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1.  Mortality and cancer incidence in a pooled cohort of US firefighters from San Francisco, Chicago and Philadelphia (1950–2009) 
To examine mortality patterns and cancer incidence in a pooled cohort of 29 993 US career firefighters employed since 1950 and followed through 2009.
Mortality and cancer incidence were evaluated by life table methods with the US population referent. Standardised mortality (SMR) and incidence (SIR) ratios were determined for 92 causes of death and 41 cancer incidence groupings. Analyses focused on 15 outcomes of a priori interest. Sensitivity analyses were conducted to examine the potential for significant bias.
Person-years at risk totalled 858 938 and 403 152 for mortality and incidence analyses, respectively. All-cause mortality was at expectation (SMR=0.99, 95% CI 0.97 to 1.01, n=12 028). There was excess cancer mortality (SMR=1.14, 95% CI 1.10 to 1.18, n=3285) and incidence (SIR=1.09, 95% CI 1.06 to 1.12, n=4461) comprised mainly of digestive (SMR=1.26, 95% CI 1.18 to 1.34, n=928; SIR=1.17, 95% CI 1.10 to 1.25, n=930) and respiratory (SMR=1.10, 95% CI 1.04 to 1.17, n=1096; SIR=1.16, 95% CI 1.08 to 1.24, n=813) cancers. Consistent with previous reports, modest elevations were observed in several solid cancers; however, evidence of excess lymphatic or haematopoietic cancers was lacking. This study is the first to report excess malignant mesothelioma (SMR=2.00, 95% CI 1.03 to 3.49, n=12; SIR=2.29, 95% CI 1.60 to 3.19, n=35) among US firefighters. Results appeared robust under differing assumptions and analytic techniques.
Our results provide evidence of a relation between firefighting and cancer. The new finding of excess malignant mesothelioma is noteworthy, given that asbestos exposure is a known hazard of firefighting.
PMCID: PMC4499779  PMID: 24142974
2.  Colon cancer lymph node evaluation among Military Health System beneficiaries: An analysis by race/ethnicity 
Annals of surgical oncology  2014;22(1):195-202.
The number of lymph nodes examined during colon cancer surgery falls below nationally recommended guidelines in the general population, with blacks and Hispanics less likely to have adequate nodal evaluation in comparison to whites. The Department of Defense’s (DoD’s) Military Health System (MHS) provides equal access to medical care for its beneficiaries, regardless of racial/ethnic background. This study aimed to investigate whether racial/ethnic treatment differences exist in the MHS, an equal access medical care system.
Linked data from the DoD cancer registry and administrative claims databases were used and included 2,155 colon cancer cases. Multivariate logistic regression assessed the association between race/ethnicity and the number of lymph nodes examined (<12 and ≥ 12) overall and for stratified analyses.
No overall racial/ethnic difference in the number of lymph nodes examined was identified. Further stratified analyses yielded similar results, except potential racial/ethnic differences were found among persons with poorly differentiated tumors, where non-Hispanic blacks (NHBs) tended to be less likely to have ≥12 lymph nodes dissected (OR: 0.34, 95% CI: 0.14-0.80, p-value: 0.01) compared to non-Hispanic whites.
Racial/ethnic disparities in the number of lymph nodes evaluated among patients with colon cancer were not apparent in an equal-access healthcare system. However, among poorly differentiated tumors, there might be racial/ethnic differences in nodal yield, suggesting the possible effects of factors other than access to healthcare.
PMCID: PMC4275347  PMID: 25059789
3.  Surveillance mammography among female DoD beneficiaries: a study by race and ethnicity 
Cancer  2013;119(19):3531-3538.
Annual surveillance mammography is recommended after breast cancer diagnosis. Previous studies have suggested that surveillance mammography varies by demographics and initial tumor characteristics, which are related to access to healthcare. The Department of Defense's Military Health System (MHS) provides beneficiaries with equal healthcare access and thus offers an excellent opportunity to assess whether racial differences in surveillance mammography persist when access to care is equal.
Among female beneficiaries with a history of breast cancer logistic regression was used to assess racial/ethnic variation in surveillance mammography during three 12-month periods, beginning one year after diagnosis adjusting for demographic, tumor and health characteristics.
