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1.  Hiding in Plain View: An Ancient Dog in the Modern World 
Science (New York, N.Y.)  2014;343(6169):376-378.
PMCID: PMC5204361  PMID: 24458629
2.  Transmissible Tumors: Breaking the Cancer Paradigm 
Trends in genetics : TIG  2015;32(1):1-15.
Transmissible tumors are those that have transcended the bounds of their incipient hosts by evolving the ability to infect another individual through direct transfer of cancer cells; thus becoming parasitic cancer clones. Coitus, biting, and scratching are transfer mechanisms for the two primary species studied, the domestic dog (Canis lupus familiaris) and the Tasmanian devil (Sarcophilus harrisii). Canine transmissible venereal tumors (CTVT) are likely thousands of years old, and have successfully travelled from host to host around the world, while the Tasmanian devil facial tumor disease (DFTD) is much younger and geographically localized. The dog tumor is not necessarily lethal, while the devil tumor has driven the population to near extinction. Transmissible tumors are uniform in that they have complex immunologic profiles, which allow them to escape immune detection by their hosts, sometimes for long periods of time. In this review we explore how transmissible tumors in CTVT, DFTD, and as well as the soft-shelled clam and Syrian hamster can advance studies tumor biology.
PMCID: PMC4698198  PMID: 26686413
cancer; infectious; transmissible; clonal; canine; devil
3.  Epigenomic profiling of DNA methylation in paired prostate cancer versus adjacent benign tissue 
The Prostate  2015;75(16):1941-1950.
Aberrant DNA methylation may promote prostate carcinogenesis. We investigated epigenome-wide DNA methylation profiles in prostate cancer (PCa) compared to adjacent benign tissue to identify differentially methylated CpG sites.
The study included paired PCa and adjacent benign tissue samples from 20 radical prostatectomy patients. Epigenetic profiling was done using the Infinium HumanMethylation450 BeadChip. Linear models that accounted for the paired study design and False Discovery Rate Q-values were used to evaluate differential CpG methylation. mRNA expression levels of the genes with the most differentially methylated CpG sites were analyzed.
In total, 2,040 differentially methylated CpG sites were identified in PCa versus adjacent benign tissue (Q-value <0.001), the majority of which were hypermethylated (n = 1,946; 95%). DNA methylation profiles accurately distinguished between PCa and benign tissue samples. Twenty-seven top-ranked hypermethylated CpGs had a mean methylation difference of at least 40% between tissue types, which included 25 CpGs in 17 genes. Furthermore, for ten genes over 50% of promoter region CpGs were hypermethylated in PCa versus benign tissue. The top-ranked differentially methylated genes included three genes that were associated with both promoter hypermethylation and reduced gene expression: SCGB3A1, HIF3A, and AOX1. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings.
This study of PCa versus adjacent benign tissue showed many differentially methylated CpGs and regions in and outside gene promoter regions, which may potentially be used for the development of future epigenetic-based diagnostic tests or as therapeutic targets.
PMCID: PMC4928710  PMID: 26383847
Prostate cancer; DNA methylation; mRNA expression; tumor; benign
4.  Whole-genome sequence, SNP chips and pedigree structure: building demographic profiles in domestic dog breeds to optimize genetic-trait mapping 
Disease Models & Mechanisms  2016;9(12):1445-1460.
In the decade following publication of the draft genome sequence of the domestic dog, extraordinary advances with application to several fields have been credited to the canine genetic system. Taking advantage of closed breeding populations and the subsequent selection for aesthetic and behavioral characteristics, researchers have leveraged the dog as an effective natural model for the study of complex traits, such as disease susceptibility, behavior and morphology, generating unique contributions to human health and biology. When designing genetic studies using purebred dogs, it is essential to consider the unique demography of each population, including estimation of effective population size and timing of population bottlenecks. The analytical design approach for genome-wide association studies (GWAS) and analysis of whole-genome sequence (WGS) experiments are inextricable from demographic data. We have performed a comprehensive study of genomic homozygosity, using high-depth WGS data for 90 individuals, and Illumina HD SNP data from 800 individuals representing 80 breeds. These data were coupled with extensive pedigree data analyses for 11 breeds that, together, allowed us to compute breed structure, demography, and molecular measures of genome diversity. Our comparative analyses characterize the extent, formation and implication of breed-specific diversity as it relates to population structure. These data demonstrate the relationship between breed-specific genome dynamics and population architecture, and provide important considerations influencing the technological and cohort design of association and other genomic studies.
Summary: Successful application of whole-genome sequencing and genome-wide association studies for identifying both loci and mutations in canines is influenced by breed structure and demography, motivating researchers to generate breed-specific strategies for canine genetic studies.
