[Show abstract][Hide abstract]ABSTRACT: 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.
Full-text · Article · Mar 2016 · Nature Communications
[Show abstract][Hide abstract]ABSTRACT: Evidence from a small number of studies suggests longer telomere length measured in peripheral leukocytes is associated with
an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by
unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal
a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and
NHL risk in a study of 10,102 NHL cases of the four most common B-cell histologic types and 9,562 controls using a genetic
risk score comprising nine telomere length-associated single nucleotide polymorphisms (SNPs). This approach uses existing
genotype data and estimates telomere length by weighting the number of telomere length associated variant alleles an individual
carries with the published change in Kb of telomere length. Analysis of the telomere length genetic risk score resulted in
an association between longer telomere length and increased NHL risk (four B-cell histologic types combined; odds ratio (OR)=1.49,
95% CI=1.22-1.82, p-value=8.5×10−5). Subtype specific analyses indicated chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal
NHL subtype contributing to this association (OR=2.60, 95% CI=1.93-3.51, P-value=4.0×10−10). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma (MZL) subtypes as well
as age for the follicular lymphoma (FL) subtype. Our results indicate a genetic background that favors longer telomere length
may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length
with increased NHL risk.
No preview · Article · Feb 2016 · Human Molecular Genetics
[Show abstract][Hide abstract]ABSTRACT: Background: 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.
Full-text · Article · Oct 2015 · JNCI Journal of the National Cancer Institute
[Show abstract][Hide abstract]ABSTRACT: Various occupations have been associated with an elevated NHL risk but results have been inconsistent across studies.
To investigate occupational risk of non-Hodgkin lymphoma (NHL) and four common NHL subtypes with particular focus on occupations of a priori interest.
We conducted a pooled analysis of 10,046 cases and 12,025 controls from 10 NHL studies participating in the InterLymph Consortium. We harmonized the occupational coding using the 1968 International Standard Classification of Occupations (ISCO) and grouped occupations previously associated with NHL into 25 a priori groups. Odds ratios (OR), adjusted for center, age and sex were determined for NHL overall and the subtypes diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and peripheral T-cell lymphoma (PTCL).
We confirmed previously reported positive associations between NHL and farming occupations (field crop/vegetable farm workers OR = 1.26; 95% confidence interval (CI): 1.05, 1.51; general farm workers OR = 1.19, 95% CI: 1.03, 1.37), and with specific occupations as women's hairdressers (OR = 1.34; 95% CI: 1.02, 1.74), charworkers/cleaners (OR = 1.17; 95% CI: 1.01, 1.36), spray-painters (OR = 2.07; 95% CI: 1.30, 3.29), electrical wiremen (OR = 1.24; 95% CI: 1.00, 1.54), and carpenters (OR = 1.42; 95% CI: 1.04, 1.93). We observed subtype specific associations for DLBCL and CLL/SLL in women's hairdressers and for DLBCL and PTCL in textile workers.
Our pooled analysis of 10 international studies adds to evidence suggesting that farming, hairdressing, and textile industry-related exposures may contribute to NHL risk. Associations with women's hairdresser and textile occupations may be specific for certain NHL subtypes.
No preview · Article · Sep 2015 · Environmental Health Perspectives
[Show abstract][Hide abstract]ABSTRACT: Purpose:
Cigarette smoking is an established risk factor for pancreatic cancer (PC). We examined the association between cigarette smoking and PC in a San Francisco Bay Area clinic-based, case-control study.
A total of 536 cases and sex and age frequency-matched controls (n = 869) were recruited predominately from the University of California San Francisco (UCSF) medical clinics between 2006 and 2011. Participants were interviewed in-person using structured questionnaires. Adjusted odds ratios (ORs) were computed.
Forty-eight percent of cases and controls reported never having smoked cigarettes; 39% of cases and 40% of controls were former smokers; 13% of cases and 12% of controls were current smokers. No association was found for either former (OR = 0.85, 95% confidence interval [CI] = 0.66-1.1) or current cigarette smoking (men: OR = 1.0, 95% CI = 0.60-1.7; women: OR = 1.2, 95% CI = 0.73-2.1). No dose-response relationships were detected with number of cigarettes/day, smoking intensity, duration, or years since last smoked. Comparisons with a 1995-1999 population-based UCSF study demonstrated a significantly increased proportion of never smokers in this study (P < .001).
This study revealed no significant associations between cigarette smoking and PC in the San Francisco Bay Area during 2006-2011. Data suggest a reduction in the duration of smoking within the referral population.