Overall surveillance mammography decreased from 70% during the first year to 59% during the third year (p<0.01). Although there was an overall tendency for surveillance mammography to be higher among minority women compared to non-Hispanic white women, after adjusting for covariates, the difference was significant only during the first year among blacks (odds ratio (OR)=1.46; 95% Confidence Interval (CI)=1.10-1.95) and the second year among Asian Pacific Islanders (OR=2.29; 95%CI=1.52-3.44) and Hispanics (OR=1.92; 95%CI=1.17-3.18). When stratified by age at diagnosis and type of breast cancer surgery, significant racial differences tended to be observed among younger women (<50 years) and only among women who had mastectomies.
Minority women were equally or more likely than non-Hispanic white women to receive surveillance mammography within the MHS. The racial disparities in surveillance mammography reported in other studies were not observed in a system with equal access to care.
PMCID: PMC3787997  PMID: 23913448
breast cancer; mammography; surveillance; survivor; epidemiology; healthcare access
4.  Breast reconstruction after mastectomy among Department of Defense beneficiaries by race 
Cancer  2014;120(19):3033-3039.
Post-mastectomy breast reconstruction increased approximately 20% between 1998 and 2008 in the United States and has been found to improve body image, self-esteem and quality of life. These procedures, however, tend to be less common among minority women, which may be due to variations in healthcare access. The Department of Defense (DoD) provides equal healthcare access, thereby affording an exceptional environment to assess whether racial variations persist when access to care is equal.
Linked DoD cancer registry and medical claims data were used. The receipt of reconstruction was compared between white (n=2,974) and black women (n=708) who underwent mastectomies to treat incident, histologically-confirmed, breast cancer diagnosed from 1998 to 2007.
During the study period, post-mastectomy reconstruction increased among both black (27.3% to 40.0%) and white (21.8% to 40.6%) female breast cancer patients. Receipt of reconstruction did not vary significantly by race (odds ratio: 0.93; 95% confidence interval 0.76-1.15). Reconstruction decreased significantly with increasing age, tumor stage and receipt of radiotherapy and was significantly more common in more recent years, among active servicewomen, Tricare Prime (HMO) beneficiaries and women whose sponsor was an officer.
The receipt of reconstruction did not vary by race within this equal access health system, indicating that the racial disparities reported in previous studies may have partially been due to variations in healthcare access. Additional research to determine why a large proportion of breast cancer patients do not undergo reconstruction might be beneficial, particularly because these procedures have been associated with non-cosmetic benefits.
PMCID: PMC4172542  PMID: 24965236
breast cancer; mastectomy; reconstruction; racial disparities; epidemiology; healthcare access
5.  Lung cancer survival among black and white patients in an equal access health system 
Racial disparities in lung cancer outcomes have been observed in the general population. However, it is unclear whether survival differences persist when patients have equal access to healthcare. Our objective was to determine if lung cancer survival differed among black and white patients in the U.S. Military Health System (MHS), an equal access healthcare system.
The study subjects were 10,181 black and white patients identified through the Department of Defense’s Automated Central Tumor Registry, who were ≥20 years old and diagnosed with lung cancer between 1990 and 2003. Racial differences in all-cause survival were examined using the Kaplan–Meier method and Cox proportional hazards regression models stratified by histology. For comparison, survival rates in the general population were calculated using Surveillance, Epidemiology and End Results (SEER)-9 data.
Analyses included 9,154 white and 1,027 black patients: 1,834 small cell lung cancers, 3,876 adenocarcinomas, 2,741 squamous cell carcinomas, and 1,730 large cell carcinomas. Although more favorable crude survival was observed among black patients than white patients with small cell lung cancer (p=0.04), survival was similar between the two groups after covariate adjustment. Racial differences in survival were non-significant for adenocarcinomas, squamous cell carcinomas and large cell carcinomas. Survival rates appeared to be better in the MHS than in the general population.
Conclusions and Impact
All-cause survival was similar among black and white lung cancer patients in the MHS. Providing equal access to healthcare may eliminate racial disparities in lung cancer survival while improving the outcome of all cases.
PMCID: PMC4151240  PMID: 22899731
equal access to healthcare; histologic subtypes; lung cancer; racial disparity; survival
6.  Melanoma incidence rates among whites in the U.S. military 
The U.S. Military and general populations may differ in the exposure to sunlight and other risk factors for melanoma, and therefore the incidence rates of melanoma may be different in these two populations. However, few studies have compared melanoma incidence rates and trends over time between the military and the general population.
Melanoma incidence rates from 1990 to 2004 among white active-duty military personnel and the general U.S. population were compared using data from the Department of Defense (DoD)’s Automated Central Tumor Registry (ACTUR) and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.
