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.
Tempol; radiation; carcinogenesis; antioxidant; chemoprevention
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.
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.
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.
Burkitt lymphoma; epidemiology; multimodal cancer; non-Hodgkin lymphoma; HIV/AIDS
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.
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.
Inflammation; Androgens; Genes; Testosterone; Polymorphism; Single Nucleotide
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.
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.
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.
Fanconi anemia; gene frequency; prevalence; epidemiologic methods
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.
hemophilia A; inhibitor; factor VIII; IL10; IL2; IL12; IL1
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.
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.
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
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.
RASopathies; Cancer risk; Mortality
Contralateral breast cancer (CBC) is the most frequent new malignancy among women diagnosed with a first breast cancer. Although temporal trends for first breast cancers have been well studied, trends for CBC are not so well established.
Patients and Methods
We examined temporal trends in CBC incidence using US Surveillance, Epidemiology, and End Results database (1975 to 2006). Data were stratified by estrogen receptor (ER) status of the first breast cancer for the available time period (1990+). We estimated the annual percent change (EAPC) in CBC rates using Poisson regression models adjusted for the age at and time since first breast cancer diagnosis.
Before 1985, CBC incidence rates were stable (EAPC, 0.27% per year; 95% CI, −0.4 to 0.9), after which they declined with an EAPC of −3.07% per year (95% CI, −3.5 to −2.7). From 1990 forward, the declines were restricted to CBC after an ER-positive cancer (EAPC, −3.18%; 95% CI, −4.2 to −2.2) with no clear decreases after an ER-negative cancer. Estimated current age-specific CBC rates (per 100/year) after an ER-positive first cancer were: 0.45 for first cancers diagnosed before age 30 years and 0.25 to 0.37 for age 30 years or older. Rates after an ER-negative cancer were higher: 1.26 before age 30 years, 0.85 for age 30 to 35 years, and 0.45 to 0.65 for age 40 or older.
Results show a favorable decrease of 3% per year for CBC incidence in the United States since 1985. This overall trend was driven by declining CBC rates after an ER-positive cancer, possibly because of the widespread usage of adjuvant hormone therapies, after the results of the Nolvadex Adjuvant Trial Organisation were published in 1983, and/or other adjuvant treatments.
Background and aim
Age-specific analyses of non-cardia gastric cancer incidence reveal divergent trends among US whites: rates are declining in individuals aged 40 years and older but rising in younger persons. To investigate this heterogeneity further, incidence trends were evaluated by anatomical subsite.
Gastric cancer incidence data for 1976–2007 were obtained from the US National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program and the US Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR). Incidence rates and estimated annual percentage change were calculated by age group (25–39, 40–59 and 60–84 years), race/ethnicity and subsite.
Based on data from the nine oldest SEER registries (covering ~10% of the US population), rates for all non-cardia subsites decreased in whites and blacks, except for corpus cancer, which increased between 1976 and 2007 with estimated annual percentage changes of 1.0% (95% CI 0.1% to 1.9%) for whites and 3.5% (95% CI 1.8% to 5.2%) for blacks. In contrast, rates for all non-cardia subsites including corpus cancer declined among other races. In combined data from NPCR and SEER registries (covering 89% of the US population), corpus cancer significantly increased between 1999 and 2007 among younger and middle-aged whites; in ethnic-specific analyses, rates significantly increased among the same age groups in non-Hispanic whites and were stable among Hispanic whites. Age-specific rates for all subsites declined or were stable in this period among blacks and other races.
Long- and short-term incidence trends for gastric cancers indicate a shifting distribution by anatomical subsite. Corpus cancer may have distinctive aetiology and changing risk factor exposures, warranting further investigation.
Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer.
Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes.
The strongest associations with RCC risk were observed for SLC19A1 (Pmin-P = 0.03) and MTHFR (Pmin-P = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake.
To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.
For the last 50 years, overall age-standardized incidence rates for noncardia gastric cancer have steadily declined in most populations. However, overall rates are summary measures that may obscure important age-specific trends.
To examine effects of age at diagnosis on noncardia gastric cancer incidence trends in the United States.
Design, Setting, and Participants
Descriptive study with age-period-cohort analysis of cancer registration data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program, which covers approximately 26% of the US population. From 1977 through 2006, there were 83 225 adults with incident primary gastric cancer, including 39 003 noncardia cases.
Main Outcome Measures
Overall and age-specific incidence rates, adjusted for period and cohort effects using age-period-cohort models. Results were stratified by race, sex, and socioeconomic status.
