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1.  The Role of Hormones in the Differences in the Incidence of Breast Cancer between Mongolia and the United Kingdom 
PLoS ONE  2014;9(12):e114455.
There are striking differences in breast cancer incidence between Asian and western women. Rates vary substantially within Asia also, with Mongolia's even lower than China's. These profound differences have been speculated to be due in part to diet, mediated by circulating hormone concentrations.
Sex steroid hormone concentrations were measured in women living in Ulaanbaatar, Mongolia and the United Kingdom (U.K.). Diet was obtained by interview and national survey data. Mean hormone differences were compared by country, and systematic variation by number of days since last menstrual period was modeled and adjusted for age and parity; difference in overall area under the curves was assessed.
The diet in Mongolia was higher in meat and dairy than in the U.K. Mean testosterone concentrations were 18.5% lower (p<0.0001) while estradiol concentrations were 19.1% higher (p = 0.02) in Mongolian than British women, adjusted for age and parity. Progesterone was almost 50% higher in Mongolian women (p = 0.04), particularly during the follicular phase and early luteal surge. Hormone concentrations generally were similar in Mongolian women born in Ulaanbaatar compared with those born in rural areas, although there was a decreasing progesterone trend by degree of westernization (rural Mongolia; urban Mongolia; U.K.). Mean hormone differences were similar when restricted to parous women, and with further adjustment for body mass index, height, and smoking status.
These data augment accumulating evidence that circulating estrogens are unlikely to explain reduced breast cancer rates in Asia compared with the west, and suggest casting a wider net with respect to biomarkers. Lower testosterone and higher progesterone in Mongolian women raise the possibility that these hormones may be important to consider. In addition, the almost exclusive dietary reliance of Mongolians on meat and dairy argues against beneficial effects of a low-fat diet on circulating hormones explaining international breast cancer differences.
PMCID: PMC4275167  PMID: 25536229
2.  Worldwide Trends in Incidence Rates for Oral Cavity and Oropharyngeal Cancers 
Journal of Clinical Oncology  2013;31(36):4550-4559.
Human papillomavirus (HPV) has been identified as the cause of the increasing oropharyngeal cancer (OPC) incidence in some countries. To investigate whether this represents a global phenomenon, we evaluated incidence trends for OPCs and oral cavity cancers (OCCs) in 23 countries across four continents.
We used data from the Cancer Incidence in Five Continents database Volumes VI to IX (years 1983 to 2002). Using age-period-cohort modeling, incidence trends for OPCs were compared with those of OCCs and lung cancers to delineate the potential role of HPV vis-à-vis smoking on incidence trends. Analyses were country specific and sex specific.
OPC incidence significantly increased during 1983 to 2002 predominantly in economically developed countries. Among men, OPC incidence significantly increased in the United States, Australia, Canada, Japan, and Slovakia, despite nonsignificant or significantly decreasing incidence of OCCs. In contrast, among women, in all countries with increasing OPC incidence (Denmark, Estonia, France, the Netherlands, Poland, Slovakia, Switzerland, and United Kingdom), there was a concomitant increase in incidence of OCCs. Although increasing OPC incidence among men was accompanied by decreasing lung cancer incidence, increasing incidence among women was generally accompanied by increasing lung cancer incidence. The magnitude of increase in OPC incidence among men was significantly higher at younger ages (< 60 years) than older ages in the United States, Australia, Canada, Slovakia, Denmark, and United Kingdom.
OPC incidence significantly increased during 1983 to 2002 predominantly in developed countries and at younger ages. These results underscore a potential role for HPV infection on increasing OPC incidence, particularly among men.
PMCID: PMC3865341  PMID: 24248688
Long-term breast cancer trends in incidence in the United States (US) show rising ER positive rates and falling ER negative rates. We hypothesized that these divergent trends reflect etiologic heterogeneity and that comparable trends should be observed in other countries with similar risk factor profiles. We, therefore, analyzed invasive female breast cancers in Denmark, a country with similar risk factors as the US. We summarized the overall trend in age-standardized rates with the estimated annual percentage change (EAPC) statistic (1993–2010) and used age-period-cohort models to estimate age-specific EAPCs, cohort rate ratios (CRRs), and projections for future time periods (2011–2018). In Denmark, the overall rate of ER positive cancers rose between 1993 and 2010 by 3·0%/year (95% CI: 2·8 to 3·3%/yr) while the overall rate of ER negative cancers fell by 2·1%/year (95% CI: −2·5 to −1·6%/yr). The ER positive rate increased fastest among postmenopausal women and the ER negative rate decreased fastest among premenopausal women, reflecting that cohorts born after 1944 were at relatively higher risk of ER positive tumors and lower risk of ER negative tumors. If current trends continue, ER positive cancers will increase at least 13% by 2018 in Denmark, ER negative cancers will fall 15% by 2018, and breast cancer overall will increase at least 7% by 2018. Divergent ER-specific trends are consistent with distinct etiologic pathways. If trends in known risk factors are responsible, the Danish and US experience may foreshadow a common pattern worldwide.