Age-adjusted melanoma rates overall were significantly lower in the military than in the general population; the incidence rate ratio (IRR) was 0.75 for men and 0.56 for women. Age-specific rates, however, were significantly lower among younger individuals aged <45 years but significantly higher among those aged 45 years or older (p-values<0.05). Melanoma incidence rose from 1990–1994 to 2000–2004 in both populations, with the most rapid increase (40%) among younger men in the military. Melanoma incidence rates also varied by branch of military service; rates were highest in the Air Force.
These results suggest that melanoma incidence rate patterns differ between the military and the general population.
Further studies of risk factors for melanoma in the military are needed to explain these findings.
PMCID: PMC4148910  PMID: 21148122
Melanoma; incidence rates; Active duty; military; SEER program
7.  Breast Conserving Surgery versus Mastectomy: The Influence of Comorbidities on Choice of Surgical Operation in the Department of Defense Healthcare System 
American journal of surgery  2013;206(3):393-399.
Studies on the effect of comorbidities on breast cancer operation have been limited and inconsistent. This study investigated whether pre-existing comorbidities influenced breast cancer surgical operation in an equal access healthcare system.
This study was based on linked Department of Defense cancer registry and medical claims data. The study subjects were patients diagnosed with stage I–III breast cancer during 2001 to 2007. Logistic regression was used to determine if comorbidity was associated with operation type and time between diagnosis and operation.
Breast cancer patients with comorbidities were more likely to receive mastectomy (OR=1.27, 95% CI, 1.14–1.42) than breast conserving surgery plus radiation. Patients with comorbidities were also more likely to delay having operation than those without comorbidities (OR=1.27, 95% CI, 1.14–1.41).
In an equal access healthcare system, comorbidity was associated with having a mastectomy and with a delay in undergoing operation.
PMCID: PMC4148911  PMID: 23866763
Breast cancer; breast conserving surgery; comorbidity; Department of Defense health system; mastectomy; military
8.  Race and Colon Cancer Survival in an Equal-Access Healthcare System 
Studies have shown that whites have a higher colorectal cancer survival rate than blacks. However, it is unclear whether racial disparities result from unequal access to medical care or factors other than healthcare access or both. This study assessed whether non-Hispanic Whites (NHWs) and non-Hispanic Blacks (NHBs) differ in colon cancer (CC) survival in an equal-access healthcare system and examined whether racial differences varied by demographic and tumor characteristics. The study included 2,537 Military Health System patients diagnosed with CC between 1998 and 2007. Median follow-up time was 31.4 months. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) for race, overall and stratified by age at diagnosis, sex, and tumor stage. No difference in overall survival (OS) between NHWs and NHBs was observed in general. However, among patients younger than 50 years old, NHBs experienced significantly worse OS than NHWs (HR: 2.27, 95% CI: 1.48–3.49). Further stratification by sex and tumor stage showed that this racial disparity was confined to women (HR: 2.80, 95% CI: 1.30–6.00) and patients with distant stage disease (HR: 2.65, 95% CI: 1.38–5.08) in this age group. When medical care is equally available to NHWs and NHBs, similar overall CC survival was observed; however, evidence of racial differences in survival was apparent for patients younger than 50 years old. This study suggests that factors other than access to care may be related to racial disparities in CC survival among younger, but not older, patients.
PMCID: PMC4143979  PMID: 23576691
race; colon cancer; survival; equal-access
9.  Racial variation in breast cancer treatment among Department of Defense beneficiaries 
Cancer  2011;118(3):812-820.
Although the overall age-adjusted incidence rates for female breast cancer are higher among whites than blacks, mortality rates are higher among blacks. Many attribute this discrepancy to disparities in healthcare access and to blacks presenting with later stage disease. Within the Department of Defense (DoD) Military Health System all beneficiaries have equal access to healthcare. The aim of this study was to determine if breast cancer treatment varied between white and black female breast cancer patients in the DoD system.
The study data were drawn from the DoD cancer registry and medical claims databases. Study subjects included 2,308 white and 391 black female beneficiaries diagnosed with breast cancer between 1998 and 2000. Multivariate logistic regression analyses that controlled for demographic factors, tumor characteristics, and comorbidities were used to assess racial differences in the receipt of surgery, chemotherapy and hormonal therapy.