Overall age-standardized annual incidence per 100 000 population declined during the study period from 5.9 (95% confidence interval [CI], 5.7-6.1) to 4.0 (95% CI, 3.9-4.1) in whites, from 13.7 (95% CI, 12.5-14.9) to 9.5 (95% CI, 9.1-10.0) in blacks, and from 17.8 (95% CI, 16.1-19.4) to 11.7 (95% CI, 11.2-12.1) in other races. Age-specific trends among whites varied significantly between older and younger age groups (P < .001 for interaction by age): incidence per 100 000 declined significantly from 19.8 (95% CI, 19.0-20.6) to 12.8 (95% CI, 12.5-13.1) for ages 60 to 84 years and from 2.6 (95% CI, 2.4-2.8) to 2.0 (95% CI, 1.9-2.1) for ages 40 to 59 years but increased significantly from 0.27 (95% CI, 0.19-0.35) to 0.45 (95% CI, 0.39-0.50) for ages 25 to 39 years. Conversely, rates for all age groups declined or were stable among blacks and other races. Age-period-cohort analysis confirmed a significant increase in whites among younger cohorts born since 1952 (P < .001).
From 1977 through 2006, the incidence rate for noncardia gastric cancer declined among all race and age groups except for whites aged 25 to 39 years, for whom it increased. Additional surveillance and analytical studies are warranted to identify risk factors that may explain this unfavorable trend.
Severe congenital neutropenia (SCN) is a heterogeneous bone marrow failure syndrome predisposing to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We studied 82 North American and Australian SCN patients enrolled in the Severe Chronic Neutropenia International Registry who were on long-term treatment with granulocyte colony-stimulating factor and for whom the neutrophil elastase (ELA2) gene was sequenced. There was no significant difference in the risk of MDS/AML in patients with mutant versus wild-type ELA2: the respective cumulative incidences at 15 years were 36% and 25% (P = 0·96). Patients with either mutant or wild-type ELA2 should be followed closely for leukaemic transformation.
severe congenital neutropenia; neutrophil elastase ELA2; acute myeloid leukaemia; myelodysplastic syndromes; granulocyte colony-stimulating factor
Epidemiologic studies are reporting associations between lead exposure and human cancers. A polymorphism in the 5-aminolevulinic acid dehydratase (ALAD) gene affects lead toxicokinetics and may modify the adverse effects of lead.
The objective of this study was to evaluate single-nucleotide polymorphisms (SNPs) tagging the ALAD region among renal cancer cases and controls to determine whether genetic variation alters the relationship between lead and renal cancer. Occupational exposure to lead and risk of cancer was examined in a case-control study of renal cell carcinoma (RCC). Comprehensive analysis of variation across the ALAD gene was assessed using a tagging SNP approach among 987 cases and 1298 controls. Occupational lead exposure was estimated using questionnaire-based exposure assessment and expert review. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression.
The adjusted risk associated with the ALAD variant rs8177796CT/TT was increased (OR = 1.35, 95%CI = 1.05–1.73, p-value = 0.02) when compared to the major allele, regardless of lead exposure. Joint effects of lead and ALAD rs2761016 suggest an increased RCC risk for the homozygous wild-type and heterozygous alleles (GGOR = 2.68, 95%CI = 1.17–6.12, p = 0.01; GAOR = 1.79, 95%CI = 1.06–3.04 with an interaction approaching significance (pint = 0.06).. No significant modification in RCC risk was observed for the functional variant rs1800435(K68N). Haplotype analysis identified a region associated with risk supporting tagging SNP results.
A common genetic variation in ALAD may alter the risk of RCC overall, and among individuals occupationally exposed to lead. Further work in larger exposed populations is warranted to determine if ALAD modifies RCC risk associated with lead exposure.
Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.
To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphism (SNPs) in the 8q24 risk regions, spanning 128,101,433–128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone) and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55–74 years old) from a prospective cohort study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log transformed biomarker levels.
Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P<1.1×10−3) and bioavailable testosterone (P<6.3×10−4). Suggestive associations were seen for a cluster of 9 SNPs in prostate cancer risk region 1 and androstenedione (P<0.05).
These preliminary findings require confirmation in larger studies, but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions may correlate with androgen levels.
These results may provide some clues for the strong link between 8q24 and prostate cancer risk.