PMCID: PMC3749265  PMID: 23616071
Breast cancer; Estrogen receptor; Epidemiology; Age-period-cohort models
We describe outcomes after allogeneic transplantation in 34 patients with dyskeratosis congenita transplanted between 1981 and 2009. The median age at transplantation was 13 years (range 2 – 35). Approximately 50% of transplants were from related donors. Bone marrow was the predominant source of stem cells (n=24/34). The day-28 probability of neutrophil recovery was 73% and the day-100 platelet recovery was 72%. The day-100 probability of grade II-IV acute GVHD and the 3-year probability of chronic GVHD were 24% and 37%, respectively. The 10-year probability of survival was 30%; 14 patients were alive at last follow-up. Ten deaths occurred within 4 months from transplantation due to graft failure (n=6) or other transplant-related complications; 9 of these patients had been transplanted from mismatched related or from unrelated donors. Another 10 deaths occurred after 4 months; 6 of them occurred more than 5 years from transplantation, 4 of these were attributed to pulmonary failure. Transplant-regimen intensity and transplants from mismatched related or unrelated donors were associated with early mortality. Transplantation of grafts from HLA-matched siblings with cyclophosphamide-containing non-radiation regimens was associated with early low toxicity. Late mortality was attributed mainly to pulmonary complications and likely related to the underlying disease.
PMCID: PMC3736557  PMID: 23751955
5.  Genetic Regulation of Fetal Haemoglobin in Inherited Bone Marrow Failure Syndromes 
British journal of haematology  2013;162(4):542-546.
Patients with inherited bone marrow failure syndromes (IBMFS) have “stress erythropoiesis”, with anaemia, macrocytosis, increased fetal haemoglobin (Hb F) and high erythropoietin levels. In haemoglobinopathies, Hb F levels are regulated by 3 quantitative trait loci, HBS1L-MYB, BCL11A and Xmn1-HBG2. In our study of 97 patients with an IBMFS, increased Hb F was associated with young age, male gender, anaemia, high erythropoietin levels, and alternative alleles in Xmn1-HBG2 [adjusted p = 0.04 for the total group, driven by Fanconi anaemia (p=0.02) and dyskeratosis congenita (p=0.09)]. Thus Hb F is regulated in IBMFS by Xmn1-HBG2 as it is in the haemoglobinopathies.
PMCID: PMC3720816  PMID: 23713742
Fetal haemoglobin; inherited bone marrow failure syndromes; quantitative trait loci; Fanconi anaemia; dyskeratosis congenita
6.  Association between Class III Obesity (BMI of 40–59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies 
PLoS Medicine  2014;11(7):e1001673.
In a pooled analysis of 20 prospective studies, Cari Kitahara and colleagues find that class III obesity (BMI of 40–59) is associated with excess rates of total mortality, particularly due to heart disease, cancer, and diabetes.
Please see later in the article for the Editors' Summary
The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.
Methods and Findings
In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19–83 y at baseline, classified as obese class III (BMI 40.0–59.9 kg/m2) compared with those classified as normal weight (BMI 18.5–24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976–2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.
Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight.
Please see later in the article for the Editors' Summary
Editors' Summary
The number of obese people (individuals with an excessive amount of body fat) is increasing rapidly in many countries. Worldwide, according to the Global Burden of Disease Study 2013, more than a third of all adults are now overweight or obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30 kg/m2 (a 183-cm [6-ft] tall man who weighs more than 100 kg [221 lbs] is obese). Compared to people with a healthy weight (a BMI between 18.5 and 24.9 kg/m2), overweight and obese individuals (who have a BMI between 25.0 and 29.9 kg/m2 and a BMI of 30 kg/m2 or more, respectively) have an increased risk of developing diabetes, heart disease, stroke, and some cancers, and tend to die younger. Because people become unhealthily fat by consuming food and drink that contains more energy (kilocalories) than they need for their daily activities, obesity can be prevented or treated by eating less food and by increasing physical activity.
Why Was This Study Done?
Class III obesity (extreme, or morbid, obesity), which is defined as a BMI of more than 40 kg/m2, is emerging as a major public health problem in several high-income countries. In the US, for example, 6% of adults are now morbidly obese. Because extreme obesity used to be relatively uncommon, little is known about the burden of disease, including total and cause-specific mortality (death) rates, among individuals with class III obesity. Before we can prevent and treat class III obesity effectively, we need a better understanding of the health risks associated with this condition. In this pooled analysis of prospective cohort studies, the researchers evaluate the risk of total and cause-specific death and the years of life lost associated with class III obesity. A pooled analysis analyzes the data from several studies as if the data came from one large study; prospective cohort studies record the characteristics of a group of participants at baseline and follow them to see which individuals develop a specific condition.
