Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
CLL; NHL; SNPs; IRF8; risk locus
Monoclonal B cell lymphocytosis (MBL) is a hematologic condition wherein small B cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and “CLL-like” MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. Ninety-one unique MBL clones were detected: 73 CLL-like MBL (CD5+CD20dimsIgdim), 11 atypical MBL (CD5+CD20+sIg+), and 7 CD5neg MBL (CD5negCD20+sIgneg). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b, and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70, and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on 7 CLL-like MBL, and showed activation of B cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.
Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic haematological condition characterized by low absolute levels of B-cell clones with a surface immunophenotype similar to that of chronic lymphocytic leukaemia (CLL). In the general population, MBL increases with age with a prevalence of 5–9% in individuals over age 60 years. It has been reported to be higher among first-degree relatives from CLL families. We report results of multi-parameter flow cytometry among 505 first-degree relatives with no personal history of lymphoproliferative disease from 140 families having at least two cases of CLL. Seventeen percent of relatives had MBL. Age was the most important determinant where the probability for developing MBL by age 90 years was 61%. MBL clustered in certain families but clustering was independent of the number of known CLL cases in a family. As is the case with CLL, males had a significantly higher risk for MBL than did females (p=0.04). MBL patients had significantly higher mean absolute lymphocyte counts (2.4 × 109/l) and B-cell counts (0.53 × 109/l) than those with a normal B-cell immunophenotype. Our findings show that MBL occurs at a very high rate in high risk CLL families. Both the age and gender distribution of MBL are parallel to CLL, implying a shared inherited risk.
chronic lymphocytic leukaemia; high risk families; monoclonal B-cell lymphocytosis; flow cytometry
There is strong and consistent evidence that a genetic component contributes to the etiology of chronic lymphocytic leukemia (CLL). A recent genome-wide association study (GWAS) of CLL identified 7 genetic variants that increased the risk of CLL within a European population.
We evaluated the association of these variants, or variants in linkage disequilibrium (LD) with these variants, with CLL risk in an independent sample of 438 CLL cases and 328 controls.
Of these 7 SNPs, 6 had p-trend < 0.05 and had estimated odds ratios (ORs) that were strikingly comparable to those of the previous study. Associations were seen for rs9378805 (OR = 1.47, 95% CI: 1.19, 1.80, p-trend = 0.0003) near IRF4 and rs735665 near GRAMD1B (OR= 1.47; 95% CI: 1.14, 1.89; p-trend = 0.003). However, no associations (P> 0.05) were found for rs11083846, nor were any found for any SNPs in LD with rs11083846.
Our results confirm the previous findings and further support the role of a genetic basis in the etiology of CLL; however, more research is needed to elucidate the causal SNP(s) and the potential manner in which these SNPs or linked SNPs function in CLL pathogenesis.
IRF4; CLL; genetic association
To identify susceptibility loci for non-Hodgkin lymphoma (NHL) subtypes, we conducted a three-stage genome-wide association study. We identified two variants associated with follicular lymphoma (FL) in 1,465 FL cases/6,958 controls at 6p21.32 (rs10484561, rs7755224, r2=1.0; combined p-values=1.12×10-29, 2.00×10-19), providing further support that MHC genetic variation influences FL susceptibility. Confirmatory evidence of a previously reported association was also found between chronic lymphocytic leukemia/small lymphocytic lymphoma and rs735665 (combined p-value=4.24×10-9).
Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.
Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.
GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl
2, on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.
Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
The rs588765-rs16969968 haplotype modifies lung cancer risk more than effects from individual variations at rs16969968 or rs588765, and therefore may be a marker of genetic susceptibility to lung cancer even among never-smokers. This knowledge may facilitate our understanding of lung cancer etiology.