There was no significant difference in surgery type, particularly when mastectomy was compared to breast conserving surgery plus radiation (blacks vs. whites: OR=1.1; 95% CI=0.8–1.5). Among those with local stage tumors, blacks were as likely as whites to receive chemotherapy (OR=1.2; 95% CI=0.9–1.8) and hormonal therapy (OR=1.0; 95% CI=0.7–1.4). Among those with regional stage tumors, blacks were significantly less likely than whites to receive chemotherapy (OR=0.4; 95% CI=0.2–0.7) and hormonal therapy (OR=0.5; 95% CI=0.3–0.8).
Even within an equal access healthcare system, stage-related racial variations in breast cancer treatment are evident. Studies that identify driving factors behind these within-stage racial disparities are warranted.
PMCID: PMC4123115  PMID: 21766298
10.  Racial variation in tumor stage at diagnosis among Department of Defense beneficiaries 
Cancer  2011;118(5):1397-1403.
Tumor stage at diagnosis often varies by racial/ethnic group, possibly due to inequitable healthcare access. Within the Department of Defense (DoD) Military Health System, beneficiaries have equal healthcare access. This study aimed to determine if tumor stage differed between whites and blacks for breast, cervical, colorectal and prostate cancers, which have effective screening regimens, based on data from the DoD’s Automated Cancer Tumor Registry from 1990–2003.
Distributions of tumor stage (localized vs. non-localized) between whites and blacks in the military were compared stratified by sex, active duty status, and age at diagnosis. Logistic regression was used to further adjust for age, marital status, year of diagnosis, geographic region, military service branch and tumor grade. Distributions of tumor stage were then compared between the military and general populations.
Racial differences in the distribution of stage were significant only among non-active duty beneficiaries. After adjusting for covariates, earlier stages of breast cancer after age 49 and prostate cancer after age 64 were significantly more common among white than black non-active duty beneficiaries (p<0.05), although the absolute difference for prostate cancer was minimal. Racial differences in stage for cervical and colorectal cancers were not significant after adjustment. Compared to the general population, the racial differences in the military were similar or slightly attenuated.
Racial disparities in stage at diagnosis were apparent in the DoD’s equal access healthcare system among older non-active duty beneficiaries. Socioeconomic status, supplemental insurance, cultural beliefs and biological factors may be related to these results.
PMCID: PMC3197959  PMID: 21837685
11.  Thyroid cancer incidence among active duty U.S. military personnel, 1990-2004 
Increases in thyroid papillary carcinoma incidence rates have largely been attributed to heightened medical surveillance and improved diagnostics. We examined papillary carcinoma incidence in an equal-access healthcare system by demographics, which are related to incidence.
Incidence rates during 1990-2004 among white and black individuals aged 20-49 years in the military and the general U.S. population were compared using data from the Department of Defense’s Automated Central Tumor Registry and the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER-9) program.
Incidence was significantly higher in the military than in the general population among white women [incidence rate ratio (IRR)=1.42, 95% 95% confidence interval (CI)=1.25-1.61], black women (IRR=2.31, 95% CI=1.70-2.99), and black men (IRR=1.69, 95% CI=1.10-2.50). Among whites, differences between the two populations were confined to rates of localized tumors (women: IRR=1.73, 95% CI=1.47-2.00; men: IRR=1.51, 95% CI=1.30-1.75), which may partially be due to variation in staging classification. Among white women, rates were significantly higher in the military regardless of tumor size, and rates rose significantly over time both for tumors ≤2 cm (military: IRR=1.64, 95% CI=1.18-2.28; general population: IRR=1.55, 95% CI=1.45-1.66) and >2 cm (military: IRR=1.74, 95% CI=1.07-2.81; general population: IRR=1.48, 95% CI=1.27-1.72). Among white men, rates increased significantly only in the general population. Incidence also varied by military service branch.
Heightened medical surveillance does not appear to fully explain the differences between the two populations or the temporal increases in either population.
These findings suggest the importance of future research into thyroid cancer etiology.
PMCID: PMC3210876  PMID: 21914838
Thyroid Neoplasms; Incidence; SEER Program; Military Personnel; United States/epidemiology
12.  Polymorphisms in integrin genes and lymphoma risk 
Leukemia research  2011;35(7):968-970.