PMCID: PMC5200897  PMID: 27874836
Population; Homozygosity; Canine; Inbreeding
5.  Epigenetic signature of Gleason score and prostate cancer recurrence after radical prostatectomy 
Clinical Epigenetics  2016;8:97.
Identifying the subset of patients with clinically localized prostate cancer (PCa) at the highest risk of recurrence remains challenging, and better prognostic markers are needed. Gleason score is the best predictor of PCa aggressiveness and prognosis. In the present study, we generated an epigenetic signature based on high versus low Gleason score tumors and evaluated its ability to predict recurrence after radical prostatectomy.
Genome-wide DNA methylation data from The Cancer Genome Atlas (TCGA; no. of patients = 333) and the elastic net method were used to generate an epigenetic signature by contrasting patients with high (8–10) versus low (≤6) Gleason score tumors. The signature was then tested in a cohort of 523 patients with clinically localized disease who had radical prostatectomy. Samples taken from the primary tumor were used for DNA methylation and mRNA expression profiling. Patients were followed for PCa recurrence on average for 8 years after diagnosis.
The epigenetic signature includes 52 differentially methylated CpG sites. In the testing cohort, the signature was associated with poorer recurrence-free survival (hazard ratio per 25 % increase = 1.78; 95 % confidence interval 1.48, 2.16). The signature significantly improved the area under the curve (AUC) for PCa recurrence compared to clinical-pathological parameters alone, particularly among patients diagnosed with Gleason score 7 tumors (0.64 vs. 0.76, P = 1.34E−4). Results were comparable for patients with Gleason 3 + 4 and those with 4 + 3 tumors. Gene Set Enrichment Analysis showed that higher levels of the signature were associated with increased expression of genes related to cell cycle proliferation and decreased expression of androgen-responsive genes.
This report shows evidence that DNA methylation patterns measured in prostate tumor cells are predictive of PCa aggressiveness. The epigenetic signature may have clinical utility to improve prognostication particularly in patients with intermediate Gleason score 7 tumors.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0260-z) contains supplementary material, which is available to authorized users.
PMCID: PMC5024414  PMID: 27651837
Clinically localized prostate cancer; Tumor tissue; DNA methylation; Gene expression; Risk prediction for prognosis; Genome-wide profiling; Elastic net regularization
6.  Expression of Cell Cycle-regulated Genes and Prostate Cancer Prognosis in a Population-based Cohort 
The Prostate  2015;75(13):1354-1362.
Prostate cancer (PCa) is clinically and biologically heterogeneous, making it difficult to predict at detection whether it will take an indolent or aggressive disease course. Cell cycle-regulated genes may be more highly expressed in actively dividing cells, with transcript levels reflecting tumor growth rate. Here we evaluated expression of cell cycle genes in relation to PCa outcomes in a population-based cohort.
Gene expression data were generated from tumor tissues obtained at radical prostatectomy for 383 population-based patients (12.3-years average follow-up). The overall mean and individual transcript levels of 30 selected cell cycle genes was compared between patients with no evidence of recurrence (73%) and those who recurred (27%) or died (7%) from PCa.
The multivariate adjusted hazard ratio (HR) for a change from the 25th to 75th percentile of mean gene expression level (range 8.02–10.05) was 1.25 (95% CI 0.96–1.63; P = 0.10) for PCa recurrence risk, and did not vary substantially by Gleason score, TMPRSS2-ERG fusion status, or family history of PCa. For lethal PCa, the HR for a change (25th to 75th percentile) in mean gene expression level was 2.04 (95% CI 1.26–3.31; P = 0.004), adjusted for clinicopathological variables. The ROC curve for mean gene expression level alone (AUC = 0.740) did not perform as well as clinicopathological variables alone (AUC = 0.803) for predicting lethal PCa, and the addition of gene expression to clinicopathological variables did not substantially improve prediction (AUC = 0.827; P = 0.18). Higher TK1 expression was strongly associated with both recurrent (P = 6.7×10−5) and lethal (P = 6.4×10−6) PCa.
Mean expression level for 30 selected cell cycle-regulated genes was unrelated to recurrence risk, but was associated with a two-fold increase in risk of lethal PCa. However, gene expression had less discriminatory accuracy than clinical variables alone for predicting lethal events. Transcript levels for several genes in the panel were significantly overexpressed in lethal vs. non-recurrent PCa.
PMCID: PMC4992473  PMID: 25990700
cell cycle-regulated genes; gene expression; patient outcomes; population-based cohort; prostate cancer
7.  Commonalities in Development of Pure Breeds and Population Isolates Revealed in the Genome of the Sardinian Fonni's Dog 
Genetics  2016;204(2):737-755.
