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.     

Difference in direct charge-parity violation between charged and neutral B meson decays

Equal amounts of matter and antimatter are predicted to have been produced in the Big Bang, but our observable Universe is clearly matter-dominated. One of the prerequisites for understanding this elimination of antimatter is the nonconservation of charge-parity (CP) symmetry. So far, two types of CP violation have been observed in the neutral K meson (K(0)) and B meson (B(0)) systems: CP violation involving the mixing between K(0) and its antiparticle (and likewise for B(0) and ), and direct CP violation in the decay of each meson. The observed effects for both types of CP violation are substantially larger for the B(0) meson system. However, they are still consistent with the standard model of particle physics, which has a unique source of CP violation that is known to be too small to account for the matter-dominated Universe. Here we report that the direct CP violation in charged B(+/-)-->K(+/-)pi(0) decay is different from that in the neutral B(0) counterpart. The direct CP-violating decay rate asymmetry, (that is, the difference between the number of observed B(-)-->K(-)pi(0) event versus B(+)-->K(+) pi(0) events, normalized to the sum of these events) is measured to be about +7%, with an uncertainty that is reduced by a factor of 1.7 from a previous measurement. However, the asymmetry for versus B(0)-->K(+)pi(-) is at the -10% level. Although it is susceptible to strong interaction effects that need further clarification, this large deviation in direct CP violation between charged and neutral B meson decays could be an indication of new sources of CP violation-which would help to explain the dominance of matter in the Universe.     

A putative RUNX1 binding site variant between SLC9A3R1 and NAT9 is associated with susceptibility to psoriasis

Psoriasis (OMIM 177900) is a chronic inflammatory skin disorder of unknown pathogenesis affecting approximately 2% of the Western population. It occurs more frequently in individuals with human immunodeficiency virus, and 20-30% of individuals with psoriasis have psoriatic arthritis. Psoriasis is associated with HLA class I alleles, and previous linkage analysis by our group identified a second psoriasis locus at 17q24-q25 (PSORS2; ref. 7). Linkage to this locus was confirmed with independent family sets. Additional loci have also been proposed to be associated with psoriasis. Here we describe two peaks of strong association with psoriasis on chromosome 17q25 separated by 6 Mb. Associated single-nucleotide polymorphisms (SNPs) in the proximal peak lie in or near SLC9A3R1 (also called EBP50 and NHERF1) and NAT9, a new member of the N-acetyltransferase family. SLC9A3R1 is a PDZ domain-containing phosphoprotein that associates with members of the ezrin-radixin-moesin family and is implicated in diverse aspects of epithelial membrane biology and immune synapse formation in T cells. The distal peak of association is in RAPTOR (p150 target of rapamycin (TOR)-scaffold protein containing WD-repeats). Expression of SLC9A3R1 is highest in the uppermost stratum Malpighi of psoriatic and normal skin and in inactive versus active T cells. A disease-associated SNP lying between SLC9A3R1 and NAT9 leads to loss of RUNX1 binding. This is the second example of loss of a RUNX1 binding site associated with susceptibility to an autoimmune disease. It also suggests defective regulation of SLC9A3R1 or NAT9 by RUNX1 as a susceptibility factor for psoriasis.