Immune deficiency is one of the best characterized and strongest known risk factors for non-Hodgkin lymphoma (NHL). We studied the association between single nucleotide polymorphisms (SNPs) in integrin genes that are important components in human innate immunity and the risk of NHL in a population-based case–control study of women in Connecticut, USA. A total of 373 tag SNPs in 33 gene regions were included in the analysis of 448 cases and 525 controls. The ADAM19 rs11466782 SNP was associated with an increased risk of lymphoma (OR, 1.73; 95 % CI, 1.28–2.35; P additive = 0.0004), and the ICAM3 rs2304240 (OR, 0.67; 95 % CI, 0.52–0.86; P additive = 0.002) and the PTGDR rs708486 SNPs (OR, 0.75; 95 % CI, 0.63–0.90; P additive = 0.002) were associated with reduced risk of lymphoma. Two gene regions (ADAM19 (P=0.009) and ICAM3 (P=0.009)) displayed global associations with lymphoma risk at the P<0.01 level. While our results suggest that genetic polymorphisms in integrin genes may play a role in the genesis of lymphoma in women, they should be viewed as exploratory until they are replicated in additional populations.
PMCID: PMC3232182  PMID: 21239057
lymphoma; integrin; innate immunity; single nucleotide polymorphism
13.  Genetic variation in Th1/Th2 pathway genes and risk of non-Hodgkin lymphoma: A pooled analysis of three population-based case-control studies 
British journal of haematology  2011;153(3):341-350.
The balance between Th1 and Th2 activity is critical in lymphoid cell development and differentiation. Immune dysfunction underlies lymphomagenesis, so an alteration in the regulation of key Th1/Th2 cytokines may lead to the development of non-Hodgkin lymphoma (NHL). To study the impact of polymorphism in Th1/Th2 cytokines on NHL risk, we analyzed 145 tag single nucleotide polymorphisms (SNPs) in 17 Th1/Th2 cytokine and related genes in three population-based case-control studies (1,946 cases and 1,808 controls). Logistic regression was used to compute odds ratios (OR) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. A gene-based analysis adjusting for the number of tag SNPs genotyped in each gene showed significant associations with risk of NHL combined and one or more NHL subtypes for Th1 (IL12A and IL12RB1) and Th2 (IL4, IL10RB, and IL18) genes. The strongest association was for IL12A rs485497, which plays a central role in bridging the cellular and humoral pathways of innate resistance and antigen-specific adaptive immune responses (allele risk OR=1.17; P(trend)=0.00099). This SNP was also associated specifically with risk of follicular lymphoma (allele risk OR=1.26; P(trend)=0.0012). These findings suggest that genetic variation in Th1/Th2 cytokine genes may contribute to lymphomagenesis.
PMCID: PMC3075370  PMID: 21418175
Non-Hodgkin lymphoma; single nucleotide polymorphisms; immunogenetics; case-control study
14.  Variation in innate immunity genes and risk of multiple myeloma 
Hematological oncology  2011;29(1):42-46.
Multiple myeloma (MM) is a B-cell lymphoid malignancy suspected to be associated with immunologic factors. Given recent findings associating single-nucleotide polymorphisms (SNPs) in innate immunity genes with non-Hodgkin lymphoma, we conducted an investigation of innate immune gene variants using specimens from a population-based case-control study of MM conducted in Connecticut women. Tag SNPs (N=1,461) summarizing common variation in 149 gene regions were genotyped in non-Hispanic Caucasian subjects (103 cases, 475 controls). Odds ratios (OR) and 95% confidence intervals (CI) relating SNP associations with MM were computed using unconditional logistic regression, while the MinP test was used to investigate associations with MM at the gene level. We calculated permutation-adjusted P-values and false discovery rates (FDR) to account for the number of comparisons performed in SNP-level and gene-level tests, respectively. Three genes were associated with MM when controlling for a FDR of ≤10%: SERPINE1 (PMinP<0.0001; FDR=0.02), HGF (PMinP=0.0006; FDR=0.06) and CCR7 (PMinP=0.001; FDR=0.08). Two SNPs demonstrated robust associations: SERPINE1 rs2227667 (P=2.1×10−5, Ppermutation=0.03) and HGF rs17501108 (P=5.0×10−5, Ppermutation=0.07). Our findings suggest that genetic variants in SERPINE1 and HGF, and possibly CCR7, are associated with MM risk, and warrant further investigation in other studies.
PMCID: PMC2980579  PMID: 20658475
epidemiology; myeloma; genetics
15.  Oral Contraceptive Use Among Women in the Military and the General U.S. Population 
Journal of Women's Health  2010;19(5):839-845.
