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BackgroundWe previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.Materials and methodsGenotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.ResultsCF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.ConclusionWe identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.

To date only five patients with 8p23.2-pter microdeletions manifesting a mild-to-moderate cognitive impairment and/or developmental delay, dysmorphisms and neurobehavioral issues were reported. The smallest microdeletion described by Wu in 2010 suggested a critical region (CR) of 2.1 Mb including several genes, out of which FBXO25, DLGAP2, CLN8, ARHGEF10 and MYOM2 are the main candidates. Here we present seven additional patients with 8p23.2-pter microdeletions, ranging from 71.79 kb to 4.55 Mb. The review of five previously reported and nine Decipher patients confirmed the association of the CR with a variable clinical phenotype characterized by intellectual disability/developmental delay, including language and speech delay and/or motor impairment, behavioral anomalies, autism spectrum disorder, dysmorphisms, microcephaly, fingers/toes anomalies and epilepsy. Genotype analysis allowed to narrow down the 8p23.3 candidate region which includes only DLGAP2, CLN8 and ARHGEF10 genes, accounting for the main signs of the broad clinical phenotype associated to 8p23.2-pter microdeletions. This region is more restricted compared to the previously proposed CR. Overall, our data favor the hypothesis that DLGAP2 is the actual strongest candidate for neurodevelopmental/behavioral phenotypes. Additional patients will be necessary to validate the pathogenic role of DLGAP2 and better define how the two contiguous genes, ARHGEF10 and CLN8, might contribute to the clinical phenotype.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes(1,2). The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution(1,3,4). Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such asBCL9, MCL1,ARNT(also known asHIF1B),TERTandMYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompassesBCL9, MCL1andARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassingMYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassingCCND1) in HER2(+)breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.

Large-scale chromosomal translocations are frequent oncogenic drivers in acute myeloid leukemia (AML). These translocations often occur in critical transcriptional/epigenetic regulators and contribute to malignant cell growth through alteration of normal gene expression. Despite this knowledge, the specific gene expression alterations that contribute to the development of leukemia remain incompletely understood. Here, through characterization of transcriptional regulation by the RUNX1-ETO fusion protein, we have identified Ras-association domain family member 2 (RASSF2) as a critical gene that is aberrantly transcriptionally repressed in t(8;21)-associated AML. Re-expression of RASSF2 specifically inhibits t(8;21) AML development in multiple models. Through biochemical and functional studies, we demonstrate RASSF2-mediated functions to be dependent on interaction with Hippo kinases, MST1 and MST2, but independent of canonical Hippo pathway signaling. Using proximity-based biotin labeling we define the RASSF2-proximal proteome in leukemia cells and reveal association with Rac GTPase-related proteins, including an interaction with the guanine nucleotide exchange factor, DOCK2. Importantly, RASSF2 knockdown impairs Rac GTPase activation, and RASSF2 expression is broadly correlated with Rac-mediated signal transduction in AML patients. Together, these data reveal a previously unappreciated mechanistic link between RASSF2, Hippo kinases, and Rac activity with potentially broad functional consequences in leukemia.

The molecular alterations of pancreatic acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MANECs) are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. We have investigated c-MYC gene amplification in a series of 35 ACCs and 4 MANECs to evaluate its frequency and a possible prognostic role. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti-c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. All MANECs showed c-MYC amplification and/or polysomy which were observed in 54% pure ACCs. Six cases (15.3%) showed nuclear immunoreactivity for c-myc, but only 4/39 cases showed simultaneous c-MYC amplification/polysomy and nuclear protein expression. c-myc immunoreactivity as well as c-MYC amplification and/or chromosome 8 polysomy was not statistically associated with prognosis. Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs.

Cohen syndrome (CS) is an uncommon autosomal recessive genetic disorder attributed to damage on VPS13B gene, locus 8q22-q23. Characteristic phenotype consists of intellectual disability, microcephaly, facial dysmorphism, ophthalmic abnormalities, truncal obesity and hipotony. Worldwide, around 150 cases have been published, mostly in Finish patients. We report the case of a 3 year-old male, with short height, craniosynostosis, facial dysmorphism, hipotony, and developmental delay. He was diagnosed with Cohen syndrome using Microarray Comparative Genomic Hibridization (aCGH) that showed homozygous deletion of 0.153 Mb on 8q22.2 including VPS13B gene, OMIM #216550. With this report we contribute to enlarge epidemiological databases on an uncommon genetic disorder. Besides, we illustrate on the contribution of aCGH to the etiological diagnosis of patients with unexplained intellectual disability, delayed psychomotor development, language difficulties, autism and multiple congenital anomalies.

Acquired isolated factor VII deficiency is a rare bleeding disorder and has been reported in 31 cases. This is in contrast to congenital factor VII deficiency, which while also infrequent is the most common rare congenital bleeding disorder. Acquired isolated factor VII deficiency has been described primarily in patients with solid malignancies, sepsis, and in the presence of anti-factor VII autoantibodies. We report a case of acute myelogenous leukemia with an associated trisomy 8 cytogenetic abnormality presenting with factor VII deficiency. The factor VII deficiency cleared after induction chemotherapy and with the disappearance of the cytogenetic and molecular abnormalities. We discuss a possible link between trisomy 8 and vitamin K metabolism, which might result in acquired factor VII deficiency in acute myelogenous leukemia.

