To clarify the role of previous lung diseases (chronic bronchitis, emphysema, pneumonia, and tuberculosis) in the development of lung cancer, the authors conducted a pooled analysis of studies in the International Lung Cancer Consortium. Seventeen studies including 24,607 cases and 81,829 controls (noncases), mainly conducted in Europe and North America, were included (1984–2011). Using self-reported data on previous diagnoses of lung diseases, the authors derived study-specific effect estimates by means of logistic regression models or Cox proportional hazards models adjusted for age, sex, and cumulative tobacco smoking. Estimates were pooled using random-effects models. Analyses stratified by smoking status and histology were also conducted. A history of emphysema conferred a 2.44-fold increased risk of lung cancer (95% confidence interval (CI): 1.64, 3.62 (16 studies)). A history of chronic bronchitis conferred a relative risk of 1.47 (95% CI: 1.29, 1.68 (13 studies)). Tuberculosis (relative risk = 1.48, 95% CI: 1.17, 1.87 (16 studies)) and pneumonia (relative risk = 1.57, 95% CI: 1.22, 2.01 (12 studies)) were also associated with lung cancer risk. Among never smokers, elevated risks were observed for emphysema, pneumonia, and tuberculosis. These results suggest that previous lung diseases influence lung cancer risk independently of tobacco use and that these diseases are important for assessing individual risk.
bronchitis; chronic; emphysema; lung diseases; lung neoplasms; meta-analysis; pneumonia; pulmonary disease; chronic obstructive; tuberculosis
Lung cancer is mainly caused by smoking, but the quantitative relations between smoking and histologic subtypes of lung cancer remain inconclusive. Using one of the largest lung cancer datasets ever assembled, we explored the impact of smoking on risks of the major cell types of lung cancer. This pooled analysis included 13,169 cases and 16,010 controls from Europe and Canada. Studies with population controls comprised 66.5% of the subjects. Adenocarcinoma (AdCa) was the most prevalent subtype in never smokers and in women. Squamous cell carcinoma (SqCC) predominated in male smokers. Age-adjusted odds ratios (ORs) were estimated with logistic regression. ORs were elevated for all metrics of exposure to cigarette smoke and were higher for SqCC and small cell lung cancer (SCLC) than for AdCa. Current male smokers with an average daily dose of >30 cigarettes had ORs of 103.5 (95% CI 74.8-143.2) for SqCC, 111.3 (95% CI 69.8-177.5) for SCLC, and 21.9 (95% CI 16.6-29.0) for AdCa. In women, the corresponding ORs were 62.7 (95% CI 31.5-124.6), 108.6 (95% CI 50.7-232.8), and 16.8 (95% CI 9.2-30.6), respectively. Whereas ORs started to decline soon after quitting, they did not fully return to the baseline risk of never smokers even 35 years after cessation. The major result that smoking exerted a steeper risk gradient on SqCC and SCLC than on AdCa is in line with previous population data and biological understanding of lung cancer development.
cigarette smoking; lung cancer; relative risk characterization; tobacco smoke; stem cells
Background and Methods
Familial aggregation of lung cancer exists after accounting for cigarette smoking. However, the extent to which family history affects risk by smoking status, histology, relative type and ethnicity is not well described. This pooled analysis included 24 case-control studies in the International Lung Cancer Consortium. Each study collected age of onset/interview, gender, race/ethnicity, cigarette smoking, histology and first-degree family history of lung cancer. Data from 24,380 lung cancer cases and 23,305 healthy controls were analyzed. Unconditional logistic regression models and generalized estimating equations were used to estimate odds ratios and 95% confidence intervals.