To compare oral contraceptive (OC) use during a 12-month period among women aged 18–39 years in the U.S. military and the general U.S. population using data from the Military Health System Management Analysis and Reporting Tool (M2) and the National Health and Nutrition Examination Survey (NHANES), respectively.
OC use was age adjusted to the 2000 U.S. Census population. Comparisons between the military (n = 83,181) and the general population (unweighted n = 360), as well as between the military branches, were conducted overall and stratified by age, race/ethnicity, and marital status.
OC use was higher in the military (34%) than in the general population (29%, p < 0.05). This difference increased with age and was most pronounced among Hispanics (military, 32.2%; general population, 19.8%). Within the military, OC use was highest in the Air Force (39%) and lowest in the Army (30%, p < 0.05).
These findings suggest that OC use differs between the military and the general population and within the military by service branch. Further studies that assess whether OC use is related to variations in health outcomes between these two populations and within the military are warranted.
PMCID: PMC2940458  PMID: 20350205
16.  AGRICOH: A Consortium of Agricultural Cohorts 
AGRICOH is a recently formed consortium of agricultural cohort studies involving 22 cohorts from nine countries in five continents: South Africa (1), Canada (3), Costa Rica (2), USA (6), Republic of Korea (1), New Zealand (2), Denmark (1), France (3) and Norway (3). The aim of AGRICOH, initiated by the US National Cancer Institute (NCI) and coordinated by the International Agency for Research on Cancer (IARC), is to promote and sustain collaboration and pooling of data to investigate the association between a wide range of agricultural exposures and a wide range of health outcomes, with a particular focus on associations that cannot easily be addressed in individual studies because of rare exposures (e.g., use of infrequently applied chemicals) or relatively rare outcomes (e.g., certain types of cancer, neurologic and auto-immune diseases). To facilitate future projects the need for data harmonization of selected variables is required and is underway. Altogether, AGRICOH provides excellent opportunities for studying cancer, respiratory, neurologic, and auto-immune diseases as well as reproductive and allergic disorders, injuries and overall mortality in association with a wide array of exposures, prominent among these the application of pesticides.
PMCID: PMC3108113  PMID: 21655123
agriculture; cohort studies; consortium, pesticides; occupational exposures
17.  GWAS of Follicular Lymphoma Reveals Allelic Heterogeneity at 6p21.32 and Suggests Shared Genetic Susceptibility with Diffuse Large B-cell Lymphoma 
PLoS Genetics  2011;7(4):e1001378.
Non-Hodgkin lymphoma (NHL) represents a diverse group of hematological malignancies, of which follicular lymphoma (FL) is a prevalent subtype. A previous genome-wide association study has established a marker, rs10484561 in the human leukocyte antigen (HLA) class II region on 6p21.32 associated with increased FL risk. Here, in a three-stage genome-wide association study, starting with a genome-wide scan of 379 FL cases and 791 controls followed by validation in 1,049 cases and 5,790 controls, we identified a second independent FL–associated locus on 6p21.32, rs2647012 (ORcombined = 0.64, Pcombined = 2×10−21) located 962 bp away from rs10484561 (r2<0.1 in controls). After mutual adjustment, the associations at the two SNPs remained genome-wide significant (rs2647012:ORadjusted = 0.70, Padjusted = 4×10−12; rs10484561:ORadjusted = 1.64, Padjusted = 5×10−15). Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct haplotype from that of rs10484561 and tags a novel allele with an opposite (protective) effect on FL risk. Moreover, in a follow-up analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma (ORcombined = 1.36, Pcombined = 1.4×10−7). Our results reveal the presence of allelic heterogeneity within the HLA class II region influencing FL susceptibility and indicate a possible shared genetic etiology with diffuse large B-cell lymphoma. These findings suggest that the HLA class II region plays a complex yet important role in NHL.
Author Summary
Earlier studies have established a marker rs10484561, in the HLA class II region on 6p21.32, associated with increased follicular lymphoma (FL) risk. Here, in a three-stage genome-wide association study of 1,428 FL cases and 6,581 controls, we identified a second independent FL–associated marker on 6p21.32, rs2647012, located 962 bp away from rs10484561. The associations at two SNPs remained genome-wide significant after mutual adjustment. Haplotype and coalescence analyses indicated that rs2647012 arose on an evolutionarily distinct lineage from that of rs10484561 and tags a novel allele with an opposite, protective effect on FL risk. Moreover, in an analysis of the top 6 FL–associated SNPs in 4,449 cases of other NHL subtypes, rs10484561 was associated with risk of diffuse large B-cell lymphoma. Our results reveal the presence of allelic heterogeneity at 6p21.32 in FL risk and suggest a shared genetic etiology with the common diffuse large B-cell lymphoma subtype.