The role of haplotypes and the interaction of haplotypes and smoking in lung cancer risk have not been well characterized. We analyzed data from an Italian population-based, case–control study with 1815 lung cancer patients and 1959 healthy controls in discovery, and performed a validation using a case–control study with 2983 lung cancer patients and 3553 healthy controls of European ancestry for replication. Sliding window haplotype analysis within chromosome 15, evaluating 4722250 haplotypes and pair-wise haplotype analysis identified that CHRNA5 rs588765-rs16969968 was the most significant haplotype associated with lung cancer risk (omnibus P = 8.35×10−15 in discovery and 7.26×10−14 in replication), and improved the prediction of case status over that provided by the individual SNPs rs16969968 or rs588765 (likelihood ratio test P = 0.006 for rs16969968 and 3.83×10−14 for rs588765 in discovery, 0.009 for rs16969968 and 4.62×10−13 for rs588765 in replication, compared with rs588765-rs16969968). Compared with the wild-type homozygous diplotype, CA/CA homozygote exhibited an approximately 2-fold increase risk for lung cancer (OR = 2.12; 95% CI 1.46–3.07 in discovery, and OR = 2.01; 95% CI 1.51–2.67 in replication). Even among never-smokers, CA/CA homozygote showed an increased risk of lung cancer with borderline significance in discovery (adjusted OR = 1.75, 95% CI 0.96–3.19) and statistical significance in replication (adjusted OR = 2.10, 95% CI 1.12–3.96), compared with combined genotypes (CG/CG + CG/TG). Accordingly, rs588765-rs16969968 may be a genetic marker to lung cancer risk, even among never-smokers.
Very few studies have examined sleep duration in relation to cancer incidence with the exception of breast cancer.
We assessed the associations between sleep duration and incidences of total and 18 site-specific cancers in the NIH-AARP Health and Diet Study cohort, with 173,327 men and 123,858 women aged 51–72 years at baseline. Self-reported sleep duration categories were assessed via questionnaire. We used multivariable Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI), using 7–8 hours/night as the reference.
We observed a significantly increased risk of stomach cancer among male short sleepers (multivariable HR5-6 vs. 7–8 hours = 1.29; 95%CI: 1.05, 1.59; Ptrend = 0.03). We also observed suggestive associations in either short or long sleepers, which did not reach overall significance (Ptrend >0.05), including increased risks in male short sleepers for cancers of head and neck (HR<5vs.7-8 hours = 1.39; 95%CI:1.00–1.95), bladder (HR5-6vs.7-8 hours = 1.10; 95%CI:1.00–1.20), thyroid (HR<5 vs. 7–8 hours = 2.30; 95%CI:1.06, 5.02), Non-Hodgkin Lymphoma (NHL) (HR5-6vs.7-8 hours = 1.17; 95%CI:1.02–1.33), and myeloma (HR<5vs.7-8 hours = 2.06; 95%CI:1.20–3.51). In women, the suggestive associations include a decreased total cancer risk (HR<5vs.7-8 hours = 0.9; 95%CI:0.83–0.99) and breast cancer risk (HR<5vs.7-8 hours = 0.84; 95%CI:0.71–0.98) among short sleepers. A decreased ovarian cancer risk (HR≥ 9 vs. 7–8 hours = 0.50; 95%CI:0.26–0.97) and an increased NHL risk (HR≥ 9 vs. 7–8 hours = 1.45; 95%CI:1.00–2.11) were observed among long sleepers.
In an older population, we observed an increased stomach cancer risk in male short sleepers and suggestive associations with short or long sleep duration for many cancer risks in both genders.
Current methods for detecting genetic associations lack full consideration of the background effects of environmental exposures. Recently proposed methods to account for environmental exposures have focused on logistic regressions with gene-environment interactions. In this report, we developed a test for genetic association, encompassing a broad range of risk models, including linear, logistic and probit, for specifying joint effects of genetic and environmental exposures. We obtained the test statistics by maximizing over a class of score tests, each of which involves modified standard tests of genetic association through a weight function. This weight function reflects the potential heterogeneity of the genetic effects by levels of environmental exposures under a particular model. Simulation studies demonstrate the robust power of these methods for detecting genetic associations under a wide range of scenarios. Applications of these methods are further illustrated using data from genome-wide association studies of type 2 diabetes with body mass index and of lung cancer risk with smoking.