8q24; genetic polymorphisms; serum androgens
In patients with severe congenital neutropenia (SCN), long-term therapy with granulocyte colony-stimulating factor (G-CSF) has reduced mortality from sepsis, revealing an underlying predisposition to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We have reported the early pattern of evolution to MDS/AML, but the long-term risk remains uncertain. We updated a prospective study of 374 SCN patients on long-term G-CSF enrolled in the Severe Chronic Neutropenia International Registry (SCNIR) with longer follow-up. After 10 years on G-CSF, the annual risk of MDS/AML was 2.3%/year. After 15 years on G-CSF, the cumulative incidence was 10% for death from sepsis and 22% for MDS/AML. The data continue to support the hypothesis that SCN patients with high G-CSF requirements are also at high risk of MDS/AML. The risk per year of MDS/AML in SCN now appears similar to, rather than higher than, the reported risk of AML in Fanconi anemia and dyskeratosis congenita.
severe congenital neutropenia; acute myeloid leukaemia; myelodysplastic syndromes; granulocyte colony-stimulating factor
Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond-Blackfan anaemia (DBA), and Shwachman-Diamond syndrome (SDS) comprise major inherited bone marrow failure syndromes (IBMFS). Adverse events include severe bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and solid tumours (ST). The natural history of FA is well characterised; hazard rates in the other syndromes have not yet been quantified. An open cohort was established at the National Cancer Institute (NCI) in 2002. Patients enrolled prior to December, 2007 were followed up to December, 2008. Diagnoses were confirmed with standard tests. Age-associated risks of adverse events were calculated. Most patients in each syndrome survived to young adulthood. Patients with FA had earlier onset of cancers, need for stem cell transplant, and death; followed by DC; DBA and SDS were mildest. While FA and DC patients had markedly increased risks of cancer, AML and MDS, there were no cases of leukaemia in DBA or SDS patients. The NCI cohort provides the first direct quantitative comparison of timing and magnitude of cancer risk in the IBMFS. The findings demonstrate that both FA and DC are major cancer susceptibility syndromes. The IBMFS, historically considered paediatric disorders, have important management implications for physicians treating adult patients.
bone marrow failure; Fanconi anaemia; dyskeratosis congenita; leukaemia; solid tumours
We develop methods for competing risks analysis when individual event times are correlated within clusters. Clustering arises naturally in clinical genetic studies and other settings. We develop a nonparametric estimator of cumulative incidence, and obtain robust pointwise standard errors that account for within-cluster correlation. We modify the two-sample Gray and Pepe–Mori tests for correlated competing risks data, and propose a simple two-sample test of the difference in cumulative incidence at a landmark time. In simulation studies, our estimators are asymptotically unbiased, and the modified test statistics control the type I error. The power of the respective two-sample tests is differentially sensitive to the degree of correlation; the optimal test depends on the alternative hypothesis of interest and the within-cluster correlation. For purposes of illustration, we apply our methods to a family-based prospective cohort study of hereditary breast/ovarian cancer families. For women with BRCA1 mutations, we estimate the cumulative incidence of breast cancer in the presence of competing mortality from ovarian cancer, accounting for significant within-family correlation.
BRCA1 gene; Breast neoplasm; Competing risks; Correlated survival data; Counting processes; Robust variance
Genome-wide association studies (GWAS) focus on relatively few highly significant loci while less attention is given to other genotyped markers. Employing pathway analysis to existing GWAS data may shed light on relevant biological processes, and illuminate new candidate genes. We employed a pathway-based approach to the breast cancer GWAS data of the National Cancer Institute (NCI) Cancer Genetic Markers of Susceptibility (CGEMS) project that includes 1145 cases and 1142 controls. Pathways were retrieved from three databases: KEGG, BioCarta, and the NCI’s Protein Interaction Database (PID). Genes were represented by their most strongly associated SNP, and an enrichment score (ES) reflecting the overrepresentation of gene-based association signals in each pathway was calculated using a weighted Kolmogorov-Smirnov procedure. Finally, hierarchical clustering was used to identify pathways with overlapping genes, and clusters with excess of association signals were determined by the adaptive rank-truncated product (ARTP) method. A total of 421 pathways containing 3962 genes were included in our study. Of these, three pathways (‘Syndecan-1-mediated signaling ‘, ‘Signaling of Hepatocyte Growth Factor Receptor’ and ‘Growth Hormone Signaling’) were highly enriched with association signals (PES < 0.001, False Discovery Rate (FDR) = 0.118). Our clustering analysis revealed that pathways containing key components of the RAS/RAF/MAPK canonical signaling cascade, were significantly more likely to have excess of association signals than expected by chance (PARTP = 0.0051, FDR = 0.07). These results suggest that genetic alterations associated with these three pathways and one canonical signaling cascade may contribute to breast cancer susceptibility.
Pathways; GWAS; Breast cancer; Susceptibility; Genetics