contributed to the design and execution of the overall study. M.P.P., M.J., J.R.T., G.S., L.E.M., L.A.K., X.W., V.G., K.B.J., J.D.M., N.R., S.J.C., and P Brennan contributed to the statistical analysis. M.P.P., M.J., S.J.C. and P. Brennan wrote the first draft of the manuscript. D. Zeleniak, E.P., L.A.K., X.W., K.B.J., S.H.V., S.L.M., Y.Y., A.M.M., E.S.B., N.N.C., M.F., D.L., I.G., S.H., H. Blanche, A.H., G.T., Z.W., M.Y., K.G.S., S.J.C., and M.L. supervised or conducted the genotyping. The remaining authors conducted the epidemiologic studies and contributed samples to the GWAS and/or replication. All authors contributed to the writing of the manuscript. NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2012 January 1. AbstractWe conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 cases and 8,505 controls of European background from 11 studies, and followed up 6 SNPs in three replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r 2 = 0.99 in controls), rs11894252 (P = 1.8×10 −8 ) and rs7579899 (P = 2.3×10 −9 ), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13, contains no characterized genes (P = 7.8×10 −14 ). In addition, we observed a promising association on 12q24.31 for rs4765623 which maps to the scavenger receptor class B, member 1 (SCARB1) gene (P = 2.6×10 −8 ). Our study reports novel genomic regions associated with RCC risk that may lead to new etiological insights. Table 1, Online Methods and Supplementary note). All subjects from the IARC/CNG study were genotyped at the CNG with the exception of 305 cases and 323 controls from Russia that were genotyped at the Center "Bioengineering" and at the "Kurchatov Institute" in Moscow. All subjects from the NCI study were scanned at the NCI Core Genotyping Facility. In addition, 1,438 controls from the Wellcome Trust Case-Control Consortium were genotyped at the Sanger Institute, UK 10 . All RCC cases were defined on the basis of the International Classification of Diseases for Oncology, Second Edition (ICD-O-2), and included all cancers that were coded as C64.Comparable quality control metrics were applied to the two scanned data sets and following sample and SNP exclusions, genotype data for up to 577,547 SNPs were available for 2,461 cases and 5,081 controls in the IARC/CNG scan, while data for 585,576 SNPs were available for 1,311 cases and 3,424 controls in the NCI scan (Online Methods). Primary analyses were conducted using unconditional logistic regression models for genotype trend effects (1 degree of freedom) and adjusted for sex, country, eigenvectors, and study for the USA (Online Methods). In order to compute summary findings across both scans, a metaanalysis was performed using a fixed effects model with inverse variance wei...

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

In our large pooled analysis, leanness was associated with increased HNC risk regardless of smoking and drinking status, although reverse causality cannot be excluded. The reduced risk among overweight or obese people may indicate body size is a modifier of the risk associated with smoking and drinking. Further clarification may be provided by analyses of prospective cohort and mechanistic studies.

Stromal cells appear as paraductal networks in the human parotid gland. Stromal cells are immunostained with vimentin. See Figure 1 (left panel) in Nicolescu et al., on page 380, in this issue.

The parotid histological structure includes acinar, ductal, and myoepithelial cells, surrounded by a connective stromal component. The parotid stroma is mostly regarded as an inert shell, consisting of septa, which divide the parenchyma. Telocytes were recently identified as a new stromal cell type in various organs, including exocrine pancreas. We aimed to evaluate telocytes presence in parotid stroma and whether their topographical features might support an involvement in parotid function modulation. Serial ultrathin sections of human and rat parotid glands were studied and compared by transmission electron microscopy. Twodimensional concatenation of sequenced micrographs allowed the ultrastructural identification of parotid telocytes, with their specific long, thin, and moniliform prolongations (telopodes). Telocyte location appeared frequently as a strategic one, in close contact or vicinity of both secretory (acini and ducts) and regulatory (nerves and blood vessels) apparatuses. They were also found in the interacinar and the subductal stroma. Two previously reported telocyte markers (c-kit/CD117 and vimentin) were assayed by immunohistochemistry. Actin expression was also evaluated. Telocytes are making a network, especially by branching of their long telopodes. Elements of this telocyte network are interacting with each other (homocellular connections) as well as with other cell types (heterocellular connections). These interactions are achieved either by direct contact (stromal synapse), or mediated via shed microvesicles/exosomes. Since telocyte connections include both neurovascular and exocrine elements (e.g., acini and ducts), it is attractive to think that telocytes might mediate and integrate neural and/or vascular input with parotid function.