gene-environment interaction; GWAS; score test; SNPs; environmental exposures
Body mass index (BMI) is inversely associated with lung cancer risk in observational studies, even though it increases the risk of several other cancers, which could indicate confounding by tobacco smoking or reverse causality. We used the two-sample Mendelian randomization (MR) approach to circumvent these limitations of observational epidemiology by constructing a genetic instrument for BMI, based on results from the GIANT consortium, which was evaluated in relation to lung cancer risk using GWAS results on 16,572 lung cancer cases and 21,480 controls. Results were stratified by histological subtype, smoking status and sex. An increase of one standard deviation (SD) in BMI (4.65 Kg/m2) raised the risk for lung cancer overall (OR = 1.13; P = 0.10). This was driven by associations with squamous cell (SQ) carcinoma (OR = 1.45; P = 1.2 × 10−3) and small cell (SC) carcinoma (OR = 1.81; P = 0.01). An inverse trend was seen for adenocarcinoma (AD) (OR = 0.82; P = 0.06). In stratified analyses, a 1 SD increase in BMI was inversely associated with overall lung cancer in never smokers (OR = 0.50; P = 0.02). These results indicate that higher BMI may increase the risk of certain types of lung cancer, in particular SQ and SC carcinoma.
Prior studies have found weak inverse associations between breast cancer and caffeine and coffee intake, possibly mediated through their effects on sex hormones.
High-performance liquid chromatography/tandem mass spectrometry was used to quantify levels of 15 individual estrogens and estrogen metabolites (EM) among 587 premenopausal women in the Nurses’ Health Study II with mid-luteal phase urine samples and caffeine, coffee and/or tea intakes from self-reported food frequency questionnaires. Multivariate linear mixed models were used to estimate geometric means of individual EM, pathways and ratios by intake categories, and P-values for tests of linear trend.
Compared to women in the lowest quartile of caffeine consumption, those in the top quartile had higher urinary concentrations of 16α-hydroxyestrone (28% difference; P-trend=0.01) and 16-epiestriol (13% difference; P-trend=0.04), and a decreased parent estrogens/2-, 4-, 16-pathway ratio (P-trend=0.03). Coffee intake was associated with higher 2-catechols, including 2-hydroxyestradiol (57% difference, ≥4 cups/day vs. ≤6 cups/week; P-trend=0.001) and 2-hydroxyestrone (52% difference; P-trend=0.001), and several ratio measures. Decaffeinated coffee was not associated with 2-pathway metabolism, but women in the highest (vs. lowest) category of intake (≥2 cups/day vs. ≤1–3 cups/month) had significantly lower levels of two 16-pathway metabolites, estriol (25% difference; P-trend=0.01) and 17-epiestriol (48% difference; Ptrend=0.0004). Tea intake was positively associated with 17-epiestriol (52% difference; Ptrend=0.01).
Caffeine and coffee intake were both associated with profiles of estrogen metabolism in premenopausal women.
Consumption of caffeine and coffee may alter patterns of premenopausal estrogen metabolism.
estrogen; estrogen metabolism; caffeine
The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients.
We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors.
Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-016-1021-1) contains supplementary material, which is available to authorized users.
Air pollution; Tumor stage; 16S rRNA
Previous studies have reported that survivors of non-Hodgkin lymphoma (NHL) have an increased risk of developing cutaneous melanoma; however, risks associated with specific treatments and immune-related risk factors have not been quantified.
Patients and Methods
We evaluated second melanoma risk among 44,870 1-year survivors of first primary NHL diagnosed at age 66 to 83 years from 1992 to 2009 and included in the Surveillance, Epidemiology, and End Results-Medicare database. Information on NHL treatments, autoimmune diseases, and infections was derived from Medicare claims.