What Did the Researchers Do and Find?
The researchers included 20 prospective (mainly US) cohort studies from the National Cancer Institute Cohort Consortium (a partnership that studies cancer by undertaking large-scale collaborations) in their pooled analysis. After excluding individuals who had ever smoked and people with a history of chronic disease, the analysis included 9,564 adults who were classified as class III obese based on self-reported height and weight at baseline and 304,011 normal-weight adults. Among the participants with class III obesity, mortality rates (deaths per 100,000 persons per year) during the 30-year study period were 856.0 and 663.0 in men and women, respectively, whereas the mortality rates among normal-weight men and women were 346.7 and 280.5, respectively. Heart disease was the major contributor to the excess death rate among individuals with class III obesity, followed by cancer and diabetes. Statistical analyses of the pooled data indicate that the risk of all-cause death and death due to heart disease, cancer, diabetes, and several other diseases increased with increasing BMI. Finally, compared with having a normal weight, having a BMI between 40 and 59 kg/m2 resulted in an estimated loss of 6.5 to 13.7 years of life.
What Do These Findings Mean?
These findings indicate that class III obesity is associated with a substantially increased rate of death. Notably, this death rate increase is similar to the increase associated with smoking among normal-weight people. The findings also suggest that heart disease, cancer, and diabetes are responsible for most of the excess deaths among people with class III obesity and that having class III obesity results in major reductions in life expectancy. Importantly, the number of years of life lost continues to increase for BMI values above 50 kg/m2, and beyond this point, the loss of life expectancy exceeds that associated with smoking among normal-weight people. The accuracy of these findings is limited by the use of self-reported height and weight measurements to calculate BMI and by the use of BMI as the sole measure of obesity. Moreover, these findings may not be generalizable to all populations. Nevertheless, these findings highlight the need to develop more effective interventions to combat the growing public health problem of class III obesity.
Additional Information
Please access these websites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on obesity (in several languages); Malri's story describes the health risks faced by an obese child
The UK National Health Service Choices website provides information about obesity, including a personal story about losing weight
The Global Burden of Disease Study website provides the latest details about global obesity trends
The US Department of Agriculture's website provides a personal healthy eating plan; the Weight-Control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
MedlinePlus provides links to other sources of information on obesity (in English and Spanish)
PMCID: PMC4087039  PMID: 25003901
7.  Ovarian Cancer Incidence Trends in Relation to Changing Patterns of Menopausal Hormone Therapy Use in the United States 
Journal of Clinical Oncology  2013;31(17):2146-2151.
After a report from the Women's Health Initiative (WHI) in 2002, a precipitous decline in menopausal hormonal therapy (MHT) use in the United States was linked to a decline in breast cancer incidence rates. Given that MHT use is also associated with increased ovarian cancer risk, we tested whether ovarian cancer incidence rates changed after 2002.
Using the North American Association of Central Cancer Registries database (1995 to 2008; N = 171,142 incident ovarian cancers), we applied standard analytic approaches and age-period-cohort (APC) models to estimate ovarian cancer incidence rate changes before (1995 to 2002) and after (2003 to 2008) the WHI report.
Among women age ≥ 50 years, age-standardized ovarian cancer incidence declined by 0.8% per year (95% CI, −1.8% to −0.5% per year) before the WHI announcement; after the WHI report, the rate declined by 2.4% per year (95% CI, −2.5% to −2.2% per year). APC models confirmed an accelerated decline in ovarian cancer incidence after the WHI report, adjusted for age and birth cohort effects. This sudden change was notable among women most likely to have used MHT (ie, women age 50 to 69 years, white women, and residents of regions with highest MHT prescription frequency). The largest changes were found for the endometrioid histologic subtype.
After a marked reduction in MHT use around 2002, ovarian cancer incidence rates demonstrated an accelerated decline, with the largest changes for endometrioid carcinomas. This strong temporal association, although not proving a causal role of hormones in ovarian carcinogenesis, suggests that future analytic research supporting cancer control efforts should clarify the role of hormonal exposures on the development and behavior of subtypes of ovarian cancer.
PMCID: PMC3731982  PMID: 23650423
8.  Hairy cell leukaemia: a heterogeneous disease? 
British journal of haematology  2008;142(1):45-51.