// Nathan Bucay 1, * , Kirandeep Sekhon 1, * , Shahana Majid 1 , Soichiro Yamamura 1 , Varahram Shahryari 1 , Z. Laura Tabatabai 1 , Kirsten Greene 1 , Yuichiro Tanaka 1 , Rajvir Dahiya 1 , Guoren Deng 1 , Sharanjot Saini 1 1 Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, CA, USA * These authors have contributed equally to this work Correspondence to: Sharanjot Saini, email: Sharanjot.Saini@ucsf.edu Keywords: prostate cancer, miR-3622b, EGFR, chr8p21, tumor suppressor Received: May 24, 2016 Accepted: August 13, 2016 Published: September 06, 2016 ABSTRACT Genomic loss of chromosome (chr) 8p21 region, containing prostate-specific NKX3.1 gene, is a frequent alteration of the prostate cancer (PCa) oncogenome. We propose a novel, paradigm shifting hypothesis that this frequently deleted locus is also associated with a cluster of microRNA genes- miR-3622a/b- that are lost in PCa and play an important mechanistic role in progression and metastasis. In this study, we demonstrate the role of miR-3622b in prostate cancer. Expression analyses in a cohort of PCa clinical specimens and cell lines show that miR-3622b expression is frequently lost in prostate cancer. Low miR-3622b expression was found to be associated with tumor progression and poor biochemical recurrence-free survival. Further, our analyses suggest that miR-3622b expression is a promising prostate cancer diagnostic biomarker that exhibits 100% specificity and 66% sensitivity. Restoration of miR-3622b expression in PCa cell lines led to reduced cellular viability, proliferation, invasiveness, migration and increased apoptosis. miR-3622b overexpression in vivo induced regression of established prostate tumor xenografts pointing to its therapeutic potential. Further, we found that miR-3622b directly represses Epidermal Growth Factor Receptor (EGFR). In conclusion, our study suggests that miR-3622b plays a tumor suppressive role and is frequently downregulated in prostate cancer, leading to EGFR upregulation. Importantly, miR-3622b has associated diagnostic, prognostic and therapeutic potential. Considering the association of chr8p21 loss with poor prognosis, our findings are highly significant and support a novel concept that associates a long standing observation of frequent loss of a chromosomal region with a novel miRNA in prostate cancer.

Author(s): Ustun, Celalettin; Morgan, Elizabeth; Moodie, Erica EM; Pullarkat, Sheeja; Yeung, Cecilia; Broesby-Olsen, Sigurd; Ohgami, Robert; Kim, Young; Sperr, Wolfgang; Vestergaard, Hanne; Chen, Dong; Kluin, Philip M; Dolan, Michelle; Mrozek, Krzysztof; Czuchlewski, David; Horny, Hans-Peter; George, Tracy I; Kristensen, Thomas Kielsgaard; Ku, Nam K; Yi, Cecilia Arana; Moller, Michael Boe; Marcucci, Guido; Baughn, Linda; Schiefer, Ana-Iris; Hilberink, JR; Pullarkat, Vinod; Shanley, Ryan; Kohlschmidt, Jessica; Coulombe, Janie; Salhotra, Amandeep; Soma, Lori; Cho, Christina; Linden, Michael A; Akin, Cem; Gotlib, Jason; Hoermann, Gregor; Hornick, Jason; Nakamura, Ryo; Deeg, Joachim; Bloomfield, Clara D; Weisdorf, Daniel; Litzow, Mark R; Valent, Peter; Huls, Gerwin; Perales, Miguel-Angel; Borthakur, Gautam | Abstract: BackgroundAlthough the prognosis of core-binding factor (CBF) acute myeloid leukemia (AML) is better than other subtypes of AML, 30% of patients still relapse and may require allogeneic hematopoietic cell transplantation (alloHCT). However, there is no validated widely accepted scoring system to predict patient subsets with higher risk of relapse.MethodsEleven centers in the US and Europe evaluated 247 patients with t(8;21)(q22;q22).ResultsComplete remission (CR) rate was high (92.7%), yet relapse occurred in 27.1% of patients. A total of 24.7% of patients received alloHCT. The median disease-free (DFS) and overall (OS) survival were 20.8 and 31.2 months, respectively. Age, KIT D816V mutated (11.3%) or nontested (36.4%) compared with KIT D816V wild type (52.5%), high white blood cell counts (WBC), and pseudodiploidy compared with hyper- or hypodiploidy were included in a scoring system (named I-CBFit). DFS rate at 2 years was 76% for patients with a low-risk I-CBFit score compared with 36% for those with a high-risk I-CBFit score (P l 0.0001). Low- vs high-risk OS at 2 years was 89% vs 51% (P l 0.0001).ConclusionsI-CBFit composed of readily available risk factors can be useful to tailor the therapy of patients, especially for whom alloHCT is not need in CR1 (ie, patients with a low-risk I-CBFit score).

Introduction Malignant mesothelioma is an aggressive malignancy of the thoracic cavity caused by prior asbestos exposure. In the peritoneum the mesothelioma is an extremely rare condition. In the present preliminary study, high-resolution array-comparative genomic hybridization (a-CGH) was performed to identify genetic imbalances in a series of malignant peritoneal mesothelioma cases. Materials and methods Between 1990 and 2008, among the cases recorded in the Apulia Mesothelioma Register, we found 22 peritoneal mesothelioma cases. CGH-array was performed on samples from all patients. Results The CGH-array analysis revealed multiple chromosomal imbalances. Interestingly, deletion at 8p23.1 was observed in 12 cases. Furthermore, another novel deletion at 1q21 was present in 11. Often, 1q21 and 8p23.1 losses were present in the same patient (7 cases). Losses of BAP1 and CDKN2A loci were not detected. Discussion The region at 8p23.1 contains the beta-defensin gene cluster (DEF) and 1q21 contains ubiquitin conjugating enzyme E2 (UBE2Q1). We hypotesized that the loss of function of ubiquitination, as well as of the defensins, could play an important role in the initial development and subsequent progression of mesothelioma.

Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

Preterm birth (PTB), or the delivery prior to 37 weeks of gestation, is a significant cause of infant morbidity and mortality. Although twin studies estimate that maternal genetic contributions account for approximately 30% of the incidence of PTB, and other studies reported fetal gene polymorphism association, to date no consistent associations have been identified. In this study, we performed the largest reported genome-wide association study analysis on 1,349 cases of PTB and 12,595 ancestry-matched controls from the focusing on genomic fetal signals. We tested over 2 million single nucleotide polymorphisms (SNPs) for associations with PTB across five subpopulations: African (AFR), the Americas (AMR), European, South Asian, and East Asian. We identified only two intergenic loci associated with PTB at a genome-wide level of significance: rs17591250 (P = 4.55E-09) on chromosome 1 in the AFR population and rs1979081 (P = 3.72E-08) on chromosome 8 in the AMR group. We have queried several existing replication cohorts and found no support of these associations. We conclude that the fetal genetic contribution to PTB is unlikely due to single common genetic variant, but could be explained by interactions of multiple common variants, or of rare variants affected by environmental influences, all not detectable using a GWAS alone.