A total of 202 second melanoma cases occurred among survivors of NHL, including 91 after chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and 111 after other NHL subtypes (cumulative incidence by age 85 years: CLL/SLL, 1.37%; other NHL subtypes, 0.78%). Melanoma risk after CLL/SLL was significantly increased among patients who received infused fludarabine-containing chemotherapy with or without rituximab (n = 18: hazard ratio [HR], 1.92; 95% CI, 1.09 to 3.40; n = 10: HR, 2.92; 95% CI, 1.42 to 6.01, respectively). Significantly elevated risks also were associated with T-cell activating autoimmune diseases diagnosed before CLL/SLL (n = 36: HR, 2.27; 95% CI, 1.34 to 3.84) or after CLL/SLL (n = 49: HR, 2.92; 95% CI, 1.66 to 5.12). In contrast, among patients with other NHL subtypes, melanoma risk was not associated with specific treatments or with T-cell/B-cell immune conditions. Generally, infections were not associated with melanoma risk, except for urinary tract infections (CLL/SLL), localized scleroderma, pneumonia, and gastrohepatic infections (other NHLs).
Our findings suggest immune perturbation may contribute to the development of melanoma after CLL/SLL. Increased vigilance is warranted among survivors of NHL to maximize opportunities for early detection of melanoma.
To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
It is unclear how often genetic mosaicism of chromosome X arises. Here, the authors examine women with cancer and cancer-free controls and show that X chromosome mosaicism occurs more frequently than on autosomes, especially on the inactive X chromosome, but is not linked to non-haematologic cancer risk
Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management.
We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non–surgically treated patients.
Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non–small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients.
This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events.
acute myeloid leukemia; myelodysplastic syndrome; chemotherapy; radiotherapy; autoimmune conditions; infections; non-Hodgkin lymphoma
Targeting smokers at higher lung cancer risk can improve efficiency and reduce false-positive detection in lung cancer screening. We evaluated whether time to first cigarette after waking (TTFC), a single-item measure of nicotine dependency, could improve stratification of lung cancer risk beyond standard smoking metrics (intensity, duration, and pack-years).
In 3249 ever-smokers (n = 1812 case subjects; n = 1437 control subjects) from a population-based case–control study in Italy, we examined the association between TTFC and lung cancer using logistic regression and estimated lung cancer incidence by levels of TTFC, and intensity, duration, and pack-years using absolute risk regression. Significance tests were two-sided.
Compared with smokers with TTFC greater than 60 minutes, the lung cancer odds ratios for TTFC of 31 to 60 minutes, 6 to 30 minutes, and 5 or fewer minutes (by increasing dependency) were 2.57 (95% confidence interval [CI] = 2.03 to 3.26), 2.27 (95% CI = 1.79 to 2.88), and 3.50 (95% CI = 2.64 to 4.64), respectively (P
trend < .0001). The average lung cancer incidence rates for smokers of 1 to 10, 11 to 20, 21 to 30 and more than 30 cigarettes per day were consistently higher among smokers with TTFC of 60 or fewer minutes vs more than 60 minutes (64.1 vs 11.7; 125.6 vs 28.6; 130.1 vs 40.7; and 260.8 vs 108.9 per 100000 person-years, respectively). The slopes of increase in lung cancer rates with smoking duration and pack-years were statistically significantly greater among smokers with higher dependency (P
interaction < .001).
Lung cancer risk increases with shorter TTFC; this simple nicotine dependency measure increases lung cancer risk stratification beyond standard smoking measures. Assessing TTFC may improve lung cancer risk prediction and could be useful in lung cancer screening and smoking cessation programs.
Rotating night shift work imposes circadian strain and is linked to the risk of several chronic diseases.
To examine associations between rotating night shift work and all-cause, cardiovascular disease (CVD), and cancer mortality in a prospective cohort study of 74,862 registered U.S. nurses from the Nurses’ Health Study.
Lifetime rotating night shift work (defined as ≥3 nights/month) information was collected in 1988. During 22 years (1988–2010) of follow-up, 14,181 deaths were documented, including 3,062 CVD and 5,413 cancer deaths. Cox proportional hazards models (2013) estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs.