The US National Cancer Institute’s Surveillance, Epidemiology and End Results program was used to develop aetiological clues for hairy cell leukaemia (HCL). Descriptive techniques (age-adjusted incidence trends, age-specific incidence rates (IR), and age distributions-at-diagnosis) were supplemented with mathematical models (two-component mixture, generalized linear regression, and age-period-cohort). There were 2856 cases of HCL diagnosed during 1978–2004 (IR 0·32/100 000 person-years). IRs were nearly 4-fold greater among men than women and more than 3-fold higher for Whites than Blacks. Temporal trends were stable over time. Age-specific IRs increased rapidly until approximately 40 years then rose at a slower pace. The age-specific IR curves reflected bimodal early- and late-onset age distributions-at-diagnosis (or density plots), with some variation by gender. Among both men and women, a two-component mixture model fitted the data better than a single density or cancer population. Age-period-cohort models confirmed statistically significant age-related effects after full adjustment for temporal trends (calendar-period and birth-cohort effects). In summary, age incidence patterns (rates and bimodal densities) suggested that HCL is a heterogeneous disease, consisting of at least two underlying subgroups and/or cancer populations by age-at-onset. Distinct early- and late-onset HCL populations may reflect different age-related causal pathways, risk factor profiles, and/or stem cells of origin.
PMCID: PMC4009349  PMID: 18477040
hairy cell leukaemia; chronic leukaemia; epidemiology; lymphoid malignancy; malignant haematology
9.  Estimation of the prevalence of Fanconi anemia among patients with de novo acute myelogenous leukemia who have poor recovery from chemotherapy 
Leukemia research  2011;36(1):29-31.
We speculated that some individuals with de novo acute myelogenous leukemia (AML) may have undiagnosed Fanconi Anemia (FA). Data from patients enrolled on AML protocol CCG-2961, published FA cohort studies, SEER, and Bayes rule were used to estimate the probability of FA among all newly diagnosed AML cases, and among those who had no or delayed recovery of the absolute neutrophil count following initial chemotherapy. We determined that the probability of undiagnosed FA in patients in a treatment trial for newly diagnosed patients was around 0.18%, and around 0.83% in the subset who had poor marrow recovery. We suggest that FA or other inherited bone marrow failure syndromes be considered prior to treatment, or certainly among those with poor recovery.
PMCID: PMC4008327  PMID: 21974856
Fanconi anemia; Acute myelogenous leukemia; Prevalence
10.  Familial testicular germ cell tumor: no associated syndromic pattern identified 
Testicular germ cell tumor (TGCT) is the most common malignancy in young men. Familial clustering, epidemiologic evidence of increased risk with family or personal history, and the association of TGCT with genitourinary (GU) tract anomalies have suggested an underlying genetic predisposition. Linkage data have not identified a rare, highly-penetrant, single gene in familial TGCT (FTGCT) cases. Based on its association with congenital GU tract anomalies and suggestions that there is an intrauterine origin to TGCT, we hypothesized the existence of unrecognized dysmorphic features in FTGCT.
We evaluated 38 FTGCT individuals and 41 first-degree relatives from 22 multiple-case families with detailed dysmorphology examinations, physician-based medical history and physical examination, laboratory testing, and genitourinary imaging studies.
The prevalence of major abnormalities and minor variants did not significantly differ between either FTGCT individuals or their first-degree relatives when compared with normal population controls, except for tall stature, macrocephaly, flat midface, and retro-/micrognathia. However, these four traits were not manifest as a constellation of features in any one individual or family. We did detect an excess prevalence of the genitourinary anomalies cryptorchidism and congenital inguinal hernia in our population, as previously described in sporadic TGCT, but no congenital renal, retroperitoneal or mediastinal anomalies were detected.
Overall, our study did not identify a constellation of dysmorphic features in FTGCT individuals, which is consistent with results of genetic studies suggesting that multiple low-penetrance genes are likely responsible for FTGCT susceptibility.
PMCID: PMC3937045  PMID: 24559313
Familial testicular cancer; Dysmorphology; Developmental anomalies
11.  Are Incidence rates of adult leukemia in the United States significantly associated with birth cohort? 
Leukemia is a common cancer among United States adults but there are few established risk factors. If leukemia risks are substantially influenced by exposures that vary in prevalence across generations, then population incidence rates should vary significantly by birth cohort. However, prior studies have not examined leukemia birth cohort effects using contemporary data and methods.
We used incidence data from the National Cancer Institute's Surveillance, Epidemiology and End Results Program from 1992 through 2009 for adults 25 – 84 years old and age-period-cohort models to estimate incidence rate ratios according to birth cohort for acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic myeloid leukemia (CML), and chronic lymphoid leukemia (CLL).
Leukemia incidence varied significantly between birth cohorts for each major leukemia type in men and women except female AML; changes on the order of 1% per birth year or 20% per generation were observed. The most significant birth cohort signatures were observed for CLL and AML in men, which were decreasing and increasing, respectively, in cohorts born since 1946.
