Tumor microenvironment: becoming sick of Myc

Several years ago, we described Myc as “the oncogene from hell”, since evidence had just emerged that Myc, aside from being responsible for cell-cycle progression and tumor expansion, was also able to induce genomic instability in culture, wreaking havoc in tumor cells and accelerating tumor progression (Soucek and Evan, Cancer Cell 1:406–408, 2002; Vafa et al., Mol Cell 9:1031–1044, 2002). In this review, we discuss recent publications that expand Myc’s evil armory to include coordination of the crosstalk between tumor and microenvironment. Indeed, endogenous Myc, acting as a client for upstream oncogenic lesions, instructs the tumor stroma, engages a complex inflammatory response and induces angiogenesis, thus allowing the tumor to thrive. This is highly topical in light of the fact that Hanahan and Weinberg have recently redefined the hallmarks of cancer and pointed out that genomic instability and inflammation are essential for both their acquisition and development (Hanahan and Weinberg, Cell 144:646–674, 2011). Myc, it seems, is behind it all.     

Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome

Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.     

Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Here, we performed high-resolution copy-number analysis on 125 HCC tumors and whole-exome sequencing on 24 of these tumors. We identified 135 homozygous deletions and 994 somatic mutations of genes with predicted functional consequences. We found new recurrent alterations in four genes (ARID1A, RPS6KA3, NFE2L2 and IRF2) not previously described in HCC. Functional analyses showed tumor suppressor properties for IRF2, whose inactivation, exclusively found in hepatitis B virus (HBV)-related tumors, led to impaired TP53 function. In contrast, inactivation of chromatin remodelers was frequent and predominant in alcohol-related tumors. Moreover, association of mutations in specific genes (RPS6KA3-AXIN1 and NFE2L2-CTNNB1) suggested that Wnt/β-catenin signaling might cooperate in liver carcinogenesis with both oxidative stress metabolism and Ras/mitogen-activated protein kinase (MAPK) pathways. This study provides insight into the somatic mutational landscape in HCC and identifies interactions between mutations in oncogene and tumor suppressor gene mutations related to specific risk factors.     

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.     

Further morphological and molecular studies of driftwood hoppers (Crustacea: Amphipoda: Talitridae) from Mediterranean/north-east Atlantic coastlines

An unknown talitrid was discovered in 2011 in the Swale, UK, living in driftwood. Sequencing of multiple mitochondrial and nuclear genes (cytochrome oxidase I, 18S rDNA and 28S rDNA) confirms that the unknown taxon was close to Orchestia mediterranea A. Costa 1857. The driftwood in which it was found was of Douglas fir (Pseudotsuga menziesii), probably imported from North America. Relative growth methods allow us to reject the null hypothesis that the unknown taxon was a juvenile Orchestia mediterranea. This is because the unknown taxon initiates sexual maturation at an earlier moult number (neoteny) and is predicted to reach terminal moult stages at a much smaller size (dwarfism) than its closest relative O. mediterranea. Both molecular and morphological data confirm that the unknown taxon from the Swale, UK, is a new driftwood specialist taxon, distantly related to the driftwood specialist genus Macarorchestia. Additional data for body length and sex ratios are presented for Macarorchestia. In addition, relative growth methods have shown that the driftwood species Orchestia microphtalma Amanieu and Salvat 1964 is closer to the genus Macarorchestia rather than to the wrack generalist one, Orchestia. This evidence is in line with the molecular results that do not cluster morphologically defined species of Orchestia monophyletically.     

Seed bank dynamics and habitat indicators of Arctomecon californica, a rare plant in a fragmented desert environment

Protection of endangered desert plant species is frequently complicated by a lack of information about seeds, the most stress-resistant and populous life stage. We studied the relative locations of seeds and plants of a rare endangered herbaceous perennial, the Las Vegas bearpoppy ( Arctomecon californica ) in seven 1-ha sites randomly located within a 100-ha study area that was slated for development in Las Vegas, Nevada. We also measured the physical and biological attributes of the environment supporting the seeds and plants, including soil hardness, rock cover, cryptogamic crust cover, and associated vegetation. Arctomecon californica seed density was 0.651 seeds &middot; m &ndash;2 , and seeds were found throughout the top 4 cm of soil. Seed viability among sites ranged from 26% to 79%; however, no significant changes between depths were detected. The spatial distribution of the seed bank coincided with the current A. californica adult distribution only in sites with both a high plant density and high numbers of seeds. Arctomecon californica adults occupied open areas within the gypsum environment that supported significantly less vegetative cover than the surrounding area. We observed a positive association between A. californica adults and shadscale ( Atriplex confertifolia ) and a negative association with 7 other plant species among sites. Sites with an indurated abiotic crust hosted higher numbers of A. californica adults than sites with softer soils. However, rock cover, cryptogamic crust cover, and soil hardness were poor explanatory factors for characterizing A. californica presence. We suggest that land managers should incorporate seed bank census into monitoring programs due to the extreme year-to-year fluctuations in A. californica plant population densities. A menudo la protecci&oacute;n de especies de plantas des&eacute;rticas en peligro de extinci&oacute;n se ve complicada por la falta de informaci&oacute;n sobre las semillas, la etapa de vida m&aacute;s abundante y resistente al estr&eacute;s. Estudiamos la ubicaci&oacute;n relativa de semillas y plantas de &ldquo;Las Vegas bearpoppy&rdquo; ( Arctomecon californica ), una planta perenne en peligro de extinci&oacute;n, en 7 sitios de 1 ha. localizados al azar dentro de un &aacute;rea de estudio de 100 ha que estaba destinada a la urbanizaci&oacute;n en Las Vegas, Nevada (E.U.A.). Tambi&eacute;n medimos los atributos f&iacute;sicos y biol&oacute;gicos del ambiente que sostiene las semillas y plantas, tales como dureza del suelo, rocosidad, cobertura de costra crypt&oacute;gama y vegetaci&oacute;n asociada. La densidad de semillas de A. californica fue 0.651 semillas &middot; m &ndash;2 y se observ&oacute; en los 4 cm superiores del suelo. La viabilidad de las semillas vari&oacute; del 26% al 79% entre los sitios; sin embargo, no detectamos cambios significativos entre profundidades. La distribuci&oacute;n espacial del banco de semillas coincidi&oacute; con la distribuci&oacute;n actual de adultos de A. californica, s&oacute;lo en sitios que tuvieron una alta densidad de plantas y altos n&uacute;meros de semillas. Los adultos de A. californica ocuparon &aacute;reas abiertas dentro del ambiente de yeso que sosten&iacute;a significativamente menos cobertura vegetal que las &aacute;reas circunvecinas. Observamos una asociaci&oacute;n positiva entre los adultos de A. californica y el chamizo ( Atriplex confertifolia ) y una asociaci&oacute;n negativa con siete otras especies de plantas entre sitios. Los sitios con una costra abi&oacute;tica endurecida albergaron m&aacute;s adultos de A. californica que los sitios con suelos m&aacute;s blandos. No obstante, la cubierta rocosa, la costra crypt&oacute;gama y la dureza del suelo fueron inadecuadas como factores para caracterizar la presencia de A. californica. Sugerimos que los manejadores de tierras deben incorporar censos de bancos de semillas en los programas de monitoreo, debido a las fluctuaciones extremas de un a&ntilde;o a otro en la densidad poblacional de A. californica. Normal 0 MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman";}     

Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma

Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype.