Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to evaluate the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for US-males aged 50-years. Six out of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P=7×10-4) and UGT1A6 (P=8×10-4). The 30-year absolute risk of bladder cancer in US males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile, compared to 2,000 cases prevented by a similar effort in the lowest PRS quartile (P-additive =1×10-4). The impact of eliminating smoking the on number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.
To fine-map common pancreatic cancer susceptibility regions.
We conducted targeted Roche-454 re-sequencing across 428 kb in three genomic regions identified in genome-wide association studies (GWAS) of pancreatic cancer, on chromosomes 1q32.1, 5p15.33 and 13q22.1.
An analytical pipeline for calling genotypes was developed using HapMap samples sequenced on chr5p15.33. Concordance to 1000 Genomes data for chr5p15.33 was >96%. The concordance for chr1q32.1 and chr13q22.1 with pancreatic cancer GWAS data was >99%. Between 9.2–19.0% of variants detected were not present in 1000 Genomes for the respective continental population. The majority of completely novel SNPs were less common (MAF ≤ 5%) or rare (MAF ≤ 2%), illustrating the value of enlarging test sets for discovery of less common variants. Using the dataset, we examined haplotype blocks across each region using a tag SNP analysis (r2 >0.8 for MAF ≥5%) and determined that at least 196, 243 and 63 SNPs are required for fine-mapping chr1q32.1, chr5p15.33, and chr13q22.1, respectively, in European populations.
We have characterized germline variation in three regions associated with pancreatic cancer risk and show that targeted re-sequencing leads to the discovery of novel variants and improves the completeness of germline sequence variants for fine-mapping GWAS susceptibility loci.
pancreatic cancer; targeted re-sequencing; GWAS; susceptibility loci; SNP; 1000G
Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan).
The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case–control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer.
Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2–8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52).
These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation.
Diabetes; Risk factor; Cohort consortium; Pancreatic cancer
Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma.
We analyzed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1,005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (P≤10−5) were advanced to a joint analysis with 363 additional patients from China (ChinaPC).
In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21, and 1p36.13, tagged by rs12362504 (P=1.63×10−7), rs981621 (P=1.65×10−7), and rs16861827 (P=3.75×10−7), respectively. One-hundred thirty-one SNPs with P ≤ 10−5 were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; P=1.72×10−7) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The hazard ratio (95% CI) for death was 0.74 (0.66–0.84) in PanScan I, 0.79 (0.65–0.97) in ChinaPC, and 0.76 (0.68–0.84) in the joint analysis.
Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.
Pancreatic cancer; GWAS; single nucleotide polymorphism; SET binding factor 2
Epidemiologic studies have shown consistent associations between obesity and increased thyroid cancer risk, but, to date, no studies have investigated the relationship between thyroid cancer risk and obesity-related single nucleotide polymorphisms (SNPs).
We evaluated 575 tag SNPs in 23 obesity-related gene regions in a case-control study of 341 incident papillary thyroid cancer (PTC) cases and 444 controls of European ancestry. Logistic regression models, adjusted for attained age, year of birth, and sex were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) with SNP genotypes, coded as 0, 1, and 2 and modeled continuously to calculate P-trends.
Nine out of 10 top-ranking SNPs (Ptrend<0.01) were located in the FTO (fat mass and obesity associated) gene region, while the other was located in INSR (insulin receptor). None of the associations were significant after correcting for multiple testing.
Our data do not support an important role of obesity-related genetic polymorphisms in determining the risk of PTC.
Factors other than selected genetic polymorphisms may be responsible for the observed associations between obesity and increased PTC risk.
single nucleotide polymorphisms; case-control study; obesity; body mass index; thyroid neoplasms
There is growing evidence linking genetic variations to non–Hodgkin lymphoma (NHL) etiology. To complement ongoing agnostic approaches for identifying susceptibility genes, we evaluated 488 candidate gene regions and their relation to risk for NHL and NHL subtypes.
We genotyped 6,679 tag single nucleotide polymorphisms (SNPs) in 947 cases and 826 population-based controls from a multicenter U.S. case–control study. Gene-level summary of associations were obtained by computing the minimum P value (“minP test”) on the basis of 10,000 permutations. We used logistic regression to evaluate the association between genotypes and haplotypes with NHL. For NHL subtypes, we conducted polytomous multivariate unconditional logistic regression (adjusted for sex, race, age). We calculated P-trends under the codominant model for each SNP.
Fourteen gene regions were associated with NHL (P < 0.01). The most significant SNP associated with NHL maps to the SYK gene (rs2991216, P-trend = 0.00005). The three most significant gene regions were on chromosome 6p21.3 (RING1/RXRB; AIF1; BAT4). Accordingly, SNPs in RING1/RXRB (rs2855429), AIF1 (rs2857597), and BAT4 (rs3115667) were associated with NHL (P-trends ≤ 0.0002) and both diffuse large B-cell and follicular lymphomas (P-trends < 0.05).
Our results suggest potential importance for SYK on chromosome 9 with NHL etiology. Our results further implicate 6p21.3 gene variants, supporting the need for full characterization of this chromosomal region in relation to lymphomagenesis.
Gene variants on chromosome 9 may represent a new region of interesting for NHL etiology. The independence of the reported variants in 6p21.3 from implicated variants (TNF/HLA) supports the need to confirm causal variants in this region
To design a simple matching acuity test based on hand gestures that is minimally dependent on familiarity with symbols and letters. The visual acuity results obtained from children using the Handy Eye Chart™ were compared with results obtained with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.
Evaluation of diagnostic test or technology.
60 children between 6 and 16 years of age were recruited consecutively from the Pediatric Ophthalmology section of the Emory Eye Center.
Monocular visual acuity was tested using both the new eye chart and the ETDRS chart, alternating the order of administration between subjects. Testing was performed on the subject’s eye with the poorest acuity.
Main Outcome Measures
Outcome measures were monocular logarithm of the minimum angle of resolution (logMAR) visual acuity scores for each chart.
The acuities were shown to have a strong linear correlation (r = 0.95) and a mean difference in acuity of −0.03 (95% confidence interval −0.05 to −0.01) logMAR, equivalent to approximately 1.5 letters, with the new eye chart underestimating the vision as determined by the ETDRS chart. The 95% limits of agreement were ±1.6 lines.
The present study supports the validity of the new eye chart as a measure of visual acuity in pediatric patients ages 6 to 18 with vision ranging from 20/16 to 20/200.
We conducted a genome-wide association study of gastric cancer (GC) and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 single nucleotide polymorphisms (SNPs). We report a combined analysis of 2,240 GC cases, 2,115 ESCC cases, and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex, and study, multiple variants at 10q23 had genome-wide significance for GC and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for GC (P=8.40×1010; per allele odds ratio (OR) = 1.31) and ESCC (P=3.85×10−9; OR = 1.34). The association with GC differed by anatomic subsite. For tumors located in the cardia the association was stronger (P=4.19 × 10−15; OR= 1.57) and for those located in the noncardia stomach it was absent (P=0.44; OR=1.05). Our findings at 10q23 could provide insight into the high incidence rates of both cancers in China.
To describe clinical findings, diagnostic techniques and management of Candida lens abscesses in premature infants with history of neonatal candida sepsis.
Retrospective observational review.
Three cases of Candida lens abscesses were retrospectively identified at one institution. Patients' records were analyzed for clinical, surgical and laboratory findings.
All 3 patients developed a lens opacity with signs of ocular inflammation at 20 weeks, 10 weeks, and 52 weeks postgestational age, respectively. Each patient underwent a lensectomy and anterior vitrectomy, and 2 of 3 had intravitreal injections of antifungal agents. Candida albicans was cultured from the lens/anterior chamber membrane in 2 infants and Candida parapsilosis from a lens aspirate in 1 infant. All Gram stains and cultures of the aqueous humor were negative for fungal elements. Despite successful treatment of the fungal infection, visual outcomes were light perception, counting fingers, and no light perception, respectively for the 3 cases. Two eyes developed glaucoma and one developed a retinal detachment with subsequent phthisis.
Candida lens abscesses may present as a lenticular opacity with ocular inflammation at variable times after neonatal Candida sepsis and onset can be delayed for months. Candida can be difficult to culture from an infant with a Candida lens abscess. Obtaining a culture of the lens aspirate or membranes in the anterior chamber should be included in the diagnostic work-up. The prognosis for functional vision is poor in these eyes.
We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.
Patients and Methods
Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.
Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84–2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19–1.76]), obesity (body mass index >30 kg/m2) (OR: 1.26 [1.09–1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13–2.18], case-control OR: 1.80 [1.40–2.32]), family history of pancreatic cancer (OR: 1.60 [1.20–2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10–1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97–2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19–1.40]), rs401681(5p15.33) (OR: 1.18 [1.10–1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18–1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.
Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.
Relationships are unclear between polymorphisms in genes involved in metabolism and detoxification of various chemicals and papillary thyroid cancer (PTC) risk as well as their potential modification by alcohol or tobacco intake. We evaluated associations between 1647 tagging single nucleotide polymorphisms (SNPs) in 132 candidate genes/regions involved in metabolism of exogenous and endogenous compounds (Phase I/II, oxidative stress, and metal binding pathways) and PTC risk in 344 PTC cases and 452 controls. For 15 selected regions and their respective SNPs, we also assessed interaction with alcohol and tobacco use. Logistic regression models were used to evaluate the main effect of SNPs (Ptrend) and interaction with alcohol/tobacco intake. Gene- and pathway-level associations and interactions (Pgene interaction) were evaluated by combining Ptrend values using the adaptive rank-truncated product method. While we found associations between PTC risk and nine SNPs (Ptrend≤0.01) and seven genes/regions (Pregion<0.05), none remained significant after correction for the false discovery rate. We found a significant interaction between UGT2B7 and NAT1 genes and alcohol intake (Pgene interaction=0.01 and 0.02 respectively) and between the CYP26B1 gene and tobacco intake (Pgene interaction=0.02). Our results are suggestive of interaction between the genetic polymorphisms in several detoxification genes and alcohol or tobacco intake on risk of PTC. Larger studies with improved exposure assessment should address potential modification of PTC risk by alcohol and tobacco intake to confirm or refute our findings.
Genome-wide association studies have identified susceptibility loci for esophageal squamous cell carcinoma (ESCC). We conducted a meta-analysis of all single-nucleotide polymorphisms (SNPs) that showed nominally significant P-values in two previously published genome-wide scans that included a total of 2961 ESCC cases and 3400 controls. The meta-analysis revealed five SNPs at 2q33 with P< 5 × 10−8, and the strongest signal was rs13016963, with a combined odds ratio (95% confidence interval) of 1.29 (1.19–1.40) and P= 7.63 × 10−10. An imputation analysis of 4304 SNPs at 2q33 suggested a single association signal, and the strongest imputed SNP associations were similar to those from the genotyped SNPs. We conducted an ancestral recombination graph analysis with 53 SNPs to identify one or more haplotypes that harbor the variants directly responsible for the detected association signal. This showed that the five SNPs exist in a single haplotype along with 45 imputed SNPs in strong linkage disequilibrium, and the strongest candidate was rs10201587, one of the genotyped SNPs. Our meta-analysis found genome-wide significant SNPs at 2q33 that map to the CASP8/ALS2CR12/TRAK2 gene region. Variants in CASP8 have been extensively studied across a spectrum of cancers with mixed results. The locus we identified appears to be distinct from the widely studied rs3834129 and rs1045485 SNPs in CASP8. Future studies of esophageal and other cancers should focus on comprehensive sequencing of this 2q33 locus and functional analysis of rs13016963 and rs10201587 and other strongly correlated variants.
Single nucleotide polymorphisms (SNPs) in the 8q24 chromosomal region identified from genome-wide scans have been associated with risk of several cancers including breast (rs1562430), prostate and colon (rs1447295 and rs6983267). A genome-wide scan in 26 families with papillary thyroid cancer (PTC) also found susceptibility loci in 8q24, supporting a closer evaluation of this chromosomal region in relation to risk of sporadic PTC.
We evaluated 157 tag SNPs in the 8q24 chromosomal region between 120.91 Mb and 128.78 Mb (including rs1562430, rs1447295, and rs6983267) in a case-control study of 344 PTC cases and 452 age and gender frequency-matched controls.
We used logistic regression to estimate odds ratios and compute P-values of linear trend for PTC with genotypes of interest. To account for multiple comparisons, we applied the false discovery rate (FDR) method.
We did not find a significant association between rs1562430, rs1447295, or rs6983267, and PTC risk. We found that one SNP (rs4733616) was associated with PTC risk at P = 0.003, and twelve other SNPs were associated with PTC risk at P < 0.05. However, no SNPs remained significant after FDR correction.
Our findings do not support a strong association between SNPs in the 8q24 chromosomal region and risk of sporadic PTC but several SNPs with small effects might exist.
8q24; thyroid cancer
A recent genome-wide association study of bladder cancer identified the UGT1A gene cluster on chromosome 2q37.1 as a novel susceptibility locus. The UGT1A cluster encodes a family of UDP-glucuronosyltransferases (UGTs), which facilitate cellular detoxification and removal of aromatic amines. Bioactivated forms of aromatic amines found in tobacco smoke and industrial chemicals are the main risk factors for bladder cancer. The association within the UGT1A locus was detected by a single nucleotide polymorphism (SNP) rs11892031. Now, we performed detailed resequencing, imputation and genotyping in this region. We clarified the original genetic association detected by rs11892031 and identified an uncommon SNP rs17863783 that explained and strengthened the association in this region (allele frequency 0.014 in 4035 cases and 0.025 in 5284 controls, OR = 0.55, 95%CI = 0.44–0.69, P = 3.3 × 10−7). Rs17863783 is a synonymous coding variant Val209Val within the functional UGT1A6.1 splicing form, strongly expressed in the liver, kidney and bladder. We found the protective T allele of rs17863783 to be associated with increased mRNA expression of UGT1A6.1 in in-vitro exontrap assays and in human liver tissue samples. We suggest that rs17863783 may protect from bladder cancer by increasing the removal of carcinogens from bladder epithelium by the UGT1A6.1 protein. Our study shows an example of genetic and functional role of an uncommon protective genetic variant in a complex human disease, such as bladder cancer.
Accumulating evidence suggests that alterations in immune function may be important in the etiology of papillary thyroid cancer (PTC). To identify genetic markers in immune-related pathways, we evaluated 3,985 tag single nucleotide polymorphisms (SNPs) in 230 candidate gene regions (adhesion-extravasation-migration, arachidonic acid metabolism/eicosanoid signaling, complement and coagulation cascade, cytokine signaling, innate pathogen detection and antimicrobials, leukocyte signaling, TNF/NF-kB pathway or other) in a case-control study of 344 PTC cases and 452 controls. We used logistic regression models to estimate odds ratios (OR) and calculate one degree of freedom P values of linear trend (PSNP-trend) for the association between genotype (common homozygous, heterozygous, variant homozygous) and risk of PTC. To correct for multiple comparisons, we applied the false discovery rate method (FDR). Gene region- and pathway-level associations (PRegion and PPathway) were assessed by combining individual PSNP-trend values using the adaptive rank truncated product method. Two SNPs (rs6115, rs6112) in the SERPINA5 gene were significantly associated with risk of PTC (PSNP-FDR/PSNP-trend = 0.02/6×10−6 and PSNP-FDR/PSNP-trend = 0.04/2×10−5, respectively). These associations were independent of a history of autoimmune thyroiditis (OR = 6.4; 95% confidence interval: 3.0–13.4). At the gene region level, SERPINA5 was suggestively associated with risk of PTC (PRegion-FDR/PRegion = 0.07/0.0003). Overall, the complement and coagulation cascade pathway was the most significant pathway (PPathway = 0.02) associated with PTC risk largely due to the strong effect of SERPINA5. Our results require replication but suggest that the SERPINA5 gene, which codes for the protein C inhibitor involved in many biological processes including inflammation, may be a new susceptibility locus for PTC.
To assess whether outcomes of strabismus surgery are improved by using the adjustable suture technique and to determine which subgroups of strabismus patients benefit most from the adjustable suture technique.
A retrospective chart review.
Five hundred thirty-five adults who had strabismus surgery between 1989–2010.
Success was defined as ≤10 prism diopters (PD) for horizontal deviations and ≤2 PD for vertical deviations. Differences in the proportion of successful strabismus surgery were analyzed using a chi-square test with an alpha of 0.05.
Main outcome measures
Ocular alignment in primary position at a 7-day to 12-week follow-up examination.
491 patients met the inclusion criteria (adjustable suture, n=305; non-adjustable, n=186). The success rates for non-adjustable and adjustable groups were 61.3% and 74.8% respectively (χ2=9.91, p=0.0016). Adjustable suture use was particularly beneficial for patients undergoing a reoperation for childhood strabismus (success rate: non-adjustable, 42.4%; adjustable, 65.7% p=0.0268; n=100). The differences in outcomes were not statistically significant for patients with childhood strabismus undergoing a primary surgery (non-adjustable, 65.0%; adjustable, 81.4% p=0.1354; n=90) or with thyroid orbitopathy (non-adjustable, 76.7%; adjustable, 74.1% p=0.8204; n=57).
Strabismus surgery using adjustable sutures was associated with improved short-term ocular alignment compared to strabismus surgery without the use of adjustable sutures. Adjustable sutures were most beneficial for patients undergoing reoperations for childhood strabismus.
Hormonal differences are hypothesized to contribute to the approximately ≥2-fold higher thyroid cancer incidence rates among women compared with men worldwide. Although thyroid cancer cells express estrogen receptors and estrogen has a proliferative effect on papillary thyroid cancer (PTC) cells in vitro, epidemiologic studies have not found clear associations between thyroid cancer and female hormonal factors. We hypothesized that polymorphic variation in hormone pathway genes is associated with the risk of developing papillary thyroid cancer.
We evaluated the association between PTC and 1151 tag single nucleotide polymorphisms (SNPs) in 58 candidate gene regions involved in sex hormone synthesis and metabolism, gonadotropins, and prolactin in a case-control study of 344 PTC cases and 452 controls, frequency matched on age and sex. Odds ratios and p-values for the linear trend for the association between each SNP genotype and PTC risk were estimated using unconditional logistic regression. SNPs in the same gene region or pathway were aggregated using adaptive rank-truncated product methods to obtain gene region-specific or pathway-specific p-values. To account for multiple comparisons, we applied the false discovery rate method.
Seven SNPs had p-values for linear trend <0.01, including four in the CYP19A1 gene, but none of the SNPs remained significant after correction for multiple comparisons. Results were similar when restricting the dataset to women. p-values for examined gene regions and for all genes combined were ≥0.09.
Based on these results, SNPs in selected hormone pathway genes do not appear to be strongly related to PTC risk. This observation is in accord with the lack of consistent associations between hormonal factors and PTC risk in epidemiologic studies.
The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases.