Childhood acute lymphoblastic leukemia (ALL) (age 0–14 years) is 20% more common in Latino Americans than non-Latino whites. We conduct a genome-wide association study in a large sample of 3263 Californian children with ALL (including 1949 of Latino heritage) and 3506 controls matched on month and year of birth, sex, and ethnicity, and an additional 12,471 controls from the Kaiser Resource for Genetic Epidemiology Research on Aging Cohort. Replication of the strongest genetic associations is performed in two independent datasets from the Children’s Oncology Group and the California Childhood Leukemia Study. Here we identify new risk loci on 17q12 near IKZF3/ZPBP2/GSDMB/ORMDL3, a locus encompassing a transcription factor important for lymphocyte development (IKZF3), and at an 8q24 region known for structural contacts with the MYC oncogene. These new risk loci may impact gene expression via local (four 17q12 genes) or long-range (8q24) interactions, affecting function of well-characterized hematopoietic and growth-regulation pathways., Childhood acute lymphoblastic leukemia is common in Latino Americans. Here, the authors conduct a genome-wide association study in a Californian cohort containing children of Latino heritage, and identify loci on 17q12 and 8q24 which may affect hematopoietic and growth-regulation pathways.

A major genomic alteration in prostate cancer (PCa) is frequent loss of chromosome (chr) 8p with a common region of loss of heterozygosity (LOH) at chr8p22 locus. Genomic studies implicate this locus in the initiation of clinically significant PCa and with progression to metastatic disease. However, the genes within this region have not been fully characterized to date. Here we demonstrate for the first time that a microRNA component of this region-miR-383-is frequently downregulated in prostate cancer, has a critical role in determining tumor-initiating potential and is involved in prostate cancer metastasis via direct regulation of CD44, a ubiquitous marker of PCa tumor-initiating cells (TICs)/stem cells. Expression analyses of miR-383 in PCa clinical tissues established that low miR-383 expression is associated with poor prognosis. Functional data suggest that miR-383 regulates PCa tumor-initiating/stem-like cells via CD44 regulation. Ectopic expression of miR-383 inhibited tumor-initiating capacity of CD44+ PCa cells. Also, 'anti-metastatic' effects of ectopic miR-383 expression were observed in a PCa experimental metastasis model. In view of our results, we propose that frequent loss of miR-383 at chr8p22 region leads to tumor initiation and prostate cancer metastasis. Thus, we have identified a novel finding that associates a long observed genomic alteration to PCa stemness and metastasis. Our data suggest that restoration of miR-383 expression may be an effective therapeutic modality against PCa. Importantly, we identified miR-383 as a novel PCa tissue diagnostic biomarker with a potential that outperforms that of serum PSA.

We and others first reported several inherited variants that increase glioma risk in 2009.1,2 Additional confirmation and new risk loci have been identified since then.3–8 We9 and Simon et al.10 showed that the glioma risk loci in 8q24 and 11q23 first identified by Shete et al.1 were associated with risk of lower grade infiltrating gliomas but not with glioblastomas. It is now well established that mutation in the isocitrate dehydrogenase (IDH) 1 and 2 genes leads to genome-wide histone and DNA methylation changes that result in abnormal gene expression and gliomagenesis, defining a distinct subclass of gliomas.11,12 IDH mutations occur in ∼50%–80% of grade II-III gliomas and secondary glioblastomas but in fewer than 10% of primary glioblastomas.13–17 Tumor IDH mutations are associated with younger age of onset and better overall survival among patients with gliomas of all grades and histologies18,19 and are also associated with other somatic, genetic, and epigenetic alterations.17,20 Given these observations, we hypothesized that the 8q24 and 11q23 glioma risk loci might be specific to IDH-mutated, but not to IDH-wild-type gliomas. In a separate recent publication,21 we showed that the 8q24 locus is specifically associated with risk for oligodendroglial tumors and IDH-mutated astrocytomas of all grades. Here, we report that the 11q23 glioma risk variant rs498872 T allele is associated with risk of IDH-mutated gliomas but not with risk of IDH-wild-type gliomas, regardless of grade or histology.

The PML/RARA fusion protein occurs as a result of the t(15;17) translocation in the acute promyelocytic leukaemia subtype of human acute myeloid leukaemia. Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukaemia, including acute promyelocytic leukaemia. We previously demonstrated that gain of chromosome 8-containing MYC is of central importance in trisomy 8, but the role of the nearby TRIB1 gene has not been experimentally addressed in this context. We have now tested the hypothesis that both MYC and TRIB1 have functional roles underlying leukaemogenesis of trisomy 8 by using retroviral vectors to express MYC and TRIB1 in wild-type bone marrow and in marrow that expressed a PML/RARA transgene. Interestingly, although MYC and TRIB1 readily cooperated in leukaemogenesis for wild-type bone marrow, TRIB1 provided no selective advantage to cells expressing PML/RARA. We hypothesized that this lack of cooperation between PML/RARA and TRIB1 reflected a common pathway for their effect: both proteins targeting the myeloid transcription factor C/EBPα. In support of this idea, TRIB1 expression abrogated the All Trans-Retinoic Acid response of acute promyelocytic leukaemia cells in vitro and in vivo. Our data delineate the common and redundant inhibitory effects of TRIB1 and PML/RARA on C/EBPα providing a potential explanation for the lack of selection of TRIB1 in human acute promyelocytic leukaemia, and highlighting the key role of C/EBPs in acute promyelocytic leukaemia pathogenesis and therapeutic response. In addition, the cooperativity we observed between MYC and TRIB1 in the absence of PML/RARA show that, outside of acute promyelocytic leukaemia, gain of both genes may drive selection for trisomy 8.