Our results support the hypothesis that adult leukemia risks are significantly modulated by environmental and lifestyle exposures.
A number of well-established (smoking, certain chemicals, radiation) and newly-recognized (obesity) leukemia risk factors are modifiable; ultimately, efforts to promote healthy lifestyles might also help reduce incidence rates of adult leukemia.
PMCID: PMC3518742  PMID: 23064005
Leukemia; Incidence; Age Factors; Sex Factors; United States/Epidemiology
12.  Likelihood Ratio Test for Detecting Gene (G)-Environment (E) Interactions Under an Additive Risk Model Exploiting G-E Independence for Case-Control Data 
American Journal of Epidemiology  2012;176(11):1060-1067.
There has been a long-standing controversy in epidemiology with regard to an appropriate risk scale for testing interactions between genes (G) and environmental exposure (E ). Although interaction tests based on the logistic model—which approximates the multiplicative risk for rare diseases—have been more widely applied because of its convenience in statistical modeling, interactions under additive risk models have been regarded as closer to true biologic interactions and more useful in intervention-related decision-making processes in public health. It has been well known that exploiting a natural assumption of G-E independence for the underlying population can dramatically increase statistical power for detecting multiplicative interactions in case-control studies. However, the implication of the independence assumption for tests for additive interaction has not been previously investigated. In this article, the authors develop a likelihood ratio test for detecting additive interactions for case-control studies that incorporates the G-E independence assumption. Numerical investigation of power suggests that incorporation of the independence assumption can enhance the efficiency of the test for additive interaction by 2- to 2.5-fold. The authors illustrate their method by applying it to data from a bladder cancer study.
PMCID: PMC3571244  PMID: 23118105
additive risk model; case-control studies; gene-environment independence; gene-environment interaction; multiplicative risk model
13.  The Antioxidant Tempol Reduces Carcinogenesis and Enhances Survival in Mice when Administered After Non-Lethal Total Body Radiation 
Cancer research  2012;72(18):4846-4855.
There is significant interest in the development of agents that can ameliorate radiation damage after exposure to radiation has occurred. Here we report that chronic supplementation of the antioxidant Tempol in the diet of mice can reduce body weight without toxicity, decrease cancer, and extend survival when administered after non-lethal total body radiation (TBI). These effects were apparent in two different strains of mice (C3H, CBA) exposed to TBI (3 Gy). Notably, delaying administration of the Tempol diet 1 month after TBI could also enhance survival. Tempol reduced the incidence of hematopoietic neoplasms (lymphomas) in both strains; whereas, both the onset and incidence of non-hematopoietic neoplasms were reduced in CBA mice. These results encourage further study of Tempol as a chemopreventive, to reduce the incidence of radiation-induced second malignancies after a course of definitive radiation therapy. Tempol may also find applications to reduce the risk of cancers in populations exposed to non-lethal radiation due to nuclear accidents or terrorist attacks.
PMCID: PMC3445749  PMID: 22805306
Tempol; radiation; carcinogenesis; antioxidant; chemoprevention
14.  Increasing Lung Cancer Death Rates Among Young Women in Southern and Midwestern States 
Journal of Clinical Oncology  2012;30(22):2739-2744.
Previous studies reported that declines in age-specific lung cancer death rates among women in the United States abruptly slowed in women younger than age 50 years (ie, women born after the 1950s). However, in view of substantial geographic differences in antitobacco measures and sociodemographic factors that affect smoking prevalence, it is unknown whether this change in the trend was similar across all states.
We examined female age-specific lung cancer death rates (1973 through 2007) by year of death and birth in each state by using age-period-cohort models. Cohort relative risks adjusted for age and period effects were used to compare the lung cancer death rate for a given birth cohort to a referent birth cohort (ie, the 1933 cohort herein).
Age-specific lung cancer death rates declined continuously in white women in California, but the rates declined less quickly or even increased in the remaining states among women younger than age 50 years and women born after the 1950s, especially in several southern and midwestern states. For example, in some southern states (eg, Alabama), lung cancer death rates among women born in the 1960s were approximately double those of women born in the 1930s.
The unfavorable lung cancer trend in white women born after circa 1950 in southern and midwestern states underscores the need for additional interventions to promote smoking cessation in these high-risk populations, which could lead to more favorable future mortality trends for lung cancer and other smoking-related diseases.
PMCID: PMC3402885  PMID: 22734032
15.  Regional Variations in Esophageal Cancer Rates by Census Region in the United States, 1999–2008 
PLoS ONE  2013;8(7):e67913.
