of the C4 genes typed as C4 null are deleted and several unrecognized homoduplicated C4 alleles were detected.Hence the frequencies of different C4 structural variants must be recalculated based on a direct analysis of the genes. Analysis of the C4/21-OH genes of patients with the classical (salt-wasting) form of CAH showed that some involve a deletion of the C4B and 21-OHB genes; whereas for two only the 21-OHB gene is deleted, i.e., the C4B gene is present. Together, these data provide a better understanding of the mechanisms generating and importance of deleted C4 and 21-OH null alleles in human disease.