PMCID: PMC3080853  PMID: 21533074
18.  Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32 
Nature genetics  2010;42(8):661-664.
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).
PMCID: PMC2913472  PMID: 20639881
19.  Genetic variation in cell cycle and apoptosis related genes and multiple myeloma risk 
Leukemia research  2009;33(12):1609-1614.
Genetic variation may be an important risk factor for multiple myeloma. A hallmark of tumor formation and growth is cell cycle dysregulation and apoptosis avoidance. We previously reported the association of genetic variation in caspase genes, the apoptotic-regulating family, and multiple myeloma risk. To further examine if genetic variation in key cell cycle and apoptosis genes alters multiple myeloma risk, we genotyped 276 tag SNPs in 27 gene regions in a population-based case-control study of non-Hispanic Caucasian women (108 cases; 482 controls) in Connecticut. Logistic regression assessed the effect of each SNP on multiple myeloma risk and the minP test assessed the association at the gene region level. Three gene regions were significantly associated with risk of multiple myeloma (BAX minP = 0.018, CASP9 minP = 0.025, and RIPK1 minP = 0.037). Further explorations identified the most significant variant of BAX, RIPK1, and CASP9 to be rs1042265, rs9391981, and rs751643, respectively. The A variant at rs1042265 (ORGA+AA = 0.40, 95%CI = 0.21 – 0.78) and the C variant at rs9391981 (ORGC+CC = 0.32, 95%CI = 0.12 – 0.81) were associated with a decreased risk of multiple myeloma. The G variant at rs7516435 was associated with an increased risk of multiple myeloma (ORAG = 1.48, 95%CI = 0.94 – 2.32; ORGG = 2.59, 95%CI = 1.30 – 5.15; ptrend = 0.005). Haplotype analyses supported the SNP findings. These findings suggest that genetic variation in cell cycle and apoptosis genes may play a key role in multiple myeloma and warrant further investigation through replication studies.
PMCID: PMC2749910  PMID: 19362737
multiple myeloma; caspase; BAX; RIPK1; cell cycle
20.  Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma in a pooled analysis of three studies 
British journal of haematology  2010;151(3):239-244.
Elevated incidence of lymphoma has been observed among carriers of rare high-penetrance mutations in DNA repair genes (e.g., Nijmegen breakage syndrome, Ataxia-telangectasia syndrome, etc.). Common gene variants in DNA repair genes may also influence lymphomagenesis.
Study subjects were pooled from three population-based case-control studies of non-Hodgkin lymphoma (NHL) in the US and Australia. A total of 1,946 cases and 1,808 controls were analyzed. A total of 319 tag single nucleotide polymorphisms (SNPs) in 27 DNA repair gene regions were genotyped. Unconditional logistic regression models were used to estimate the relative risk of NHL and NHL subtypes in relation to SNPs. Tail-strength statistics were used to test for the association between DNA repair pathways and NHL or NHL subtypes. The statistical significance of the smallest P-trend within each gene region was estimated by permutation-based resampling methods.
Overall, DNA repair genetic polymorphisms were associated with NHL (P = 0.005). Tests for the double strand break repair (P = 0.02) and nucleotide excision repair (P = 0.04) pathways were also significant. Four gene regions were significantly associated with NHL or NHL subtypes at the 0.05 level: RAD50, BLM, RAD51/FAM82C, and ERCC3/MAP3K2. Specifically, BLM rs441399 (P trend = 0.004) and FAM82C rs2304583 (P trend = 0.001) were associated with follicular lymphoma, and XRCC4 rs13178127 was associated with NHL overall (P trend = 0.006) significantly. In addition, the ERCC3 rs4150506 was associated with reduced risk for marginal zone lymphoma (P trend = 0.002).
These results support the hypothesis that common genetic polymorphisms in human DNA repair genes may modify the risk of NHL.