All-cause and CVD mortality were significantly increased among women with ≥5 years of rotating night shift work, compared to women who never worked night shifts. Specifically, for women with 6–14 and ≥15 years of rotating night shift work, the HRs were 1.11 (95% CI=1.06, 1.17) and 1.11 (95% CI=1.05, 1.18) for all-cause mortality and 1.19 (95% CI=1.07, 1.33) and 1.23 (95% CI=1.09, 1.38) for CVD mortality. There was no association between rotating night shift work and all-cancer mortality (HR≥15years=1.08, 95% CI=0.89, 1.19) or any other cancer, with the exception of lung cancer (HR≥15years=1.25, 95% CI=1.04, 1.51).
Women working rotating night shifts for ≥5 five years have a modest increase in all-cause and CVD mortality; those working ≥15 years of rotating night shift work have a modest increase in lung cancer mortality. These results add to prior evidence of a potentially detrimental effect of rotating night shift work on health and longevity.
Metastasis is the leading cause of death in osteosarcoma patients, the most common pediatric bone malignancy. We conducted a multi-stage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified a SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P=1.2×10−9, OR 2.43, 95% CI 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. Additionally, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib, and had lowered Nfib expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis, and that NFIB is an osteosarcoma metastasis susceptibility gene.
osteosarcoma; metastasis; genome-wide association study
Recent evidence from several relatively small nested case-control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of 7 telomere-length associated genetic variants in a large study of 5,457 never-smoking female Asian lung cancer cases and 4,493 never-smoking female Asian controls using data from a previously reported genome-wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women’s Health study, we demonstrated the utility of a genetic risk score (GRS) of 7 telomere-length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI=1.34–1.69) for upper vs. lower quartile of the weighted GRS, P-value=4.54×10−14) even after removing rs2736100 (P-value=4.81×10−3), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere-associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
association study; genetics; lung cancer; telomere length; genetic risk score
Mitochondrial DNA copy number (mtDNA CN) may be modified by mitochondria in response to oxidative stress. Previously, mtDNA CN was associated with non-Hodgkin lymphoma (NHL) risk, particularly chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We conducted a replication study in the Prostate, Lung, Colorectal, and Ovarian (PLCO) study and pooled with published ATBC (Alpha-Tocopherol, Beta-Carotene) data.
In PLCO, 292 NHL cases (95 CLL/SLL cases) and 301 controls were pooled with 142 NHL cases (47 CLL/SLL cases) and 142 controls from ATBC. Subjects answered a questionnaire and provided blood. DNA was extracted from pre-diagnostic peripheral white blood, and mtDNA CN assayed by quantitative polymerase chain reaction. Unconditional logistic regression estimated mtDNA CN and NHL risk by odds ratios (OR) and 95% confidence intervals (95% CI).
Greater mtDNA CN was associated with increased risk of CLL/SLL among males in PLCO (3rd vs. 1st tertile: OR: 2.21; 95% CI: 1.03–4.72; p-trend: 0.049) and pooled (T3 vs. T1 OR: 3.12; 95% CI: 1.72–5.68; p-trend: 0.0002). Association was stronger among male smokers (p-trend: <0.0001) and essentially identical for cases diagnosed <6, >6–8, and >8 years from blood draw (pooled: p-interaction: 0.65). mtDNA CN and risk of other NHL subtypes and multiple myeloma showed no association.
Conclusions and Impact
Mitochondrial DNA CN was associated with risk of CLL/SLL in males/male smokers. The risk was observed among cases diagnosed as long as eight years after blood draw. These results suggest that higher mtDNA CN may reflect a process involved in CLL/SLL development.
Mitochondrial DNA copy number; chronic lymphocytic leukemia/small lymphocytic lymphoma; non-Hodgkin lymphoma
Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10−39; Region 3: rs2853677, P = 3.30 × 10−36 and PConditional = 2.36 × 10−8; Region 4: rs2736098, P = 3.87 × 10−12 and PConditional = 5.19 × 10−6, Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10−6; and Region 6: rs10069690, P = 7.49 × 10−15 and PConditional = 5.35 × 10−7) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10−18 and PConditional = 7.06 × 10−16). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.