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2) = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

SQLE encodes squalene epoxidase, a key enzyme in cholesterol synthesis. SQLE has sporadically been reported among copy-number driven transcripts in multi-omics cancer projects. Yet, its functional relevance has never been subjected to systematic analyses. Here, we assessed the correlation of SQLE copy number (CN) and gene expression (GE) across multiple cancer types, focusing on the clinico-pathological associations in breast cancer (BC). We then investigated whether any biological effect of SQLE inhibition could be observed in BC cell line models. Breast, ovarian, and colorectal cancers showed the highest CN driven GE among 8,783 cases from 22 cancer types, with BC presenting the strongest one. SQLE overexpression was more prevalent in aggressive BC, and was an independent prognostic factor of unfavorable outcome. Through SQLE pharmacological inhibition and silencing in a panel of BC cell lines portraying the diversity of SQLE CN and GE, we demonstrated that SQLE inhibition resulted in a copy-dosage correlated decrease in cell viability, and in a noticeable increase in replication time, only in lines with detectable SQLE transcript. Altogether, our results pinpoint SQLE as a bona fide metabolic oncogene by amplification, and as a therapeutic target in BC. These findings could have implications in other cancer types., SCOPUS: ar.j, info:eu-repo/semantics/published

Benzene exposure causes acute myeloid leukemia and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n=28) and unexposed (n=14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P=0.0055 and P=0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to

Men who enter active surveillance because their biopsy exhibits only Gleason grade 3 (G3) frequently have higher grade tumor missed by biopsy. Thus, biomarkers are needed that, when measured on G3 tissue, can predict the presence of higher grade tumor in the whole prostate. We evaluated whether PTEN loss, chromosome 8q gain (MYC) and/or 8p loss (LPL) measured only on G3 cores is associated with un-sampled G4 tumor. A tissue microarray was constructed of prostatectomy tissue from patients whose prostates exhibited only Gleason score 3+3, only 3+4, or only 4+3 tumor (n=50 per group). Cores sampled only from areas of G3 were evaluated for PTEN loss by immunohistochemistry, and PTEN deletion, LPL/8p loss, and MYC/8q gain by fluorescence in situ hybridization (FISH). Biomarker results were compared between Gleason score 6 vs. 7 tumors using conditional logistic regression. PTEN protein loss, odds ratio=4.99, p=.033, MYC/8q gain, odds ratio=5.36, p=.010, and LPL/8p loss, odds ratio=3.96, p=.003 were significantly more common in G3 cores derived from Gleason 7 vs. Gleason 6 tumors. PTEN gene deletion was not statistically significant. Associations were stronger comparing Gleason 4+3 vs. 6 than for Gleason 3+4 vs. 6. MYC/8q gain, LPL/8p loss, and PTEN protein loss measured in G3 tissue microarray cores strongly differentiate whether the core comes from a Gleason 6 or Gleason 7 tumor. If validated to predict upgrading from G3 biopsy to prostatectomy these biomarkers could reduce the likelihood of enrolling high risk men and facilitate safe patient selection for active surveillance.

ObjectiveAutism spectrum disorder is characterized by deficits in social function and the presence of repetitive and restrictive behaviors. Following a previous test of principle, the authors adopted a quantitative approach to discovering genes contributing to the broader autism phenotype by using social responsiveness as an endophenotype for autism spectrum disorder.MethodLinkage analyses using scores from the Social Responsiveness Scale were performed in 590 families from the Autism Genetic Resource Exchange, a largely multiplex autism spectrum disorder cohort. Regional and genomewide association analyses were performed to search for common variants contributing to social responsiveness.ResultsSocial Responsiveness Scale scores were unimodally distributed in male offspring from multiplex autism families, in contrast with a bimodal distribution observed in female offspring. In correlated analyses differing by Social Responsiveness Scale respondent, genomewide significant linkage for social responsiveness was identified at chr8p21.3 (multipoint LOD=4.11; teacher/parent scores) and chr8q24.22 (multipoint LOD=4.54; parent-only scores), respectively. Genomewide or linkage-directed association analyses did not detect common variants contributing to social responsiveness.ConclusionsThe sex-differential distributions of Social Responsiveness Scale scores in multiplex autism families likely reflect mechanisms contributing to the sex ratio for autism observed in the general population and form a quantitative signature of reduced penetrance of inherited liability to autism spectrum disorder among females. The identification of two strong loci for social responsiveness validates the endophenotype approach for the identification of genetic variants contributing to complex traits such as autism spectrum disorder. While causal mutations have yet to be identified, these findings are consistent with segregation of rare genetic variants influencing social responsiveness and underscore the increasingly recognized role of rare inherited variants in the genetic architecture of autism spectrum disorder.

PurposeTo determine underlying correlations in multiplex ligation-dependent probe amplification (MLPA) data and their significance regarding survival following treatment of choroidal melanoma (CM).MethodsMLPA data were available for 31 loci across four chromosomes (1p, 3, 6, and 8) in tumor material obtained from 602 patients with CM treated at the Liverpool Ocular Oncology Center (LOOC) between 1993 and 2012. Data representing chromosomes 3 and 8q were analyzed in depth since their association with CM patient survival is well-known. Unsupervised k-means cluster analysis was performed to detect latent structure in the data set. Principal component analysis (PCA) was also performed to determine the intrinsic dimensionality of the data. Survival analyses of the identified clusters were performed using Kaplan-Meier (KM) and log-rank statistical tests. Correlation with largest basal tumor diameter (LTD) was investigated.ResultsChromosome 3: A two-cluster (bimodal) solution was found in chromosome 3, characterized by centroids at unilaterally normal probe values and unilateral deletion. There was a large, significant difference in the survival characteristics of the two clusters (log-rank, p

The association of cortical tremor, myoclonus and epileptic seizures has been reported in many Japanese and European families with different acronyms. We reviewed the familial cases presenting the clinical picture of autosomal dominant cortical tremor, myoclonus and epilepsy and analysed the phenotypic differences between the pedigrees, according to the recent genetic acquisitions. We concluded that BAFME, FAME, FEME, FCTE and ADCME are the same clinical entity even if genetically heterogeneous, with Japanese families linked to 8q24 and Italian ones to 2p11.1-q12. A third locus could also be involved. Further studies should better clarify the electrophysiological features of this condition and identify the underlying molecular defects.

8p11 myeloproliferative syndrome (EMS) is a clinical-pathologic entity characterized by rearrangements involving the FGFR1 gene, which encodes a receptor tyrosine kinase. These rearrangements invariably lead to aberrant fusion proteins in which the kinase activity is constitutively turned on, with resulting oncogenic properties. In this article, we describe a new translocation in EMS, t(7;8)(q34;p11), in which the FGFR1 gene is fused to a previously unidentified partner, the TIF1 gene. We show that both the TIF1-FGFR1 and FGFR1-TIF1 fusion proteins have the potential to be translated as a result of the translocation. Thus, our data extend the involvement of FGFR1 in EMS and lend support to the concept that there is a precise correlation between genotype and phenotype in this disease.