PMCID: PMC2967772  PMID: 20813000
non-Hodgkin lymphoma; DNA repair; single nucleotide polymorphism; pooled analysis
21.  Genetic polymorphisms in nitric oxide synthase genes modify the relationship between vegetable and fruit intake and risk of non-Hodgkin lymphoma 
Oxidative damage caused by reactive oxygen species (ROS) and other free radicals is involved in carcinogenesis. It has been suggested that high vegetable and fruit intake may reduce the risk of non-Hodgkin lymphoma (NHL) as vegetables and fruit are rich in antioxidants. The aim of this study is to evaluate the interaction of vegetable and fruit intake with genetic polymorphisms in oxidative stress pathway genes and NHL risk. This hypothesis was investigated in a population-based case-control study of NHL and NHL histological subtype in Connecticut women including 513 histologically confirmed incident cases and 591 randomly selected controls. Gene-vegetable/fruit joint effects were estimated using unconditional logistic regression model. The false discovery rate method was applied to adjust for multiple comparisons. Significant interactions with vegetable and fruit intake were mainly found for genetic polymorphisms on nitric oxide synthase (NOS) genes among those with diffuse large B-cell lymphoma (DLBCL) and Follicular lymphoma (FL). Two single nucleotide polymorphisms (SNPs) in the NOS1 gene were found to significantly modify the association between total vegetable and fruit intake and risk of NHL overall, as well as the risk of follicular lymphoma (FL). When vegetables, bean vegetables, cruciferous vegetables, green leafy vegetables, red vegetables, yellow/orange vegetables, fruit, and citrus fruit were examined separately, strong interaction effects were narrowed to vegetable intake among DLBCL patients. Our results suggest that genetic polymorphisms in oxidative stress pathway genes, especially in the nitric oxide synthase genes, modify the association between vegetable and fruit intake and risk of NHL.
PMCID: PMC2965355  PMID: 19423521
oxidative stress pathway; vegetable and fruit intake; non-Hodgkin lymphoma; nitric oxide synthase; genetic polymorphisms
22.  Cancer Incidence in the U.S. Military Population: Comparison with Rates from the SEER Program 
The U.S. active-duty military population may differ from the U.S. general population in its exposure to cancer risk factors and access to medical care. Yet, it is not known if cancer incidence rates differ between these two populations. We therefore compared the incidence of four cancers common in U.S. adults (lung, colorectum, prostate, and breast cancers) and two cancers more common in U.S. young adults (testicular and cervical cancers) in the military and general populations. Data from the Department of Defense's Automated Central Tumor Registry (ACTUR) and the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) nine cancer registries for the years 1990-2004 for persons aged 20-59 years were analyzed. Incidence rates were significantly lower in the military population for colorectal cancer in white men, lung cancer in white and black men and white women, and cervical cancer in black women. In contrast, incidence rates of breast and prostate cancers were significantly higher in the military among both whites and blacks. Incidence rates of testicular cancer did not differ between ACTUR and SEER. Although the numbers of diagnoses among military personnel were relatively small for temporal trend analysis, we found a more prominent increase in prostate cancer in ACTUR than in SEER. Overall, these results suggest that cancer patterns may differ between military and non-military populations. Further studies are needed to confirm these findings and explore contributing factors.
PMCID: PMC2780333  PMID: 19505907
Active duty; cancer; incidence; military; SEER
23.  Inferring Past Pesticide Exposures: A Matrix of Individual Active Ingredients in Home and Garden Pesticides Used in Past Decades 
Environmental Health Perspectives  2006;115(2):248-254.
In retrospective studies of the health effects of home and garden pesticides, self-reported information typically forms the basis for exposure assessment. Study participants generally find it easier to remember the types of pests treated than the specific pesticides used. However, if the goal of the study is to assess disease risk from specific chemicals, the investigator must be able to link the pest type treated with specific chemicals or products.
Our goal was to develop a “pesticide–exposure matrix” that would list active ingredients on the market for treating different types of pests in past years, and provide an estimate of the probability that each active ingredient was used.
We used several different methods for deriving the active ingredient lists and estimating the probabilities. These methods are described in this article, along with a sample calculation and data sources for each.
The pesticide–exposure matrix lists active ingredients and their probabilities of use for 96 distinct scenarios defined by year (1976, 1980, 1990, 2000), applicator type (consumer, professional), and pest type (12 categories). Calculations and data sources for all 96 scenarios are provided online.
Although we are confident that the active ingredient lists are reasonably accurate for most scenarios, we acknowledge possible sources of error in the probability estimates. Despite these limitations, the pesticide–exposure matrix should provide valuable information to researchers interested in the chronic health effects of residential pesticide exposure.
PMCID: PMC1817710  PMID: 17384773
Exposure assessment; herbicides; insecticides; pesticides; residential

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