The island inhabitants of Sardinia have long been a focus for studies of complex human traits due to their unique ancestral background and population isolation reflecting geographic and cultural restriction. Population isolates share decreased genomic diversity, increased linkage disequilibrium, and increased inbreeding coefficients. In many regions, dogs and humans have been exposed to the same natural and artificial forces of environment, growth, and migration. Distinct dog breeds have arisen through human-driven selection of characteristics to meet an ideal standard of appearance and function. The Fonni’s Dog, an endemic dog population on Sardinia, has not been subjected to an intensive system of artificial selection, but rather has developed alongside the human population of Sardinia, influenced by geographic isolation and unregulated selection based on its environmental adaptation and aptitude for owner-desired behaviors. Through analysis of 28 dog breeds, represented with whole-genome sequences from 13 dogs and ∼170,000 genome-wide single nucleotide variants from 155 dogs, we have produced a genomic illustration of the Fonni’s Dog. Genomic patterns confirm within-breed similarity, while population and demographic analyses provide spatial identity of Fonni’s Dog to other Mediterranean breeds. Investigation of admixture and fixation indices reveals insights into the involvement of Fonni’s Dogs in breed development throughout the Mediterranean. We describe how characteristics of population isolates are reflected in dog breeds that have undergone artificial selection, and are mirrored in the Fonni’s Dog through traditional isolating factors that affect human populations. Lastly, we show that the genetic history of Fonni’s Dog parallels demographic events in local human populations.
PMCID: PMC5068859  PMID: 27519604
dog; whole-genome sequence; demography; population structure
8.  Homologous Mutation to Human BRAF V600E is Common in Naturally Occurring Canine Bladder Cancer—Evidence for a Relevant Model System and Urine-based Diagnostic Test 
Molecular cancer research : MCR  2015;13(6):993-1002.
Targeted cancer therapies offer great clinical promise, but treatment resistance is common, and basic research aimed at overcoming this challenge is limited by reduced genomic and biological complexity in artificially induced rodent tumors compared to their human counterparts. Animal models that more faithfully recapitulate genotype-specific human pathology could improve the predictive value of these investigations. Here, a newly identified animal model for oncogenic BRAF-driven cancers is described. With 20,000 new cases in the United States each year, canine invasive transitional cell carcinoma of the bladder (InvTCC) is a common, naturally occurring malignancy that shares significant histological, biological, and clinical phenotypes with human muscle invasive bladder cancer. In order to identify somatic drivers of canine InvTCC, the complete transcriptome for multiple tumors was determined by RNAseq. All tumors harbored a somatic mutation that is homologous to the human BRAF(V600E) mutation, and an identical mutation was present in 87% of 62 additional canine InvTCC tumors. The mutation was also detectable in the urine sediments of all dogs tested with mutation-positive tumors. Functional experiments suggest that, like human tumors, canine activating BRAF mutations potently stimulate the mitogen activated protein kinase (MAPK) pathway. Cell lines with the mutation have elevated levels of phosphorylated MEK, compared to a line with wild type BRAF. This effect can be diminished through application of the BRAF(V600E) inhibitor vemurafenib. These findings set the stage for canine InvTCC as a powerful system to evaluate BRAF-targeted therapies, as well as therapies designed to overcome resistance, which could enhance treatment of both human and canine cancers
PMCID: PMC4470794  PMID: 25767210
Bladder Cancer; BRAF Mutation; Comparative Oncology; Canine Cancer
9.  Confirmation of Genetic Variants Associated with Lethal Prostate Cancer in a Cohort of Men from Hereditary Prostate Cancer Families 
Germline genetic variants have been suggested as prognostic biomarkers for identifying patients at high risk for lethal prostate cancer (PCa). Validation studies have confirmed the association of several single nucleotide polymorphisms (SNPs) with fatal PCa, but whether these variants affect PCa-specific mortality (PCSM) in patients with an inherited predisposition to PCa, based on familial history, is unknown. For this study, a cohort of 957 PCa patients from 270 hereditary prostate cancer (HPC) families of European ancestry was genotyped for a panel of 22 PCSM-associated SNPs. Death certificates were reviewed to confirm cause of death. Mixed-effect Cox proportional hazards models were used to assess survival according to genotypes, accounting for relatedness and clinicopathological factors. Within this cohort, 98 PCa deaths were confirmed over an average follow-up period of 12.7 years after diagnosis. Variant allele carriers for three SNPs had significantly altered risk for PCSM (rs635261 at RNASEL, HR, 0.35, 95% CI, 0.18–0.66; P = 0.002; rs915927 in XRCC1, HR, 1.91, 95% CI, 1.21–3.02; P = 0.009; and rs2494750 at AKT1, HR, 0.45, 95% CI, 0.23–0.90; P = 0.016). These results confirm the association of genetic variation in three genes with PCa lethality in a cohort of men with an inherited susceptibility to the disease and provide validation evidence that germline SNPs provide prognostic information for PCa patients. Development of a panel of germline biomarkers with clinical utility for distinguishing patients at detection who have an increased risk for fatal PCa is warranted.