Cytogenetic analysis has transformed the management of uveal melanoma in recent years and allows categorization of such tumors into low-grade tumors with a favorable prognosis and high-grade tumors that metastasize with a fatal outcome. The authors report the case of a 73-year-old man who presented with recurrent melanoma in his left socket, 26 years after enucleation for uveal melanoma. Chromosomal analysis by multiplex ligation-dependent probe amplification revealed partial loss of chromosome 3 and gains in chromosomes 6 and 8, which were missed with fluorescence in situ hybridization. The patient developed multiple liver metastases 14 months after orbital exenteration and died 8 months later. To the best of authors' knowledge, this is the first report of late recurrence of uveal melanoma after enucleation, in which multiplex ligation-dependent probe amplification chromosomal analysis has been used. The case also highlights the limitations of fluorescence in situ hybridization and the benefits of multiplex ligation-dependent probe amplification, which is more reliable at predicting survival.

Genome-wide association studies have identified more than 70 common variants that are associated with breast cancer risk. Most of these variants map to non-protein-coding regions and several map to gene deserts, regions of several hundred kilobases lacking protein-coding genes. We hypothesized that gene deserts harbor long-range regulatory elements that can physically interact with target genes to influence their expression. To test this, we developed Capture Hi-C (CHi-C), which, by incorporating a sequence capture step into a Hi-C protocol, allows high-resolution analysis of targeted regions of the genome. We used CHi-C to investigate long-range interactions at three breast cancer gene deserts mapping to 2q35, 8q24.21, and 9q31.2. We identified interaction peaks between putative regulatory elements (“bait fragments”) within the captured regions and “targets” that included both protein-coding genes and long noncoding (lnc) RNAs over distances of 6.6 kb to 2.6 Mb. Target protein-coding genes were IGFBP5, KLF4, NSMCE2, and MYC; and target lncRNAs included DIRC3, PVT1, and CCDC26. For one gene desert, we were able to define two SNPs (rs12613955 and rs4442975) that were highly correlated with the published risk variant and that mapped within the bait end of an interaction peak. In vivo ChIP-qPCR data show that one of these, rs4442975, affects the binding of FOXA1 and implicate this SNP as a putative functional variant.

Well-differentiated hepatocellular carcinoma in non-cirrhotic liver can show morphological features similar to hepatocellular adenoma. In rare instances, hepatocellular carcinoma can arise in the setting of hepatocellular adenoma. This study compares the immunohistochemical and cytogenetic features of the hepatocellular adenoma-like and hepatocellular carcinoma portions of these tumors. Immunohistochemistry for β-catenin, glutamine synthetase, serum amyloid A protein, glypican-3, and heat-shock protein 70 was done in 11 cases of hepatocellular carcinoma arising in hepatocellular adenoma in non-cirrhotic liver. Tumors with nuclear β-catenin and/or diffuse glutamine synthetase were considered β-catenin activated. Fluorescence in situ hybridization (FISH) was done in nine cases for gains of chromosomes 1, 8 and MYC. There were seven men (33-75 years) and four women (29-65 years). Focal atypical morphological features were seen in hepatocellular adenoma-like areas in 7 (64%) cases. Hepatocellular adenoma-like areas showed features of inflammatory hepatocellular adenoma in 7 (64%) cases; 4 of these were also serum amyloid A-positive in the hepatocellular carcinoma portion. β-Catenin activation, heat-shock protein 70 positivity, and chromosomal gains on FISH were seen in the hepatocellular adenoma portion in 55%, 40%, and 56% of cases, and 73%, 60%, and 78% of cases in the hepatocellular carcinoma portion, respectively. In conclusion, the hepatocellular adenoma-like portion of most cases of hepatocellular carcinoma arising in hepatocellular adenoma shows features typically seen in hepatocellular carcinoma such as focal morphological abnormalities, β-catenin activation, heat-shock protein 70 expression, and chromosomal gains. Hepatocellular adenoma-like areas in these tumors, especially in men and older women, may represent an extremely well-differentiated variant of hepatocellular carcinoma, whereas the morphologically recognizable hepatocellular carcinoma portion represents a relatively higher grade component of the tumor.

Efforts to identify lupus-associated causal variants in the FAM167A/BLK locus on 8p21 are hampered by highly associated noncausal variants. In this report, we used a trans-population mapping and sequencing strategy to identify a common variant (rs922483) in the proximal BLK promoter and a tri-allelic variant (rs1382568) in the upstream alternative BLK promoter as putative causal variants for association with systemic lupus erythematosus. The risk allele (T) at rs922483 reduced proximal promoter activity and modulated alternative promoter usage. Allelic differences at rs1382568 resulted in altered promoter activity in B progenitor cell lines. Thus, our results demonstrated that both lupus-associated functional variants contribute to the autoimmune disease association by modulating transcription of BLK in B cells and thus potentially altering immune responses.

The 8;21 translocation is the most common chromosomal aberration occurring in acute myeloid leukemia (AML). This translocation causes expression of the RUNX1-ETO (AML1-ETO) fusion protein, which cooperates with additional mutations in leukemia development. We report here that interferons (IFNs) and IFN-stimulated genes are a group of genes consistently up-regulated by RUNX1-ETO in both human and murine models. RUNX1-ETO-induced up-regulation of IFN-stimulated genes occurs primarily via type I IFN signaling with a requirement for the IFNAR complex. Addition of exogenous IFN in vitro significantly reduces the increase in self-renewal potential induced by both RUNX1-ETO and its leukemogenic splicing isoform RUNX1-ETO9a. Finally, loss of type I IFN signaling via knockout of Ifnar1 significantly accelerates leukemogenesis in a t(8;21) murine model. This demonstrates the role of increased IFN signaling as an important factor inhibiting t(8;21) fusion protein function and leukemia development and supports the use of type I IFNs in the treatment of AML.