Assessment of cancer incidence trends within the U.S. have mostly relied upon Surveillance, Epidemiology, and End Results (SEER) data, with implicit inference that such is representative of the general population. However, many cancer policy decisions are based at a more granular level. To help inform such, analyses of regional cancer incidence data are needed. Leveraging the unique resource of National Program of Cancer Registries (NPCR)-SEER, we assessed whether regional rates and trends of esophageal cancer significantly deviated from national estimates.
From NPCR-SEER, we extracted cancer case counts and populations for whites aged 45–84 years by calendar year, histology, sex, and census region for the period 1999–2008. We calculated age-standardized incidence rates (ASRs), annual percent changes (APCs), and male-to-female incidence rate ratios (IRRs).
This analysis included 65,823 esophageal adenocarcinomas and 27,094 esophageal squamous cell carcinomas diagnosed during 778 million person-years. We observed significant geographic variability in incidence rates and trends, especially for esophageal adenocarcinomas in males: ASRs were highest in the Northeast (17.7 per 100,000) and Midwest (18.1). Both were significantly higher than the national estimate (16.0). In addition, the Northeast APC was 62% higher than the national estimate (3.19% vs. 1.97%). Lastly, IRRs remained fairly constant across calendar time, despite changes in incidence rates.
Significant regional variations in esophageal cancer incidence trends exist in the U.S. Stable IRRs may indicate the predominant factors affecting incidence rates are similar in men and women.
PMCID: PMC3701616  PMID: 23861830
16.  Pediatric, elderly, and emerging adult-onset peaks in Burkitt lymphoma incidence diagnosed in four continents, excluding Africa 
American Journal of Hematology  2012;87(6):573-578.
Burkitt lymphoma (BL) in the general population and immunosuppressed persons with AIDS in United States was characterized by three age-specific incidence peaks near 10, 40 and 70 years. We hypothesized that BL from different geographical areas may exhibit pediatric, adult, and elderly age incidence peaks. We investigated this hypothesis using data on 3403 cases obtained from the International Agency for Research on Cancer (1978–2002). Data from Africa were sparse or incomplete, and thus were excluded. Age-standardized rates (ASR) and age-specific incidence rates were calculated, supplemented with calculations performed using age-period-cohort models. The ASR rose 5.3% (95% confidence interval (CI), 5.0–5.6) per year in males and 4.6% (95% CI, 4.5–4.8) in females. The ASR increased gradually in children and steeply in adults and most rapidly in the elderly both in males and females. Overall, BL male/female ASR ratio was 2.5, but it declined from 3.1 (95% CI, 3.0–3.3) for pediatric BL to 2.3 (95% CI 2.2–2.4) for adult BL and 1.5 (95% CI, 1.4–1.6) for elderly BL. Age-specific incidence peaks occurred near 10 years and 70 years in all regions and periods. A peak near 40 years of age emerged in the mid-1990s, particularly in men. Findings using APC models confirmed those based on standard analyses. Our findings, based on international BL cases, support our hypothesis that BL is multimodal and that BL peaks at different ages may be clues to differences in the etiology and/or biology of BL at those ages.
PMCID: PMC3358448  PMID: 22488262
Burkitt lymphoma; epidemiology; multimodal cancer; non-Hodgkin lymphoma; HIV/AIDS
17.  The chromosome 2p21 region harbors a complex genetic architecture for association with risk for renal cell carcinoma 
Human Molecular Genetics  2011;21(5):1190-1200.
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.
PMCID: PMC3277315  PMID: 22113997
18.  The association between inflammation-related genes and serum androgen levels in men: The Prostate, Lung, Colorectal, and Ovarian Study 
The Prostate  2011;72(1):65-71.
Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes.
In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17β-diol glucuronide [3αdiol G], and 4-Androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based p-values were generated using an adaptive rank truncated product method.
Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-value<0.1) in both SNP and gene-based tests. Specifically, T was associated with common variants in MMP2 and CD14, with the most significant SNPs being rs893226G>T in MMP2 and rs3822356T>C in CD14 (FDR q-value=0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione.
These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk.
PMCID: PMC3156884  PMID: 21520164
Inflammation; Androgens; Genes; Testosterone; Polymorphism; Single Nucleotide
19.  Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States 
Journal of Clinical Oncology  2011;29(32):4294-4301.
Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking.
Patients and Methods
HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses.
HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay (P trend < .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P < .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive (P = .003) but not for HPV-negative patients (P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020.
Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.
PMCID: PMC3221528  PMID: 21969503
20.  Incidence of Breast Cancer in the United States: Current and Future Trends 
The incidence of breast cancer increased in the United States until circa 2000 then decreased, mostly among women with estrogen receptor (ER)–positive cancers. Time trends provide important clues for cancer etiology and prevention; however, the observed trends of ER-positive and ER-negative breast cancers can be biased by missing ER data.