PMCID: PMC4331209  PMID: 25273821
Hereditary prostate cancer; mortality; SNPs; XRCC1; AKT1
11.  Demographically-Based Evaluation of Genomic Regions under Selection in Domestic Dogs 
PLoS Genetics  2016;12(3):e1005851.
Controlling for background demographic effects is important for accurately identifying loci that have recently undergone positive selection. To date, the effects of demography have not yet been explicitly considered when identifying loci under selection during dog domestication. To investigate positive selection on the dog lineage early in the domestication, we examined patterns of polymorphism in six canid genomes that were previously used to infer a demographic model of dog domestication. Using an inferred demographic model, we computed false discovery rates (FDR) and identified 349 outlier regions consistent with positive selection at a low FDR. The signals in the top 100 regions were frequently centered on candidate genes related to brain function and behavior, including LHFPL3, CADM2, GRIK3, SH3GL2, MBP, PDE7B, NTAN1, and GLRA1. These regions contained significant enrichments in behavioral ontology categories. The 3rd top hit, CCRN4L, plays a major role in lipid metabolism, that is supported by additional metabolism related candidates revealed in our scan, including SCP2D1 and PDXC1. Comparing our method to an empirical outlier approach that does not directly account for demography, we found only modest overlaps between the two methods, with 60% of empirical outliers having no overlap with our demography-based outlier detection approach. Demography-aware approaches have lower-rates of false discovery. Our top candidates for selection, in addition to expanding the set of neurobehavioral candidate genes, include genes related to lipid metabolism, suggesting a dietary target of selection that was important during the period when proto-dogs hunted and fed alongside hunter-gatherers.
Author Summary
Identification of the genomic regions under selection during dog domestication is extremely challenging because the demographic fluctuations associated with domestication can produce signals in polymorphism data that mimic those imposed by selective sweeps. We perform the first analysis of selection on the dog lineage that explicitly incorporates a demographic model, that by controlling for the rate of false discovery, more robustly identifies targets of selection. To do so, we conduct a selection scan using three wolf genomes representing the putative centers of dog domestication, two basal dog breeds (Basenji and Dingo), and a golden jackal as outgroup, for which we previously inferred a demographic model. We find that our demographically informed analyses filters out many signals that would be otherwise classified as putative selection signals under an empirical outlier approach. We identify 68 regions of the genome that have likely experienced positive selection. Besides identifying a number of new neurobehavioral candidate genes, our candidate regions contain genes related to lipid metabolism, including CCRN4L, which is centered in the 3rd ranked region. This suggests a previously unreported locus of dietary adaptation, potentially due to the change in diet composition as hunting efficiency increased when proto dogs began hunting alongside hunter-gatherers.
PMCID: PMC4778760  PMID: 26943675
12.  Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci 
Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa.
We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history.
The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2–5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09).
Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.
We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.
PMCID: PMC4491026  PMID: 25837820
Prostate Cancer risk; Genetic and Molecular Epidemiology; Genitourinary Cancers: Prostate; Risk Assessment; Methodology; Modelling and biostatistics; Methodology for SNP data analysis; Statistical methods in Genetics
13.  Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci 
Genome-wide association studies have identified multiple genetic variants associated with prostate cancer (PrCa) risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of PrCa.
We genotyped 25 PrCa susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical Odds Ratios for PrCa associated with different risk strata defined by PRS and derived age-specific absolute risks of developing PrCa by PRS stratum and family history.
The PrCa risk for men in the top 1% of the PRS distribution was 30.6 (95% CI 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI 3.2-5.5) fold compared with the median risk. The absolute risk of PrCa by age 85 was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation=0.09).
Risk profiling can identify men at substantially increased or reduced risk of PrCa. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of PrCa. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles.
We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.
PMCID: PMC4491026  PMID: 25837820
Prostate Cancer risk; Genetic and Molecular Epidemiology; Genitourinary Cancers: Prostate; Risk Assessment; Methodology; Modelling and biostatistics; Methodology for SNP data analysis; Statistical methods in Genetics
14.  Epigenomic profiling of prostate cancer identifies differentially methylated genes in TMPRSS2:ERG fusion-positive versus fusion-negative tumors 
Clinical Epigenetics  2015;7:128.