Genetic variation at 8q24 is associated with prostate, bladder, breast, colorectal, thyroid, lung, ovarian, UADT, liver and stomach cancers. However, a role for variation at 8q24 in familial clustering of upper gastrointestinal cancers has not been studied. In order to explore potential inherited susceptibility, we analyzed epidemiologic data from a population-based case-control study of upper gastrointestinal cancers from Taixing, China. The study population includes 204 liver, 206 stomach, and 218 esophageal cancer cases and 415 controls. Associations between 8q24 rs1447295, rs16901979, rs6983267 and these cancers were stratified by family history of cancer. Odds ratios and 95% confidence intervals were adjusted for potential confounders: age, sex, education, tobacco smoking, alcohol consumption, and BMI at interview. We also adjusted for hepatitis B and aflatoxin (liver cancer) and Helicobacter pylori (stomach cancer). In a dominant model, among those with a family history of cancer, rs1447295 was positively associated with liver cancer (OR(adj) 2.80; 95% CI 1.15-6.80). Heterogeneity was observed (P(heterogeneity) = 0.029) with rs6983267 and liver cancer, with positive association in the dominant model among those with a family history of cancer and positive association in the recessive model among those without a family history of cancer. When considered in a genetic risk score model, each additional 8q24 risk genotype increased the odds of liver cancer by two-fold among those with a family history of cancer (OR(adj) 2.00; 95% CI 1.15-3.47). These findings suggest that inherited susceptibility to liver cancer may exist in the Taixing population and that variation at 8q24 might be a genetic component of that inherited susceptibility.

As there is increasing evidence that aberrant defensin expression is related to susceptibility for infectious disease and inflammatory disorders, we sought to determine if copy number of the beta-defensin gene cluster located on chromosome 8p23.1 (DEFB107, 106, 105, 104, 103, DEFB4 and SPAG11), that shows copy number variation as a block, was associated with susceptibility to otitis media (OM). The gene DEFB103 within this complex encodes human beta defensin-3 (hBD-3), an antimicrobial peptide (AP) expressed by epithelial cells that line the mammalian airway, important for defense of mucosal surfaces and previously shown to have bactericidal activity in vitro against multiple human pathogens, including the three that predominate in OM. To this end, we conducted a retrospective case-control study of 113 OM prone children and 267 controls aged five to sixty months. We identified the copy number of the above defined beta-defensin gene cluster (DEFB-CN) in each study subject by paralogue ratio assays. The mean DEFB-CN was indistinguishable between subjects classified as OM prone based on a recent history of multiple episodes of OM and control subjects who had no history of OM (4.4 ± 0.96 versus 4.4 ± 1.08, respectively: Odds Ratio [OR]: 1.16 (95% CI: 0.61, 2.20). Despite a lack of direct association, we observed a statistically significant correlation between DEFB-CN and nasopharyngeal bacterial colonization patterns. Collectively, our findings suggested that susceptibility to OM might be mediated by genetic variation among individuals, wherein a DEFB-CN less than 4 exerts a marked influence on the microbiota of the nasopharynx, specifically with regard to colonization by the three predominant bacterial pathogens of OM.

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican–Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans., Dyslipidemia and obesity have a high prevalence in populations with Amerindian backgrounds, such as Mexican–Americans. Here, the authors design an approach to identify Amerindian risk genes in Mexicans and identify five genomic loci, which include RORA and SIK3 that may contribute to the risk of dyslipidemia and obesity in Amerindian populations.

Prognostic gene mutations and distinct gene- and microRNA-expression signatures in acute myeloid leukemia with a sole trisomy 8

Background: Colorectal cancer (CRC) is a disease of complex aetiology, with much of the expected inherited risk being due to several common low risk variants. Genome-Wide Association Studies (GWAS) have identified 20 CRC risk variants. Nevertheless, these have only been able to explain part of the missing heritability. Moreover, these signals have only been inspected in populations of Northern European origin. Results: Thus, we followed the same approach in a Spanish cohort of 881 cases and 667 controls. Sixty-four variants at 24 loci were found to be associated with CRC at p-values

Idiopathic generalized epilepsy (IGE) is characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Twin and family studies suggest that genetic factors play a key part in IGE. A multilocus model appears to best fit the observed inheritance patterns. Mapping of IGE-related genes has been previously attempted using parametric methods, with conflicting results. In particular, recent evidence argues both for and against a chromosome 6p locus (EJM1) for juvenile myoclonic epilepsy, a subtype of IGE. We have approached the problem of mapping IGE loci using non-parametric methods, which have recently been successful for other complex diseases. No evidence for linkage to chromosome 6p was obtained. However, we obtained evidence for involvement of a locus at chromosome 8q24, close to the marker D8S256. The same 8q24 region was previously implicated in families with benign neonatal familial convulsions (BNFC), a generalized epilepsy syndrome that is inherited as a simple dominant mendelian trait. There is an apparent conserved syntenic group of genes in human 8q24 and a region of mouse chromosome 15, which harbors the stargazer (stg) locus. Homozygous mutant mice at the stg locus show a form of generalized epilepsy that resembles human absence epilepsy. Our findings may have implications for a locus on 8q24 predisposing to IGE.

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10(-34)), rs1867277A (p=5.90×10(-24)), rs944289T (p=6.95×10(-7)), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (P(GG vs GT + TT)=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10(-13)) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (∼11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma., Author Summary Loss of vision from glaucoma, a common cause of blindness worldwide, is due to irreversible damage to the optic nerve. Current therapies cannot prevent glaucoma-related optic nerve disease and very little is known about the underlying responsible molecular events. Glaucoma patients affected by the “normal-pressure” subtype of glaucoma (NPG) have increased susceptibility to optic nerve degeneration. Although NPG has a high heritability, common predisposing genetic variants have not been identified. Therefore, we performed a meta-analysis of two independent genome-wide association studies for a common form of glaucoma, primary open angle glaucoma (POAG), followed by NPG subgroup analysis. We found that SNPs in the CDKN2BAS gene region on 9p21 and a highly conserved region with a probable regulatory function on 8q22 were associated with NPG and with optic nerve disease in a second type of glaucoma, exfoliation glaucoma. Both genomic regions are predicted to influence TGF-beta activity, and using whole-genome data we showed that the TGF-beta signaling pathway overall is associated with NPG. These results reveal new insights into the molecular pathogenesis of optic nerve disease in glaucoma and are an important step toward the development of preventative and protective therapies.

