Characterizing the cancer genome in lung adenocarcinoma

Somatic alterations in cellular DNA underlie almost all human cancers(1). The prospect of targeted therapies(2) and the development of high-resolution, genome-wide approaches(3-8) are now spurring systematic efforts to characterize cancer genomes. Here we report a large-scale project to characterize copy-number alterations in primary lung adenocarcinomas. By analysis of a large collection of tumours ( n = 371) using dense single nucleotide polymorphism arrays, we identify a total of 57 significantly recurrent events. We find that 26 of 39 autosomal chromosome arms show consistent large-scale copy-number gain or loss, of which only a handful have been linked to a specific gene. We also identify 31 recurrent focal events, including 24 amplifications and 7 homozygous deletions. Only six of these focal events are currently associated with known mutations in lung carcinomas. The most common event, amplification of chromosome 14q13.3, is found in similar to 12% of samples. On the basis of genomic and functional analyses, we identify NKX2-1 ( NK2 homeobox 1, also called TITF1), which lies in the minimal 14q13.3 amplification interval and encodes a lineage-specific transcription factor, as a novel candidate proto-oncogene involved in a significant fraction of lung adenocarcinomas. More generally, our results indicate that many of the genes that are involved in lung adenocarcinoma remain to be discovered.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62944/1/nature06358.pd

Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene.

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation

Melanoma genome sequencing reveals frequent PREX2 mutations

Melanoma is notable for its metastatic propensity, lethality in the advanced setting and association with ultraviolet exposure early in life. To obtain a comprehensive genomic view of melanoma in humans, we sequenced the genomes of 25 metastatic melanomas and matched germline DNA. A wide range of point mutation rates was observed: lowest in melanomas whose primaries arose on non-ultraviolet-exposed hairless skin of the extremities (3 and 14 per megabase (Mb) of genome), intermediate in those originating from hair-bearing skin of the trunk (5–55 per Mb), and highest in a patient with a documented history of chronic sun exposure (111 per Mb). Analysis of whole-genome sequence data identified PREX2 (phosphatidylinositol-3,4,5-trisphosphate-dependent Rac exchange factor 2)—a PTEN-interacting protein and negative regulator of PTEN in breast cancer—as a significantly mutated gene with a mutation frequency of approximately 14% in an independent extension cohort of 107 human melanomas. PREX2 mutations are biologically relevant, as ectopic expression of mutant PREX2 accelerated tumour formation of immortalized human melanocytes in vivo. Thus, whole-genome sequencing of human melanoma tumours revealed genomic evidence of ultraviolet pathogenesis and discovered a new recurrently mutated gene in melanoma.National Human Genome Research Institute (U.S.

The disability insurance legal assessment in Switzerland against the background of the latest legislative amendments and new jurisprudence

In der Schweiz gibt es 11 verschiedene, historisch gewachsene Sozialversicherungen, deren grundsätzliche Ausgestaltung im Allgemeinen Teil des Sozialversicherungsgesetzes (ATSG) dargelegt ist. Die soziale Sicherung für behinderte Menschen und solche mit chronischen Erkrankungen wird u. a. von der Invalidenversicherung gewährleistet, die durch das Bundesgesetz über die Invalidenversicherung – aktuell in der 6. Revision – geregelt wird. Da sich die Rechtsprechung bezüglich der Invalidenversicherung in den letzten 10 Jahren erheblich gewandelt hat – was sich insbesondere auf die Leistungszusprache bei psychischen Störungen auswirkt – soll der vorliegende Beitrag einen Überblick über die für den medizinischen Experten relevanten juristischen Aspekte geben. Es ist hervorzuheben, dass die Rechtsprechung Prinzipien zur Einordung von Folgen spezifischer Krankheitsentitäten normativ festgelegt und diese im letzten Jahrzehnt weiterausgebaut hat. Die vom Rechtsanwender vorgenommene Prüfung der „willentlichen Überwindbarkeit“ stellt dabei auf einen Kriterienkatalog ab, der aus medizinischer Sicht nicht ausreichend belegt ist. In der juristischen Literatur der Schweiz wird diese gegenwärtige (Rechts-)Praxis kontrovers diskutiert, und Anpassungen werden erwogen. = There are 11 different historically established social security insurances in Switzerland. Social security for disabled and chronically ill people is mostly covered by the disability insurance. The disability insurance is governed by a federal law which has been revised six times, the last amendments having been introduced in 2012. The disability insurance legislation has changed much in the past 10 years and this has had a particularly great impact on the benefits awarded for psychiatric disorders. This article outlines several important facets of the disability insurance legislation relevant to psychiatric work capacity evaluations. Of particular interest are the special legal rules applied to specific illness groups, which have been expanded during the last decade. The concept of “voluntary surmountability” has arguably had the most impact and is based on a catalogue of criteria with an insufficient scientific foundation. The impact and possible changes of the current jurisdiction is currently being discussed in the Swiss juristic literature and amendments are under consideration