About half of all prostate cancers harbor the TMPRSS2:ERG (T2E) gene fusion. While T2E-positive and T2E-negative tumors represent specific molecular subtypes of prostate cancer (PCa), previous studies have not yet comprehensively investigated how these tumor subtypes differ at the epigenetic level. We therefore investigated epigenome-wide DNA methylation profiles of PCa stratified by T2E status.
The study included 496 patients with clinically localized PCa who had a radical prostatectomy as primary treatment for PCa. Fluorescence in situ hybridization (FISH) “break-apart” assays were used to determine tumor T2E-fusion status, which showed that 266 patients (53.6 %) had T2E-positive PCa. The study showed global DNA methylation differences between tumor subtypes. A large number of differentially methylated CpG sites were identified (false-discovery rate [FDR] Q-value <0.00001; n = 27,876) and DNA methylation profiles accurately distinguished between tumor T2E subgroups. A number of top-ranked differentially methylated CpGs in genes (FDR Q-values ≤1.53E−29) were identified: C3orf14, CACNA1D, GREM1, KLK10, NT5C, PDE4D, RAB40C, SEPT9, and TRIB2, several of which had a corresponding alteration in mRNA expression. These genes may have various roles in the pathogenesis of PCa, and the calcium-channel gene CACNA1D is a known ERG-target. Analysis of The Cancer Genome Atlas (TCGA) data provided confirmatory evidence for our findings.
This study identified substantial differences in DNA methylation profiles of T2E-positive and T2E-negative tumors, thereby providing further evidence that different underlying oncogenic pathways characterize these molecular subtypes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-015-0161-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4676897  PMID: 26692910
DNA methylation; CpG site; Epigenetics; Epigenomic profiling; Prostate cancer; Gene fusion; TMPRSS2; ERG; Tumor tissue; Unsupervised clustering; mRNA expression; C3orf14; CACNA1D; GREM1; KLK10; NT5C; PDE4D; RAB40C; SEPT9; TRIB2; TCGA
15.  Two Susceptibility Loci Identified for Prostate Cancer Aggressiveness 
Nature communications  2015;6:6889.
Most men diagnosed with prostate cancer will experience indolent disease; hence discovering genetic variants that distinguish aggressive from non-aggressive prostate cancer is of critical clinical importance for disease prevention and treatment. In a multistage, case-only genome-wide association study of 12,518 prostate cancer cases, we identify two loci associated with Gleason score, a pathological measure of disease aggressiveness: rs35148638 at 5q14.3 (RASA1, P=6.49×10-9) and rs78943174 at 3q26.31 (NAALADL2, P=4.18×10-8). In a stratified case-control analysis, the SNP at 5q14.3 appears specific for aggressive prostate cancer (P=8.85×10-5) with no association for non-aggressive prostate cancer compared to controls (P=0.57). The proximity of these loci to genes involved in vascular disease suggests potential biological mechanisms worthy of further investigation.
PMCID: PMC4422072  PMID: 25939597
16.  Comprehensive Analysis of Pathogenic Deletion Variants in Fanconi Anemia Genes 
Human mutation  2014;35(11):1342-1353.
Fanconi anemia (FA) is a rare recessive disease resulting from mutations in one of at least 16 different genes. Mutation types and phenotypic manifestations of FA are highly heterogeneous and influence the clinical management of the disease. We analyzed 202 FA families for large deletions, using high-resolution Comparative Genome Hybridization arrays (arrayCGH), Single Nucleotide Polymorphism arrays (SNParrays) and DNA sequencing. We found pathogenic deletions in 88 FANCA, seven FANCC, two FANCD2, and one FANCB families. We find 35% of FA families carry large deletions, accounting for 18% of all FA pathogenic variants. Cloning and sequencing across the deletion breakpoints revealed that 52 FANCA deletion ends, and one FANCC deletion end extended beyond the gene boundaries, potentially affecting neighboring genes with phenotypic consequences. Seventy-five percent of the FANCA deletions are Alu-Alu mediated, predominantly by AluY elements, and appear to be caused by Non-Allelic Homologous Recombination. Individual Alu hotspots were identified. Defining the haplotypes of four FANCA deletions shared by multiple families revealed that three share a common ancestry. Knowing the exact molecular changes that lead to the disease may be critical for a better understanding of the FA phenotype, and to gain insight into the mechanisms driving these pathogenic deletion variants.
PMCID: PMC4407816  PMID: 25168418
Fanconi anemia; array CGH; FANCA; FANCB; FANCC; FANCD2
17.  Validation study of genes with hypermethylated promoter regions associated with prostate cancer recurrence 
One challenge in prostate cancer (PCa) is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in PCa, but few studies of DNA methylation in relation to features of more aggressive tumors or PCa recurrence have been completed.