Individuals with a first-degree relative with lung cancer had a 1.51-fold increase in risk of lung cancer, after adjustment for smoking and other potential confounders(95% CI: 1.39, 1.63). The association was strongest for those with a family history in a sibling, after adjustment (OR=1.82, 95% CI: 1.62, 2.05). No modifying effect by histologic type was found. Never smokers showed a lower association with positive familial history of lung cancer (OR=1.25, 95% CI: 1.03, 1.52), slightly stronger for those with an affected sibling (OR=1.44, 95% CI: 1.07, 1.93), after adjustment.
The increased risk among never smokers and similar magnitudes of the effect of family history on lung cancer risk across histological types suggests familial aggregation of lung cancer is independent of those associated with cigarette smoking. While the role of genetic variation in the etiology of lung cancer remains to be fully characterized, family history assessment is immediately available and those with a positive history represent a higher risk group.
Owing to their role in controlling the efflux of toxic compounds, transporters are central players in the process of detoxification and elimination of xenobiotics, which in turn is related to cancer risk. Among these transporters, ATP-binding cassette B1/multidrug resistance 1 (ABCB1/MDR1), ABCC2/multidrug resistance protein 2 (MRP2), and ABCG2/breast cancer resistance protein (BCRP) affect susceptibility to many hematopoietic malignancies. The maintenance of regulated expression of these transporters is governed through the activation of intracellular “xenosensors” like the nuclear receptor 1I2/pregnane X receptor (NR1I2/PXR). SNPs in genes encoding these regulators have also been implicated in the risk of several cancers. Using a tagging approach, we tested the hypothesis that common polymorphisms in the transporter genes ABCB1, ABCC2, ABCG2, and the regulator gene NR1I2 could be implicated in lymphoma risk. We selected 68 SNPs in the 4 genes, and we genotyped them in 1,481 lymphoma cases and 1,491 controls of the European cases-control study (EpiLymph) using the Illumina™ GoldenGate assay technology.Carriers of the SNP rs6857600 minor allele in ABCG2, was associated with a decrease in risk of B-cell lymphoma (B-NHL) overall (p<0.001). Furthermore, a decreased risk of chronic lymphocytic leukemia (CLL) was associated with the ABCG2 rs2231142 variant (p=0.0004), which could be replicated in an independent population. These results suggest a role for this gene in B-NHL susceptibility, especially for CLL.
Lymphoma; multidrug resistance 1 (MDR1); multidrug resistance protein 2 (MRP2); breast cancer resistance protein (BCRP); pregnane X receptor (PXR)
Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. While sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as LFS- associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer (GC) in LFS.
Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute LFS registry. We identified subjects with GC documented either by pathology report or death certificate, and performed pathology review of the available specimens.
Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. GC was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at GC diagnosis were 43 and 36 years, respectively (range 24-74 years), significantly younger compared to the median age at diagnosis in the general population based on SEER data (71 years). Five (8.1%) families reported 2 or more cases of GC and 6 (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies.
Early-onset GC appears to be a component of LFS, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of GC.
Li Fraumeni syndrome; gastric cancer; hereditary gastric cancer syndromes; germline mutations; TP53
Gene expression microarray and next generation sequencing efforts on conventional, clear cell renal cell carcinoma (ccRCC) have been mostly performed in North American and Western European populations, while the highest incidence rates are found in Central/Eastern Europe. We conducted whole-genome expression profiling on 101 pairs of ccRCC tumours and adjacent non-tumour renal tissue from Czech patients recruited within the “K2 Study”, using the Illumina HumanHT-12 v4 Expression BeadChips to explore the molecular variations underlying the biological and clinical heterogeneity of this cancer. Differential expression analysis identified 1650 significant probes (fold change ≥2 and false discovery rate <0.05) mapping to 630 up- and 720 down-regulated unique genes. We performed similar statistical analysis on the RNA sequencing data of 65 ccRCC cases from the Cancer Genome Atlas (TCGA) project and identified 60% (402) of the downregulated and 74% (469) of the upregulated genes found in the K2 series. The biological characterization of the significantly deregulated genes demonstrated involvement of downregulated genes in metabolic and catabolic processes, excretion, oxidation reduction, ion transport and response to chemical stimulus, while simultaneously upregulated genes were associated with immune and inflammatory responses, response to hypoxia, stress, wounding, vasculature development and cell activation. Furthermore, genome-wide DNA methylation analysis of 317 TCGA ccRCC/adjacent non-tumour renal tissue pairs indicated that deregulation of approximately 7% of genes could be explained by epigenetic changes. Finally, survival analysis conducted on 89 K2 and 464 TCGA cases identified 8 genes associated with differential prognostic outcomes. In conclusion, a large proportion of ccRCC molecular characteristics were common to the two populations and several may have clinical implications when validated further through large clinical cohorts.