To highlight possible similarities and differences in receptor tyrosine kinase (RTK) and downstream signalling activation profiles between clear-cell sarcomas (CCS) and metastatic melanomas (MM), frozen, and paired-matched fixed samples of six CCS with EWSR1 rearrangement (EWSR1+), five CCS without EWSR1 rearrangement (EWSR1-), and seven MM were investigated by means of biochemical, immunohistochemical, FISH, molecular analyses, and immunofluorescence confocal microscopy. Fixed samples of a further 10 CCS and 14 MM were investigated by means of sequencing for BRAF, NRAS, and KRAS mutations and FISH analyses for the gain of chromosomes 22 and 8. RTK analysis of all CCS/MM samples showed activation of short-form (sf) recepteur d'origine nantais (RON) RTK and of PDGFRB, MET, and HER3. Analysis of downstream signaling revealed consistent phosphorylation patterns of PI3K/AKT, RSK, and the mTOR targets S6 and 4EBP1. Analysis of frozen and fixed material from 21 CCS and 21 MM showed the presence of the V600E BRAF mutation in 2/12 EWSR1+ and 3/9 EWSR1- CCS and 9/21 MM and demonstrated a significant (P < 0.001) correlation between the gain of chromosomes 22 and 8 and EWSR1- CCS. Our results show that BRAF mutation can also be present in CCS and support the proposed aberration of chromosomes 22 and 8 as a possibly useful nonrandom hallmark of EWSR1- CCS. Besides, they broaden the spectrum of the similarities of RTK pathway activation between CCS and MM, thus suggesting that new drugs found to be active in melanoma and RON inhibitors could have a role in CCS treatment. © 2011 Wiley Periodicals, Inc.

© 2011 BioMed Central Ltd. Two recent reports identify ZNF703 as an oncogene driving selection of frequent chromosome 8p12 amplifications in luminal B breast tumors. The estrogen-responsive ZNF703 gene encodes a transcriptional cofactor that, when overexpressed, induces cell proliferation and interferes with transforming growth factor beta signaling. In MCF7 cells, increased ZNF703 expression results in activation of genes involved in stem cell self-renewal - while in primary human mammary epithelial cells, ZNF703 increases the ratio of luminal to basal progenitors. Expression of the murine homolog of ZNF703 reduces cell adhesion and promotes metastasis. ZNF703 overexpression thus alters regulation of proliferation and differentiation in luminal B tumors.

Fibroblast growth factors (FGFs) are important signaling molecules which act during early vertebrate central nervous system development. FGF17, together with FGF8, is a key factor in the patterning of the mid-hindbrain region with a complex picture of spatiotemporal gene expression during the various stages of cerebellar development. Disruption or reduced expression of fgf17 in mice has been associated with cerebellar vermis abnormalities. We have identified a de novo 2.3-Mb deletion of chromosome 8p21.2-p21.3 in a girl with severe growth retardation, seizures, and classical Dandy-Walker malformation. Analysis of gene expression in blood lymphocytes and skin fibroblasts revealed markedly reduced levels of FGF17, which is located 1 Mb from the proximal deletion breakpoint. This is the first report of a human cerebellar malformation associated with transcriptional downregulation of the FGF17 gene.

Photoparoxysmal response (PPR) is considered to be a risk factor for idiopathic generalised epilepsy (IGE) and it has a strong genetic basis. Two genome-wide linkage studies have been published before and they identified loci for PPR at 6p21, 7q32, 13q13, 13q31 and 16p13. Here we combine these studies, augmented with additional families, in a mega-analysis of 100 families. Non-parametric linkage analysis identified three suggestive peaks for photosensitivity, two of which are novel (5q35.3 and 8q21.13) and one has been found before (16p13.3). We found no evidence for linkage at four previously detected loci (6p21, 7q32, 13q13 and 13q31).Our results suggest that the different family data sets are not linked to a shared locus. Detailed analysis showed that the peak at 16p13 was mainly supported by a single subset of families, while the peaks at 5q35 and 8q21 had weak support from multiple subsets.Family studies clearly support the role of PPR as a risk factor for IGE. This mega-analysis shows that distinct loci seem to be linked to subsets of PPR-positive families that may differ in subtle clinical phenotypes or geographic origin. Further linkage studies of PPR should therefore include in-depth phenotyping to make appropriate subsets and increase genetic homogeneity. (C) 2010 Elsevier B.V. All rights reserved.

2008 has brought us the first fruits from genomewide association studies (GWASs), an unbiased and comprehensive approach to identify common risk alleles for complex diseases of adulthood. By genotyping >310 000 single nucleotide polymorphisms (SNPs) in over 1700 intracranial aneurysm (IA) cases and 7400 controls from Finland and the Netherlands, a multinational team of investigators recently identified several common SNPs that showed significant association with IA.1 SNPs on chromosomes 2q, 8q and 9p were found to replicate in an independent sample from Japan with similar odds ratios (OR) in all 3 samples. Pooled OR were between 1.24 and 1.36, and analyses of the combined effects suggested a significant linear relationship with risk score in each cohort, with a more than 3-fold increase from the lowest to highest strata. Collectively, the 3 loci were calculated to account for 38% to 46% of the population–attributable fraction of IA, which is substantial. Although additional work in other ethnic groups is required, the consistency emphasizes the robustness of the findings. The critical genetic intervals on chromosomes 8q and 9p both harbor genes that are implicated in the regulation of stem (progenitor) cell populations and expressed in the adult vasculature. SOX17 , the main candidate gene on 8q, is required for both endothelial formation and maintenance—an interesting aspect when considering the predominant location of IA at arterial branch points and sites of endothelial shear stress. The association between common variants at 9p and IA had already been reported in another study earlier last year.2 The 9p21.3 region was originally identified as a major risk locus for coronary artery disease and myocardial infarction.3 Subsequent analyses revealed that the same chromosomal region is also implicated in the risk of IA and abdominal aortic aneurysms. The estimated risk for IA conferred by the main risk …

Inverted 8p duplication deletions are recurrent chromosomal rearrangements that are mediated through non-allelic homologous recombination (NAHR) between olfactory receptor (OR) gene clusters at 8p23.1. These rearrangements result in a proximal inverted duplication of various extent, a single copy region between the OR gene clusters and a terminal 8p deletion. The terminal deletions are stabilized by direct addition of telomeric repeats, so called telomere healing. Here, we report a patient with an unusual inverted duplication deletion of 8p. Stabilization of the broken chromosome end was achieved by telomere capture instead of telomere healing, resulting in an additional duplication of 8q24.13-->qter on the short arm of chromosome 8. Moreover, the inverted duplication was only 3.4 Mb in size (restricted to band 8p22) and thus cytogenetically undetectable. To the best of our knowledge this is the smallest inverted duplication reported hitherto. We describe the molecular characterization by FISH and array CGH of this unusual inv dup del (8p) and a previously reported patient with a similar 8q duplication and review the literature on cases associated with telomere capture.