We used the Infinium® HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized PCa who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the SEER registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared to those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined.
During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared to those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46x10−6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2×10−4). DNA methylation profiles did not differ by recurrence status for the other genes.
These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and PCa recurrence.
Tumor DNA methylation profiling may help distinguish PCa patients at higher risk for disease recurrence.
PMCID: PMC4082437  PMID: 24718283
DNA methylation; prostate cancer recurrence; hypermethylation; HOXD3
18.  Methodological Considerations in Estimation of Phenotype Heritability Using Genome-Wide SNP Data, Illustrated by an Analysis of the Heritability of Height in a Large Sample of African Ancestry Adults 
PLoS ONE  2015;10(6):e0131106.
Height has an extremely polygenic pattern of inheritance. Genome-wide association studies (GWAS) have revealed hundreds of common variants that are associated with human height at genome-wide levels of significance. However, only a small fraction of phenotypic variation can be explained by the aggregate of these common variants. In a large study of African-American men and women (n = 14,419), we genotyped and analyzed 966,578 autosomal SNPs across the entire genome using a linear mixed model variance components approach implemented in the program GCTA (Yang et al Nat Genet 2010), and estimated an additive heritability of 44.7% (se: 3.7%) for this phenotype in a sample of evidently unrelated individuals. While this estimated value is similar to that given by Yang et al in their analyses, we remain concerned about two related issues: (1) whether in the complete absence of hidden relatedness, variance components methods have adequate power to estimate heritability when a very large number of SNPs are used in the analysis; and (2) whether estimation of heritability may be biased, in real studies, by low levels of residual hidden relatedness. We addressed the first question in a semi-analytic fashion by directly simulating the distribution of the score statistic for a test of zero heritability with and without low levels of relatedness. The second question was addressed by a very careful comparison of the behavior of estimated heritability for both observed (self-reported) height and simulated phenotypes compared to imputation R2 as a function of the number of SNPs used in the analysis. These simulations help to address the important question about whether today's GWAS SNPs will remain useful for imputing causal variants that are discovered using very large sample sizes in future studies of height, or whether the causal variants themselves will need to be genotyped de novo in order to build a prediction model that ultimately captures a large fraction of the variability of height, and by implication other complex phenotypes. Our overall conclusions are that when study sizes are quite large (5,000 or so) the additive heritability estimate for height is not apparently biased upwards using the linear mixed model; however there is evidence in our simulation that a very large number of causal variants (many thousands) each with very small effect on phenotypic variance will need to be discovered to fill the gap between the heritability explained by known versus unknown causal variants. We conclude that today's GWAS data will remain useful in the future for causal variant prediction, but that finding the causal variants that need to be predicted may be extremely laborious.
PMCID: PMC4488332  PMID: 26125186
19.  Association analysis of 9,560 prostate cancer cases from the International Consortium of Prostate Cancer Genetics confirms the role of reported prostate-cancer associated SNPs for familial disease 
Human genetics  2013;133(3):347-356.
Previous GWAS studies have reported significant associations between various common SNPs and prostate cancer risk using cases unselected for family history. How these variants influence risk in familial prostate cancer is not well studied. Here, we analyzed 25 previously reported SNPs across 14 loci from prior prostate cancer GWAS. The International Consortium for Prostate Cancer Genetics (ICPCG) previously validated some of these using a family-based association method (FBAT). However, this approach suffered reduced power due to the conditional statistics implemented in FBAT. Here, we use a case-control design with an empirical analysis strategy to analyze the ICPCG resource for association between these 25 SNPs and familial prostate cancer risk. Fourteen sites contributed 12,506 samples (9,560 prostate cancer cases, 3,368 with aggressive disease, and 2,946 controls from 2,283 pedigrees). We performed association analysis with Genie software which accounts for relationships. We analyzed all familial prostate cancer cases and the subset of aggressive cases. For the familial prostate cancer phenotype, 20 of the 25 SNPs were at least nominally associated with prostate cancer and 16 remained significant after multiple testing correction (p≤1E−3) occurring on chromosomal bands 6q25, 7p15, 8q24, 10q11, 11q13, 17q12, 17q24, and Xp11. For aggressive disease, 16 of the SNPs had at least nominal evidence and 8 were statistically significant including 2p15. The results indicate that the majority of common, low-risk alleles identified in GWAS studies for all prostate cancer also contribute risk for familial prostate cancer, and that some may be contribute risk to aggressive disease.