In follow-up of a recent genome-wide association study (GWAS) that identified a locus in chromosome 2p21 associated with risk for renal cell carcinoma (RCC), we conducted a fine mapping analysis of a 120 kb region that includes EPAS1. We genotyped 59 tagged common single-nucleotide polymorphisms (SNPs) in 2278 RCC and 3719 controls of European background and observed a novel signal for rs9679290 [P = 5.75 × 10−8, per-allele odds ratio (OR) = 1.27, 95% confidence interval (CI): 1.17–1.39]. Imputation of common SNPs surrounding rs9679290 using HapMap 3 and 1000 Genomes data yielded two additional signals, rs4953346 (P = 4.09 × 10−14) and rs12617313 (P = 7.48 × 10−12), both highly correlated with rs9679290 (r2 > 0.95), but interestingly not correlated with the two SNPs reported in the GWAS: rs11894252 and rs7579899 (r2 < 0.1 with rs9679290). Genotype analysis of rs12617313 confirmed an association with RCC risk (P = 1.72 × 10−9, per-allele OR = 1.28, 95% CI: 1.18–1.39) In conclusion, we report that chromosome 2p21 harbors a complex genetic architecture for common RCC risk variants.
Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein–Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification.
We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided.
Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 × 10−13) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 10−25) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 × 10−15; rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 10−10) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 × 10−31). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10−9), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 × 10−4) and replication series (P = .03).
Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.
The relationship between two measures of excess body weight, body mass index (BMI) and body size score, and risk of pancreatic cancer was examined among 574 pancreatic cancer cases and 596 frequency-matched controls from the Czech Republic and Slovakia enrolled between 2004 and 2009. Analyses using multivariable logistic regression showed an increased risk of pancreatic cancer associated with elevated quartiles of BMI at ages 20 [fourth quartile: odds ratio (OR) = 1.79, 95% confidence interval (CI): 1.23, 2.61] and 40 (fourth quartile: OR = 1.57, 95% CI: 1.09, 2.27) compared to the lowest quartile. Consistent results were observed for body size score at ages 20 (high versus low: OR = 1.66, 95% CI: 1.08, 2.57) and 40 (medium versus low: OR = 1.36, 95% CI: 1.00, 1.86), but no association was found for BMI and body size score at two years prior to interview. Stronger risk estimates for BMI were observed in males than females, particularly at age 20, but the analysis of body size yielded similar estimates by sex. When considering excess body weight at both ages 20 and 40 jointly, the highest risk estimates were observed among subjects with elevated levels at both time periods in the analysis of BMI (OR=1.86, 95% CI: 1.32, 2.62) and body size (OR=1.53, 95% CI: 1.09, 2.13). These findings, based on two different measures, provide strong support for an increased risk of pancreatic cancer associated with excess body weight, possibly strongest during early adulthood.
body mass index; body size; pancreatic cancer; risk factor; weight gain
The EPILYMPH study applied a detailed occupational exposure assessment approach to a large multi-centre case–control study conducted in six European countries. This paper analysed multiple myeloma (MM) risk associated with level of education, and lifetime occupational history and occupational exposures, based on the EPILYMPH data set.