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27–1.36)) than ER-negative (1.08 (1.03–1.14)) disease (P for heterogeneity = 10−13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10−5, 10−8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10−4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09–1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83–0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment., Author Summary This report from the Breast Cancer Association Consortium evaluates whether common variants in five recently identified breast cancer susceptibility loci (FGFR2, TNRC9, MAP3K1, 8q24, and LSP1) influence the clinical presentation of breast cancer and survival after diagnosis. We studied these susceptibility loci in relation to clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls of European or Asian origin from 20 studies. The association, with overall survival, was evaluated in 13,527 cases from 13 studies. The most notable findings were that the genetic variants in the fibroblast growth factor receptor 2 (FGFR2) gene and the 8q24 region were more strongly related to ER-positive than ER-negative disease, and to low rather than high grade tumors. The loci did not significantly influence survival after accounting for known prognostic factors. Analyses indicated that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative diseases are biologically distinct tumors. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

Much of the evolution of human behavior remains a mystery, including how certain disadvantageous behaviors are so prevalent. Nicotine addiction is one such phenotype. Several loci have been implicated in nicotine related phenotypes including the nicotinic receptor gene clusters (CHRNs) on chromosomes 8 and 15. Here we use 1000 Genomes sequence data from 3 populations (Africans, Asians and Europeans) to examine whether natural selection has occurred at these loci. We used Tajima's D and the integrated haplotype score (iHS) to test for evidence of natural selection. Our results provide evidence for strong selection in the nicotinic receptor gene cluster on chromosome 8, previously found to be significantly associated with both nicotine and cocaine dependence, as well as evidence selection acting on the region containing the CHRNA5 nicotinic receptor gene on chromosome 15, that is genome wide significant for risk for nicotine dependence. To examine the possibility that this selection is related to memory and learning, we utilized genetic data from the Collaborative Studies on the Genetics of Alcoholism (COGA) to test variants within these regions with three tests of memory and learning, the Wechsler Adult Intelligence Scale (WAIS) Block Design, WAIS Digit Symbol and WAIS Information tests. Of the 17 SNPs genotyped in COGA in this region, we find one significantly associated with WAIS digit symbol test results. This test captures aspects of reaction time and memory, suggesting that a phenotype relating to memory and learning may have been the driving force behind selection at these loci. This study could begin to explain why these seemingly deleterious SNPs are present at their current frequencies.

We present two cases of small B-cell lymphomas of particular diagnostic interest because the histological patterns were at variance with their immunophenotype. One of these lymphomas, involving the gallbladder and duodenum, showed a marginal zone lymphoma-like (MALT type) pattern of cellular infiltration with CD5 negativity but (unexpectedly) Cyclin D1 positivity. Fluorescence in situ hybridization analysis of this case was performed because of the aberrant expression of Cyclin D1, and was clearly positive for the Cyclin D1 gene translocation. The second case, occurring in a lymph node, showed the typical growth pattern of a follicular lymphoma but it had an atypical immunophenotype, namely, expression of Cyclin D1, CD10, and Bcl2 and focally Bcl6, accompanied by a lack of CD5 and CD23. The Cyclin D1 gene translocation was detected by fluorescence in situ hybridisation (FISH), whereas c-myc and Bcl2 genes translocation were absent. Numerical chromosomal changes, which were visualized for chromosomes 8, 11, and 18 could be correlated to the aberrant immunoprofile. In this context, we discuss the diagnostic value of Cyclin D1, CD5, CD23, CD10, Bcl6 markers revealed by immunohistochemistry, as well as the significance of detection by FISH of chromosomal translocations such as t(11;14) and t(14;18). The question still remains as to whether such cases should be designated as specific lymphoma entities or reported as unclassifiable and the chromosome aberration reported.

Hereditary spastic paraplegias are neurodegenerative disorders characterized clinically by progressive spasticity of the lower limbs; they are inherited as autosomal dominant, autosomal recessive and X-linked traits. We have analyzed four autosomal recessive HSP families gathered from southern Italy. We performed genetic analysis using microsatellite markers associated with SPG5, SPG7, SPG11 and SPG14. Positive lod scores were obtained with markers located on chromosome 8. The lod scores for the four combined families were significantly higher than 3 for D8S509, D8S1102, D8S1723 and D8S260 with a maximum two-point lod score at θ = 0 of 3.99 for the marker D8S260. In one of the examined families, the haplotype analysis suggests two key recombination events demonstrating that the gene is localized in the 11 cM region flanked by markers D8S285 and D8S544, refining the ARHSP region by approximately 22 cm. We also analyzed five candidate genes localized within the HSP region: TOX, syndecan-binding-protein (SDCBP), RAB2, CA8 and PENK, but we did not find disease causing mutations.

Purpose: A recent genome-wide scan revealed a major susceptibility locus for idiopathic generalized epilepsies (IGEs) in the chromosomal region 8p12 in 32 IGE families without members with juvenile myoclonic epilepsy (JME). This study explored the presence of an IGE locus in the chromosomal region 8p12.Methods: Our study included 176 multiplex families of probands with common IGE syndromes. Parametric and nonparametric multipoint linkage analyses were carried out between the IGE trait and six microsatellite polymorphisms encompassing the putative susceptibility locus. To explore the associated phenotype-genotype relation, two distinct subgroups of families were selected by the presence (n = 64) or absence (n = 112) of a family member with JME. To adjust the phenotypic spectrum toward adolescent-onset IGEs, a third subgroup of 28 families without JME was chosen through an IGE proband with seizure onset at age 10-20 years.Results: Parametric and nonparametric multipoint linkage analyses provided no evidence for linkage between IGE and markers encompassing the putative IGE locus in the chromosomal region 8p12. Furthermore, we found no hint of linkage along the candidate region in any of the three family subgroups.Conclusions: We failed to provide evidence for a major IGE locus in the chromosomal region 8p12. On the contrary, these parametric linkage results provide strong evidence against linkage across the candidate region under a broad range of genetic models. If there is a susceptibility locus for IGE in the chromosomal region 8p12, then the size of the effect or the proportion of linked families is too small to detect linkage in the investigated family sample.