We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 single nucleotide polymorphisms (SNPs) in 1,145 cases of invasive breast cancer among postmenopausal white women, and 1,142 controls. We identified a set of four SNPs in intron 2 of FGFR2, a tyrosine kinase receptor previously shown to be amplified and/or over-expressed in some breast cancers, as highly associated with breast cancer and we confirmed this association in 1,776 cases and 2,072 controls from three additional studies. In both association testing and ancestral recombination graph analysis, FGFR2 haplotypes were associated with risk of breast cancer. Across the four studies the association with all four SNPs was highly statistically significant (Ptrend for the most strongly associated SNP, rs1219648 = 1.1 × 10−10; population attributable risk = 16%). Four SNPs at other chromosomal loci most strongly associated with breast cancer in the initial GWAS were not associated with risk in the three replication studies. Our summary results from the GWAS are freely available online in a form that should speed the identification of additional loci conferring risk.
Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 × 10–9; allelic odds ratio 1.20 with 95% CI: 1.13–1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r2= 1.00; P = 8.9 × 10–9; allelic odds ratio 1.16 with 95% CI: 1.10–1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis.
To determine the validity and reliability of a novel questionnaire to measure vision related quality of life (VRQOL) in children 8–18 years old for use in juvenile idiopathic arthritis-associated uveitis (JIA-U) –Effects of Youngsters’ Eyesight on Quality of Life (EYE-Q).
Several steps validated the EYE-Q. We interviewed experts and children on how vision affects a child’s activities. We developed new items and selected relevant items from existing instruments. We administered initial versions of the EYE-Q to normal-sighted children and those with JIA-U. For this study, children with various (or no) ocular conditions were recruited from a clinical population. Visual acuity (VA) and contrast sensitivity were performed, and the EYE-Q and Pediatric Quality of Life Inventory (PedsQL) were administered. The EYE-Q was repeated 10 days later. Patients, parents and physicians rated vision severity.
Of 120 patients, 48% were female, 46.7% had no visual impairment (VI), and 52% had bilateral eye involvement. Mean age was 11.3 years. There were significant differences in the measures based on VA (p<0.001). Children with more severe VA and bilateral eye involvement had worse EYE-Q scores (p<0.001). There were significant associations between the EYE-Q and PedsQL (r = 0.375), repeat EYE-Q (r = 0.864), and clinical measures of ocular disease (r = −0.620).
Our study provides evidence of the validity and reliability of the EYE-Q in the measurement of VRQOL. The EYE-Q may complement clinical measures of VI and overall QOL and become an important tool in the assessment of QOL in JIA-U.
We report a genome-wide association study in 10,286 cases and 9,135 controls of European ancestry, in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative, identifying a new association with prostate cancer risk on chromosome 8q24 (rs620861, p=1.3×10-10, heterozygote OR = 1.17, 95% CI 1.10 – 1.24; homozygote OR = 1.33; 95% CI 1.21 – 1.45). This defines a new prostate locus on 8q24, Region 4, previously associated with breast cancer.
Previous genome-wide association studies have identified two independent variants in HNF1B as susceptibility loci for prostate cancer risk. To fine-map common genetic variation in this region, we genotyped 79 single nucleotide polymorphisms (SNPs) in the 17q12 region harboring HNF1B in 10 272 prostate cancer cases and 9123 controls of European ancestry from 10 case–control studies as part of the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. Ten SNPs were significantly related to prostate cancer risk at a genome-wide significance level of P < 5 × 10−8 with the most significant association with rs4430796 (P = 1.62 × 10−24). However, risk within this first locus was not entirely explained by rs4430796. Although modestly correlated (r2= 0.64), rs7405696 was also associated with risk (P = 9.35 × 10−23) even after adjustment for rs4430769 (P = 0.007). As expected, rs11649743 was related to prostate cancer risk (P = 3.54 × 10−8); however, the association within this second locus was stronger for rs4794758 (P = 4.95 × 10−10), which explained all of the risk observed with rs11649743 when both SNPs were included in the same model (P = 0.32 for rs11649743; P = 0.002 for rs4794758). Sequential conditional analyses indicated that five SNPs (rs4430796, rs7405696, rs4794758, rs1016990 and rs3094509) together comprise the best model for risk in this region. This study demonstrates a complex relationship between variants in the HNF1B region and prostate cancer risk. Further studies are needed to investigate the biological basis of the association of variants in 17q12 with prostate cancer.