277 MM cases and four matched controls per each case were included. Controls were randomly selected, matching for age (+/− 5 years), centre and gender. Lifetime occupations and lifetime exposure to specific workplace agents was obtained through a detailed questionnaire. Local industrial hygienists assessed likelihood and intensity for specific exposures. The odds ratio and 95% confidence intervals (OR, 95% CI) were calculated for level of education, individual occupations and specific exposures. Unconditional logistic regression models were run for individual occupations and exposures.
A low level of education was associated with MM OR=1.68 (95% CI 1.02-2.76). An increased risk was observed for general farmers (OR=1.77; 95% CI 1.05-2.99) and cleaning workers (OR=1.69; 95% CI 1.04-2.72) adjusting for level of education. Risk was also elevated, although not significant, for printers (OR=2.06; 95% CI 0.97-4.34). Pesticide exposure over a period of ten years or more increased MM risk (OR=1.62; 95% CI 1.01-2.58).
These results confirm an association of MM with farm work, and indicate its association with printing and cleaning. While prolonged exposure to pesticides seems to be a risk factor for MM, an excess risk associated with exposure to organic solvents could not be confirmed.
Multiple Myeloma; Occupation; Pesticide; Epidemiology; Case–control study; EPILYMPH study
Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21–6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 (P = 7.2 × 10−16), 6p21 (P = 2.3 × 10−14) and 15q25 (P = 2.2 × 10−63). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 (CDKN2A/p16INK4A/p14ARF/CDKN2B/p15INK4B/ANRIL; rs1333040, P = 3.0 × 10−7) which was replicated in a series of 5415 Han Chinese (P = 0.03; combined analysis, P = 2.3 × 10−8). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.
Genome-wide association studies (GWAS) require large sample sizes to obtain adequate statistical power, but it may be possible to increase the power by incorporating complementary data. In this study we investigated the feasibility of automatically retrieving information from the medical literature and leveraging this information in GWAS.
We developed a method that searches through PubMed abstracts for pre-assigned keywords and key concepts, and uses this information to assign prior probabilities of association for each single nucleotide polymorphism (SNP) with the phenotype of interest - the Adjusting Association Priors with Text (AdAPT) method. Association results from a GWAS can subsequently be ranked in the context of these priors using the Bayes False Discovery Probability (BFDP) framework. We initially tested AdAPT by comparing rankings of known susceptibility alleles in a previous lung cancer GWAS, and subsequently applied it in a two-phase GWAS of oral cancer.
Known lung cancer susceptibility SNPs were consistently ranked higher by AdAPT BFDPs than by p-values. In the oral cancer GWAS, we sought to replicate the top five SNPs as ranked by AdAPT BFDPs, of which rs991316, located in the ADH gene region of 4q23, displayed a statistically significant association with oral cancer risk in the replication phase (per-rare-allele log additive p-value [ptrend] = 2.5×10−3). The combined OR for having one additional rare allele was 0.83 (95% CI: 0.76–0.90), and this association was independent of previously identified susceptibility SNPs that are associated with overall UADT cancer in this gene region. We also investigated if rs991316 was associated with other cancers of the upper aerodigestive tract (UADT), but no additional association signal was found.
This study highlights the potential utility of systematically incorporating prior knowledge from the medical literature in genome-wide analyses using the AdAPT methodology. AdAPT is available online (url: http://services.gate.ac.uk/lld/gwas/service/config).