PMCID: PMC3945961  PMID: 24162621
prostate cancer; pedigrees; familial disease; simulation; replication
20.  Domestic Dogs and Cancer Research: A Breed-Based Genomics Approach 
ILAR Journal  2014;55(1):59-68.
Domestic dogs are unique from other animal models of cancer in that they generally experience spontaneous disease. In addition, most types of cancer observed in humans are found in dogs, suggesting that canines may be an informative system for the study of cancer genetics. Domestic dogs are divided into over 175 breeds, with members of each breed sharing significant phenotypes. The breed barrier enhances the utility of the model, especially for genetic studies where small numbers of genes are hypothesized to account for the breed cancer susceptibility. These facts, combined with recent advances in high-throughput sequencing technologies allows for an unrivaled ability to use pet dog populations to find often subtle mutations that promote cancer susceptibility and progression in dogs as a whole. The meticulous record keeping associated with dog breeding makes the model still more powerful, as it facilitates both association analysis and family-based linkage studies. Key to the success of these studies is their cooperative nature, with owners, scientists, veterinarians and breed clubs working together to avoid the cost and unpopularity of developing captive populations. In this article we explore these principals and advocate for colony-free, genetic studies that will enhance our ability to diagnose and treat cancer in dogs and humans alike.
PMCID: PMC4158346  PMID: 24936030
canine cancer; chip-seq, dog colony; exome; histiocytic sarcoma; osteosarcoma; RNA-seq; squamous cell carcinoma of the digit; transitional cell carcinoma; tumor sequencing; whole genome
21.  Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression 
Kote-Jarai, Zsofia | Saunders, Edward J. | Leongamornlert, Daniel A. | Tymrakiewicz, Malgorzata | Dadaev, Tokhir | Jugurnauth-Little, Sarah | Ross-Adams, Helen | Al Olama, Ali Amin | Benlloch, Sara | Halim, Silvia | Russell, Roslin | Dunning, Alison M. | Luccarini, Craig | Dennis, Joe | Neal, David E. | Hamdy, Freddie C. | Donovan, Jenny L. | Muir, Ken | Giles, Graham G. | Severi, Gianluca | Wiklund, Fredrik | Gronberg, Henrik | Haiman, Christopher A. | Schumacher, Fredrick | Henderson, Brian E. | Le Marchand, Loic | Lindstrom, Sara | Kraft, Peter | Hunter, David J. | Gapstur, Susan | Chanock, Stephen | Berndt, Sonja I. | Albanes, Demetrius | Andriole, Gerald | Schleutker, Johanna | Weischer, Maren | Canzian, Federico | Riboli, Elio | Key, Tim J. | Travis, Ruth C. | Campa, Daniele | Ingles, Sue A. | John, Esther M. | Hayes, Richard B. | Pharoah, Paul | Khaw, Kay-Tee | Stanford, Janet L. | Ostrander, Elaine A. | Signorello, Lisa B. | Thibodeau, Stephen N. | Schaid, Dan | Maier, Christiane | Vogel, Walther | Kibel, Adam S. | Cybulski, Cezary | Lubinski, Jan | Cannon-Albright, Lisa | Brenner, Hermann | Park, Jong Y. | Kaneva, Radka | Batra, Jyotsna | Spurdle, Amanda | Clements, Judith A. | Teixeira, Manuel R. | Govindasami, Koveela | Guy, Michelle | Wilkinson, Rosemary A. | Sawyer, Emma J. | Morgan, Angela | Dicks, Ed | Baynes, Caroline | Conroy, Don | Bojensen, Stig E. | Kaaks, Rudolf | Vincent, Daniel | Bacot, François | Tessier, Daniel C. | Easton, Douglas F. | Eeles, Rosalind A.
Human Molecular Genetics  2013;22(20):4239.
PMCID: PMC3871151
22.  Germline Missense Variants in the BTNL2 Gene Are Associated with Prostate Cancer Susceptibility 
Rare, inherited mutations account for 5%–10% of all prostate cancer (PCa) cases. However, to date, few causative mutations have been identified.
To identify rare mutations for PCa, we performed whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 PCa cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case-control study (n = 1,155 incident PCa cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry.
The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated PCa risk in the population-based study (rs41441651: OR = 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR = 2.5; 95% CI, 1.16–5.46; P = 0.019).
Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer.
Results implicate BTNL2 as a novel PCa susceptibility gene.