We developed a simple imputation method to correct invasive female breast cancer incidence for missing or unknown ER expression, using nationally representative data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program during 1980–2008, including 588 720 invasive female breast cancer patients with 471 336 233 woman-years of follow-up. Corrected rates of ER-positive and ER-negative breast cancers were used to calculate age-standardized incidence rates, estimated annual percentage changes, and projections derived from age–period–cohort models.
The recent decrease in the incidence of breast cancer overall stabilized near 200 per 100 000 woman-years by 2007–2008, reflecting a transient decrease in ER-positive cancers and a steady decrease in ER-negative cancers. The projected incidence rate for breast cancer overall through the year 2016 was similar to the incidence rate during 2007–2008. In contrast, rates of ER-positive breast cancers were projected to increase 5.3% (95% confidence interval = 5.2% to 5.4%), whereas rates of ER-negative breast cancers were projected to decrease 11.4% (95% confidence interval = 11.3% to 11.6%) during 2009–2016.
Recent changes in breast cancer incidence overall reflect the superimposition of divergent trends in ER-positive and ER-negative cancers. If current trends continue, the incidence of ER-positive breast cancers will increase, the incidence of ER-negative breast cancers will continue to decrease, and the incidence of breast cancer overall will remain similar to its current level.
PMCID: PMC3176776  PMID: 21753181
21.  How High are Carrier Frequencies of Rare Recessive Syndromes? Contemporary Estimates for Fanconi Anemia in the United States and Israel 
For many recessive genetic syndromes, carrier frequencies have been assessed through screening studies in founder populations but remain unclear in heterogeneous populations. One such syndrome is Fanconi Anemia (FA). FA is a model disease in cancer research, yet there are no contemporary data on carrier frequency or prevalence in the general United States (US) population or elsewhere. We inferred carrier frequency from birth incidence using the Hardy-Weinberg law. We estimated prevalence using birth incidence and survival data. We defined “plausible ranges” to incorporate uncertainty about completeness of case ascertainment. We made estimates for the US and Israel using demographic data from the Fanconi Anemia Research Fund and Israeli Fanconi Anemia Registry. In the US, a plausible range for the carrier frequency is 1:156 – 1:209 [midpoint 1:181]; we estimate that 550 – 975 persons were living with FA in 2010. For Israel, a plausible range for the carrier frequency is 1:66 – 1:128 [midpoint 1:93] in line with founder screening studies; we estimate that 40 – 135 Israelis were living with FA in 2008. The estimated US FA carrier frequency of 1:181 is significantly higher than the historical estimate of 1:300; hence, the gap may be narrower than previously recognized between the US carrier frequency and higher carrier frequencies of around 1:100 in several founder groups including Ashkenazi Jews. Assessment of cancer risks in heterozygous carriers merits further study. Clinical trials in FA will require co-ordination and innovative design because the number of living US patients is probably less than 1,000.
PMCID: PMC3140593  PMID: 21739583
Fanconi anemia; gene frequency; prevalence; epidemiologic methods
22.  A Case-Control Study Reveals Immunoregulatory Gene Haplotypes That Influence Inhibitor Risk in Severe Hemophilia A 
Several genes that modify risk of factor VIII inhibitors in hemophilia A patients have been identified. Aside from the underlying mutations that cause hemophilia A, inhibitor risk appears to be modified by polymorphisms in various cytokines and immunomodulators, including IL10, TNFα, and CTLA4. HLA haplotypes have not been strong determinants of inhibitor risk.
We sought to confirm previous observations on factor VIII inhibitor risk-modifying genes and to test new candidate genes encoding various otherTH1/TH2 cytokines. We also sought to determine whether normal factor VIII gene polymorphisms affect inhibitor risk in Caucasians.
We studied 915 Caucasian, severe hemophilia A patients (282 inhibitor cases and 633 non-inhibitor controls) Genes were analyzed using 368 tagging SNPs starting 20kb 5′ and ending 10kb 3′ of each gene's coding sequence; four other polymorphisms (factor V Leiden & prothrombin 20210 polymorphisms and two in HFE) were also evaluated.
Haplotypes that increased inhibitor risk were found in IL10 (OR 1.33, P = 0.04), IL12 (OR 1.31, P = 0.04), and IL1α (OR 2.16, P = 0.034). Protective haplotypes were seen in IL2 (OR 0.69, P = 0.008) and IL1β (OR 0.75, P = 0.02). One rare haplotype in the factor VIII gene increased the risk of inhibitor development by nearly four-fold (OR 3.8, P = 0.004).
We replicate previous findings for IL10; identify new associations with IL1, IL2 and IL12; and identify a rare factor VIII haplotype in Caucasians that is associated with increased inhibitor risk.