The BRCA1 mutation c.5266dupC was originally described as a founder mutation in the Ashkenazi Jewish (AJ) population. However, this mutation is also present at appreciable frequency in several European countries, which raises intriguing questions about the origins of the mutation. We genotyped 245 carrier families from 14 different population groups (Russian, Latvian, Ukrainian, Czech, Slovak, Polish, Danish, Dutch, French, German, Italian, Greek, Brazilian and AJ) for seven microsatellite markers and confirmed that all mutation carriers share a common haplotype from a single founder individual. Using a maximum likelihood method that allows for both recombination and mutational events of marker loci, we estimated that the mutation arose some 1800 years ago in either Scandinavia or what is now northern Russia and subsequently spread to the various populations we genotyped during the following centuries, including the AJ population. Age estimates and the molecular evolution profile of the most common linked haplotype in the carrier populations studied further suggest that c.5266dupC likely entered the AJ gene pool in Poland approximately 400–500 years ago. Our results illustrate that (1) BRCA1 c.5266dupC originated from a single common ancestor and was a common European mutation long before becoming an AJ founder mutation and (2) the mutation is likely present in many additional European countries where genetic screening of BRCA1 may not yet be common practice.
5385insC; 5382insC; founder mutation; c.5266dupC; BRCA1; Europe
We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 cases and 8,505 controls of European background from 11 studies, and followed up 6 SNPs in three replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r2 = 0.99 in controls), rs11894252 (P = 1.8×10−8) and rs7579899 (P = 2.3×10−9), map to EPAS1 on 2p21, which encodes hypoxia-inducible- factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13, contains no characterized genes (P = 7.8×10−14). In addition, we observed a promising association on 12q24.31 for rs4765623 which maps to the scavenger receptor class B, member 1 (SCARB1) gene (P = 2.6×10−8). Our study reports novel genomic regions associated with RCC risk that may lead to new etiological insights.
Background: The countries of Central and Eastern Europe have among the highest worldwide rates of renal cell cancer (RCC). Few studies have examined whether genetic variation in xenobiotic metabolic pathway genes may modify risk for this cancer. Methods: The Central and Eastern Europe Renal Cell Cancer study was a hospital-based case–control study conducted between 1998 and 2003 across seven centers in Central and Eastern Europe. Detailed data were collected from 874 cases and 2053 controls on demographics, work history, and occupational exposure to chemical agents. Genes [cytochrome P-450 family, N-acetyltransferases, NAD(P)H:quinone oxidoreductase I (NQO1), microsomal epoxide hydrolase (mEH), catechol-O-methyltransferase (COMT), uridine diphosphate-glucuronosyltransferase (UGT)] were selected for the present analysis based on their putative role in xenobiotic metabolism. Haplotypes were calculated using fastPhase. Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression adjusted for country of residence, age, sex, smoking, alcohol intake, obesity, and hypertension. Results: We observed an increased risk of RCC with one SNP. After adjustment for multiple comparisons it did not remain significant. Neither NAT1 nor NAT2 slow acetylation was associated with disease. Conclusion: We observed no association between this pathway and renal cell cancer.
renal cell cancer; epidemiology; NAT1; NAT2; CYP; NQO1; mEH; COMT
There is inconsistent evidence that increasing birth order may be associated with risk of non-Hodgkin lymphoma (NHL). The authors examined the association between birth order and related variables and NHL risk in a pooled analysis (1983–2005) of 13,535 cases and 16,427 controls from 18 case-control studies within the International Lymphoma Epidemiology Consortium (InterLymph). Overall, the authors found no significant association between increasing birth order and risk of NHL (P-trend = 0.082) and significant heterogeneity. However, a significant association was present for a number of B- and T-cell NHL subtypes. There was considerable variation in the study-specific risks which was partly explained by study design and participant characteristics. In particular, a significant positive association was present in population-based studies, which had lower response rates in cases and controls, but not in hospital-based studies. A significant positive association was present in higher-socioeconomic-status (SES) participants only. Results were very similar for the related variable of sibship size. The known correlation of high birth order with low SES suggests that selection bias related to SES may be responsible for the association between birth order and NHL.