No preview · Article · Aug 2015 · Annals of epidemiology
[Show abstract][Hide abstract]ABSTRACT: While alcohol consumption is known to increase the risk of several types of cancer, evidence regarding the association between alcohol and melanoma is inconclusive. This pooled analysis was conducted to examine total alcohol consumption (grams per day), and type of alcohol consumed (beer, wine, beer and wine combined, and liquor) in relation to melanoma among women using original data from eight completed case-control studies (1886 cases and 2113 controls), with adjustment for the potential confounding effects of sun exposure-related factors. We found a positive association with ever consuming alcohol [adjusted pooled odds ratio (pOR) 1.3, 95 % confidence interval (CI) 1.1-1.5]. Specifically the pORs were 1.4 (95 % CI 1.1-1.8) for wine, 1.1 (95 % CI 0.9-1.5) for beer and 1.2 (95 % CI 1.0-1.4) for liquor. However, the pOR for the highest fourth of consumption compared with never consumption was 1.0 (95 % CI 0.7-1.3) without evidence of a trend with increasing amount of total alcohol, or separately with amount of beer, wine or liquor consumed. Stratifying by anatomic site of lesion, number of nevi, age group, or histologic subtype did not alter these results. Although the results showed a weak positive association between ever consuming alcohol and melanoma occurrence, our findings do not provide strong support for the hypothesis that alcohol consumption plays a role in the development of melanoma in women.
Full-text · Article · Jul 2015 · Archives for Dermatological Research
[Show abstract][Hide abstract]ABSTRACT: Background: Anal squamous intraepithelial lesions (SIL) and cancers are increased in immunocompromised populations. Based upon anatomic and histologic similarities, the cervix is used as the model for anal screening. During cervical colposcopy, acetic acid (AA) and Lugol's staining (LS) result in characteristic changes that help distinguish low-grade (L)SIL from high-grade (H)SIL. Lesion characteristics were evaluated for their ability to distinguish anal (a)LSIL from anal (a)HSIL during high-resolution anoscopy after application of AA and LS. Methods: AA-stained lesions were described using standard cervical colposcopic criteria. LS was then applied and lesions were characterized as Lugol's-negative (L-), Lugol's-partial (L+/-), or Lugol's positive (L+) and then biopsied. Biopsies were characterized as benign, squamous atypia, LSIL or HSIL. Results: 835 anal lesions were analyzed. Sensitivity and positive predictive value (PPV) for aHSIL were highest for characteristics associated with cervical (c)HSIL. L- was independently associated with aHSIL (OR=4.7, 95% CI=3.4-6.7). In multiple logistic regression analysis, significant predictors of aHSIL were flat contour (OR=2.24, 95% CI=1.3-3.8), mosaic pattern (OR=2.0, 95% CI=1.4-2.9), vascular punctation (OR=1.5, 95% CI=1.1-2.1) and L- (OR=2.3, 95% CI=1.5-3.4). L- staining improved the PPV of aHSIL almost twofold in lesions that otherwise had a colposcopic impression of LSIL. Conclusions: Evaluating acetowhite lesions for contour, surface, vascularity, and LS may maximize the likelihood of identifying aHSIL.
[Show abstract][Hide abstract]ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.
[Show abstract][Hide abstract]ABSTRACT: Evidence on the association between vitamin D status and pancreatic cancer risk is inconsistent. This inconsistency may be partially attributable to variation in vitamin D regulating genes. We selected 11 vitamin D-related genes (GC, DHCR7, CYP2R1, VDR, CYP27B1, CYP24A1, CYP27A1, RXRA, CRP2, CASR and CUBN) totaling 213 single nucleotide polymorphisms (SNPs), and examined associations with pancreatic adenocarcinoma. Our study included 3,583 pancreatic cancer cases and 7,053 controls from the genome-wide association studies of pancreatic cancer PanScans-I-III. We used the Adaptive Joint Test and the Adaptive Rank Truncated Product statistic for pathway and gene analyses, and unconditional logistic regression for SNP analyses, adjusting for age, sex, study and population stratification. We examined effect modification by circulating vitamin D concentration (≤50, >50 nmol/L) for the most significant SNPs using a subset of cohort cases (n = 713) and controls (n = 878). The vitamin D metabolic pathway was not associated with pancreatic cancer risk (p = 0.830). Of the individual genes, none were associated with pancreatic cancer risk at a significance level of p<0.05. SNPs near the VDR (rs2239186), LRP2 (rs4668123), CYP24A1 (rs2762932), GC (rs2282679), and CUBN (rs1810205) genes were the top SNPs associated with pancreatic cancer (p-values 0.008-0.037), but none were statistically significant after adjusting for multiple comparisons. Associations between these SNPs and pancreatic cancer were not modified by circulating concentrations of vitamin D. These findings do not support an association between vitamin D-related genes and pancreatic cancer risk. Future research should explore other pathways through which vitamin D status might be associated with pancreatic cancer risk.
[Show abstract][Hide abstract]ABSTRACT: Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.
Full-text · Article · Jan 2015 · Nature Communications
[Show abstract][Hide abstract]ABSTRACT: Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.
No preview · Article · Oct 2014 · The American Journal of Human Genetics
[Show abstract][Hide abstract]ABSTRACT: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.