PMCID: PMC3769499  PMID: 23833122
23.  Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer 
Prostate cancer (PC) is the most common noncutaneous cancer in men, and epidemiological studies suggest that about 40% of PC risk is heritable. Linkage analyses in hereditary PC families have identified multiple putative loci. However, until recently, identification of specific risk alleles has proven elusive. Cooney et al used linkage mapping and segregation analysis to identify a putative risk locus on chromosome 17q21-22. In search of causative variant(s) in genes from the candidate region, a novel, potentially deleterious G84E substitution in homeobox transcription factor gene HOXB13 was observed in multiple hereditary PC families. In follow-up testing, the G84E allele was enriched in cases, especially those with an early diagnosis or positive family history of disease. This finding was replicated by others, confirming HOXB13 as a PC risk gene. The HOXB13 protein plays diverse biological roles in embryonic development and terminally differentiated tissue. In tumor cell lines, HOXB13 participates in a number of biological functions, including coactivation and localization of the androgen receptor and FOXA1. However, no consensus role has emerged and many questions remain. All HOXB13 variants with a proposed role in PC risk are predicted to damage the protein and lie in domains that are highly conserved across species. The G84E variant has the strongest epidemiological support and lies in a highly conserved MEIS protein-binding domain, which binds cofactors required for activation. On the basis of epidemiological and biological data, the G84E variant likely modulates the interaction between the HOXB13 protein and the androgen receptor, as well as affecting FOXA1-mediated transcriptional programming. However, further studies of the mutated protein are required to clarify the mechanisms by which this translates into PC risk.
PMCID: PMC4157396  PMID: 25206306
prostate cancer risk; HOXB13
24.  HOXB13 Mutations in a Population-Based, Case Control Study of Prostate Cancer 
The Prostate  2012;73(6):634-641.
Prostate cancer (PC) is the most frequently diagnosed non-skin malignancy in men in the Western world, yet few disease-associated mutations have been found. Recently, a low frequency recurring mutation in the HOXB13 gene was reported among both hereditary PC families and men from the general population.
We determined the distribution and frequency of the G84E HOXB13 variant in 1,310 incipient PC cases and 1,259 age-mated controls from a population-based, case control study of PC.
The G84E mutation was more frequent in cases than controls (1.3% versus 0.4%, respectively), and men with the HOXB13 G84E variant had a 3.3-fold higher relative risk of PC compared with noncarriers (95% CI, 1.21–8.96). There was a stronger association between the G84E variant and PC among men with no first-degree relative with PC (OR, 4.04; 95% CI, 1.12–14.51) compared to men with a family history of PC (OR, 1.49; 95% CI, 0.30–7.50; p=0.36 for interaction). We observed some evidence of higher risk estimates associated with the variant for men with higher versus lower Gleason score (OR, 4.13; 95% CI, 1.38–12.38 vs OR, 2.71; 95% CI, 0.88–8.30), and advanced versus local stage (OR, 4.47; 95% CI, 1.28–15.57 vs OR, 2.98; 95% CI, 1.04–8.49), however these differences were not statistically different.
These results confirm the association of a rare HOXB13 mutation with PC in the general population and suggest that this variant may be associated with features of more aggressive disease.
PMCID: PMC3612366  PMID: 23129385
polymorphism; prostate neoplasm; genetic susceptibility
25.  Variation in selenoenzyme genes and prostate cancer risk and survival 
The Prostate  2012;73(7):10.1002/pros.22617.
While several studies showed that selenium may prevent prostate cancer (PCa), few studies have evaluated variation in selenoenzyme genes in relation to PCa risk and survival.
We studied common variants in seven selenoenzymes genes in relation to risk of PCa and PCa-specific mortality (PCSM). In a population-based case-control study of men of European ancestry (1,309 cases, 1,266 controls), we evaluated 35 common, tagging single nucleotide polymorphisms (SNPs) in GPX1 (n = 2), GPX2 (n = 4), GPX3 (n = 6), GPX4 (n = 6), SEP15 (n = 4), SEPP1 (n = 6), and TXNRD1 (n = 7) in relation to PCa risk, and among cases, associations between these variants and risk of PCSM. We used logistic regression and Cox proportional hazards regression to estimate the relative risk of PCa and PCSM, respectively.
Of the SNPs examined, only GPX1 rs3448 was associated with overall PCa risk with an odds ratio of 0.62 for TT versus CC (95% confidence interval, 0.44–0.88). SNPs in GPX2, GPX3, GPX4, SEP15, and SEPP1 had different risk estimates for PCa in subgroups based on stage and grade. We observed associations between SNPs in GPX4 and TXNRD1 and risk of PCSM. None of these associations, however, remained significant after adjustment for multiple comparisons.
We found evidence that genetic variation in a subset of selenoenzyme genes may alter risk of PCa and PCSM. These results need validation in additional subsets.
PMCID: PMC3859305  PMID: 23143801
prostate cancer; risk; mortality; selenoenzyme genes; genetic variation

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