birth order; case-control studies; lymphoma, non-Hodgkin; selection bias; social class
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 10−3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutation carriers from nine centers. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR = 0.78, 95% CI: 0.69–0.90, Ptrend = 3.6 × 10−4 and HR = 1.25, 95% CI: 1.10–1.41, Ptrend = 4.2 × 10−4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR = 1.55, 95% CI: 1.25–1.92, Ptrend = 6 × 10−5 and HR = 1.37, 95% CI: 1.16–1.62, Ptrend = 1.7 × 10−4). The magnitude and direction of the associations were consistent with the original GWAS. In subsequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
The known breast cancer (BC) susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1,LSP1 and 2q35 confer increased risks of BC for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of three additional SNPs, rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11 and rs10941679 at 5p12 and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased BC risk for BRCA2 carriers (per-allele Hazard Ratio (HR)=1.10, 95%CI:1.03-1.18, p=0.006 and HR=1.09, 95%CI:1.01-1.19, p=0.03, respectively). Neither SNP was associated with BC risk for BRCA1 carriers and rs6504950 was not associated with BC for either BRCA1 or BRCA2 carriers. Of the nine polymorphisms investigated, seven were associated with BC for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, p-values:7×10−11-0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (p=0.0049, 0.03 respectively). All risk associated polymorphisms appear to interact multiplicatively on BC risk for mutation carriers. Based on the joint genotype distribution of the seven risk associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e. between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing BC by age 80, compared with 42-50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences may be sufficient to influence the clinical management of mutation carriers.
BRCA1; BRCA2; genetic modifier; common variant; genome-wide association study; penetrance; genetic counseling
Background. Analysis of candidate genes in individual studies has had only limited success in identifying particular gene variants that are conclusively associated with lung cancer risk. In the International Lung Cancer Consortium (ILCCO), we conducted a coordinated genotyping study of 10 common variants selected because of their prior evidence of an association with lung cancer. These variants belonged to candidate genes from different cancer-related pathways including inflammation (IL1B), folate metabolism (MTHFR), regulatory function (AKAP9 and CAMKK1), cell adhesion (SEZL6) and apoptosis (FAS, FASL, TP53, TP53BP1 and BAT3). Methods. Genotype data from 15 ILCCO case–control studies were available for a total of 8431 lung cancer cases and 11 072 controls of European descent and Asian ethnic groups. Unconditional logistic regression was used to model the association between each variant and lung cancer risk. Results. Only the association between a non-synonymous variant of TP53BP1 (rs560191) and lung cancer risk was significant (OR = 0.91, P = 0.002). This association was more striking for squamous cell carcinoma (OR = 0.86, P = 6 × 10−4). No heterogeneity by center, ethnicity, smoking status, age group or sex was observed. In order to confirm this association, we included results for this variant from a set of independent studies (9966 cases/11 722 controls) and we reported similar results. When combining all these studies together, we reported an overall OR = 0.93 (0.89–0.97) (P = 0.001). This association was significant only for squamous cell carcinoma [OR = 0.89 (0.85–0.95), P = 1 × 10−4]. Conclusion. This study suggests that rs560191 is associated to lung cancer risk and further highlights the value of consortia in replicating or refuting published genetic associations.
Background Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens.
Methods We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies.
Results Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96–1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39–2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23–1.38, P = 1 × 10–18), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19–1.35, P = 5 × 10–13). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01–1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour.
Conclusions This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.
Lung cancer; nicotine dependence; smoking quantity; UADT cancer
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p≤5×10−7). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10−8) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2×10−8) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5×10−8; rs1229984-ADH1B, p = 7×10−9; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
We have used a two-phased study approach to identify common genetic variation involved in susceptibility to upper aero-digestive tract cancer. Using Illumina HumanHap300 beadchips, 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls, were genotyped for a panel 317,000 genetic variants that represent the majority of common genetic in the human genome. The 19 top-ranked variants were then studied in an additional series of 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies. Five variants were significantly associated with UADT cancer risk after the completion of both stages, including three residing within the alcohol dehydrogenase genes (ADH1B, ADH1C, ADH7) that have been previously described. Two additional variants were found, one near the ALDH2 gene and a second variant located in HEL308, a DNA repair gene. These results implicate two variants 4q21 and 12q24 and further highlight three ADH variants UADT cancer susceptibility.