PMCID: PMC3120902  PMID: 21362111
hemophilia A; inhibitor; factor VIII; IL10; IL2; IL12; IL1
23.  Variants in or near KITLG, BAK1, DMRT1, and TERT-CLPTM1L predispose to familial testicular germ cell tumour 
Journal of medical genetics  2011;48(7):473-476.
Familial testicular germ cell tumours (TGCTs) and bilateral TGCTs comprise 1–2% and 5% of all TGCTs, respectively, but their genetic basis remains largely unknown.
To investigate the contribution of known testicular cancer risk variants in familial and bilateral TGCTs.
Methods and results
The study genotyped 106 single nucleotide polymorphisms (SNPs) in four regions (BAK1, DMRT1, KITLG, TERT-CLPTM1L) previously identified from genome-wide association studies of TGCT, including risk single nucleotide polymorphisms (SNPs) rs210138 (BAK1), rs755383 (DMRT1), rs4635969 (TERT-CLPTM1L) in 97 cases with familial TGCT and 22 affected individuals with sporadic bilateral TGCT as well as 871 controls. Using a generalised estimating equations method that takes into account blood relationships among cases, the associations with familial and bilateral TGCT were analysed. Three previously identified risk SNPs were found to be associated with familial and bilateral TGCT (rs210138: OR 1.80, CI 1.35 to 2.41, p = 7.03×10−5; rs755383: OR 1.67, CI 1.23 to 2.22, p=6.70×10−4; rs4635969: OR 1.59, CI 1.16 to 2.19, p=4.07×10−3). Evidence for a second independent association was found for an SNP in TERT (rs4975605: OR 1.68, CI 1.23 to 2.29, p=1.24×10−3). Another association with an SNP was identified in KITLG (rs2046971: OR 2.33, p=1.28×10−3); this SNP is in high linkage disequilibrium (LD) with reported risk variant rs995030.
This study provides evidence for replication of recent genome-wide association studies results and shows that variants in or near BAK1, DMRT1, TERT-CLPTM1L, and KITLG predispose to familial and bilateral TGCT. These findings imply that familial TGCT and sporadic TGCT share a common genetic basis.
PMCID: PMC3131696  PMID: 21617256
24.  Age-Period-Cohort Models in Cancer Surveillance Research: Ready for Prime Time? 
Standard descriptive methods for the analysis of cancer surveillance data include canonical plots based on the lexis diagram, directly age-standardized rates (ASR), estimated annual percentage change (EAPC), and joinpoint regression. The age-period-cohort (APC) model has been used less often. Here, we argue that it merits much broader use. Firstly, we describe close connections between estimable functions of the model parameters and standard quantities such as the ASR, EAPC, and joinpoints. Estimable functions have the added value of being fully adjusted for period and cohort effects, and generally more precise. Secondly, the APC model provides the descriptive epidemiologist with powerful new tools, including rigorous statistical methods for comparative analyses and the ability to project the future burden of cancer. We illustrate these principles using invasive female breast cancer incidence in the United States, but these concepts apply equally well to other cancer sites for incidence or mortality.
PMCID: PMC3132831  PMID: 21610223
Cancer Surveillance Research; age standardized rates (ASR); estimated annual percentage change (EAPC); joinpoint regression; Age-period-cohort (APC) model; APC estimable parameters; APC linear trends; APC deviations; APC drifts; APC fitted age at onset curve
25.  Cancer in Noonan, Costello, Cardiofaciocutaneous and LEOPARD Syndromes 
Noonan syndrome (NS), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and LEOPARD syndrome (now also referred to as Noonan syndrome with multiple lentigines or NSML) are clinically overlapping dominant disorders that are caused by mutations in RAS signaling pathway genes. The spectrum of cancer susceptibility in this group of disorders has not been studied in detail. We identified more than 1900 cases of NS, CS, CFCS, or NSML reported in the literature between 1937 to 2010; eighty-eight cancers were reported. The most common cancers reported in 1051 NS subjects were neuroblastoma (n=8), acute lymphoblastic leukemia (n=8), low grade glioma (n=6), and rhabdomyosarcoma (n=6). These associations are biologically plausible, given that somatic RAS pathway mutations are known to occur in these specific cancers. In addition, 40 childhood cases of myeloproliferative disease were described in individuals with NS, several of whom experienced a benign course of this hematologic condition. We confirmed the previously-described association between CS and cancer in 268 reported individuals: 19 had rhabdomyosarcoma, 4 had bladder cancer, and 5 had neuroblastoma. By age 20, the cumulative incidence of cancer was approximately 4% for NS and 15% for CS; both syndromes had a cancer incidence peak in childhood. The cancers described in CFCS and NSML overlapped with those reported in NS and CS. Future epidemiologic studies will be required to confirm the described cancer spectrum and to estimate precise cancer risks.
PMCID: PMC3086183  PMID: 21500339
RASopathies; Cancer risk; Mortality

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