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).
In an International Lymphoma Epidemiology Consortium pooled analysis, polymorphisms in 2 immune-system-related genes, tumor necrosis factor (TNF) and interleukin-10 (IL10), were associated with non-Hodgkin lymphoma (NHL) risk. Here, 8,847 participants were added to previous data (patients diagnosed from 1989 to 2005 in 14 case-control studies; 7,999 cases, 8,452 controls) for testing of polymorphisms in the TNF –308G>A (rs1800629), lymphotoxin-α (LTA) 252A>G (rs909253), IL10 –3575T>A (rs1800890, rs1800896), and nucleotide-binding oligomerization domain containing 2 (NOD2) 3020insC (rs2066847) genes. Odds ratios were estimated for non-Hispanic whites and several ethnic subgroups using 2-sided tests. Consistent with previous findings, odds ratios were increased for “new” participant TNF –308A carriers (NHL: per-allele odds ratio (ORallelic) = 1.10, Ptrend = 0.001; diffuse large B-cell lymphoma (DLBCL): ORallelic = 1.23, Ptrend = 0.004). In the combined population, odds ratios were increased for TNF –308A carriers (NHL: ORallelic = 1.13, Ptrend = 0.0001; DLBCL: ORallelic = 1.25, Ptrend = 3.7 × 10−6; marginal zone lymphoma: ORallelic = 1.35, Ptrend = 0.004) and LTA 252G carriers (DLBCL: ORallelic = 1.12, Ptrend = 0.006; mycosis fungoides: ORallelic = 1.44, Ptrend = 0.015). The LTA 252A>G/TNF –308G>A haplotype containing the LTA/TNF variant alleles was strongly associated with DLBCL (P = 2.9 × 10−8). Results suggested associations between IL10 –3575T>A and DLBCL (Ptrend = 0.02) and IL10 –1082A>G and mantle cell lymphoma (Ptrend = 0.04). These findings strengthen previous results for DLBCL and the LTA 252A>G/TNF –308A locus and provide robust evidence that these TNF/LTA gene variants, or others in linkage disequilibrium, are involved in NHL etiology.
lymphoma; lymphoma, non-Hodgkin; lymphotoxin-alpha; meta-analysis; polymorphism, genetic; polymorphism, single nucleotide; tumor necrosis factor-alpha
Central and Eastern Europe has among the highest rates of renal cell cancer worldwide. Few studies have been conducted in these areas to investigate the possible role of occupational exposures in renal cell cancer etiology. The purpose of this study was to examine the association of renal cell cancer with employment in specific occupations and industries.
From 1999–2003, we conducted a hospital-based case-control study in seven areas of the Czech Republic, Poland, Romania and Russia. A detailed occupational history was collected from renal cell cancer cases and controls, together with information on potential confounders. Odds ratios (OR) and 95% confidence intervals (CI) of cancer risk were calculated for having ever been employed in selected jobs and industries, with follow-up analyses examining duration of employment.
A total of 992 histologically confirmed incident renal cell cancer cases and 1,465 controls were included in the analysis. An increased risk of renal cell cancer was observed for workers in agricultural labor and animal husbandry (OR=1.43, 95% CI 1.05, 1.93), particularly among women employed as general farm workers (OR=2.73, 95% CI 1.05, 7.13). Risk gradients for agricultural work increased with longer employment. An overall increased risk of renal cell cancer was seen among architects and engineers (OR=1.89, 95% CI 1.35, 2.65), and mechanical engineers (OR=1.71, 95% CI 1.03, 2.84).
Our data suggest an association between renal cell cancer and agricultural work, particularly among female workers.
Renal cell carcinoma; Agricultural work; Solvents; Painting; Firefighting