Xuesong Han

International patterns and trends in thyroid cancer incidence, 1973–2002

During the past several decades, an increasing incidence of thyroid cancer has been reported in many parts of the world. To date, no study has compared the trends in thyroid cancer incidence across continents. We examined incidence data from cancer incidence in five continents (CI5) over the 30-year period 1973–2002 from 19 populations in the Americas, Asia, Europe, and Oceania. Thyroid cancer rates have increased from 1973–1977 to 1998–2002 for most of the populations except Sweden, in which the incidence rates decreased about 18% for both males and females. The average increase was 48.0% among males and 66.7% among females. More recently, the age-adjusted international thyroid cancer incidence rates from 1998 to 2002 varied 5-fold for males and nearly 10-fold for females by geographic region. Considerable variation in thyroid cancer incidence was present for every continent but Africa, in which the incidence rates were generally low. Our analysis of published CI5 data suggests that thyroid cancer rates increased between 1973 and 2002 in most populations worldwide, and that the increase does not appear to be restricted to a particular region of the world or by the underlying rates of thyroid cancer.

A Birth Cohort Analysis of the Incidence of Papillary Thyroid Cancer in the United States, 1973–2004

BACKGROUND The incidence of papillary thyroid cancer has been reported to be increasing during the past three decades, with a 65-126% increase between 1975 and 2004. The reason for the increase is currently unknown. This study examined the incidence pattern of papillary thyroid cancer in the United States, and evaluated the components of birth cohort (defined based on year of birth), time period, and age as determinants of the observed time trend of the disease. METHODS Using the data from the National Cancer Institutes Surveillance, Epidemiology, and End Results program for 1973-2004, we conducted both univariate analysis and age-period-cohort modeling to evaluate birth cohort patterns and evaluate age, period, and cohort effects on incidence trends over time. RESULTS The increasing incidence showed a clear birth cohort pattern for both men and women. The results from age-period-cohort modeling showed that, while period effect appeared to have had an impact on the observed incidence trends, birth cohort effect may also explain part of the increasing trend in papillary thyroid carcinoma during the study period, especially among women. CONCLUSION While a period effect that is likely due to advancements in diagnostic techniques and increased medical detection of small thyroid nodules may explain some of the observed increase in the incidence, we speculate that birth cohort-related changes in environmental exposures (such as increased exposure to diagnostic X-rays and polybrominated diphenyl ethers) have also contributed to the observed increase in papillary thyroid cancer during the past decades.

Ala394Thr polymorphism in the clock gene NPAS2: A circadian modifier for the risk of non-Hodgkin's lymphoma

Circadian disruption is theorized to cause immune dysregulation, which is the only established risk factor for non‐Hodgkins lymphoma (NHL). Genes responsible for circadian rhythm are also involved in cancer‐related biological pathways as potential tumor suppressors. However, no previous studies have examined associations between circadian genes and NHL risk. In this population‐based case control study (n = 455 cases; 527 controls), we examined the only identified nonsynonymous polymorphism (Ala394Thr; rs2305160) in the largest circadian gene, neuronal PAS domain protein 2 (NPAS2), in order to examine its impact on NHL risk. Our results demonstrate a robust association of the variant Thr genotypes (Ala/Thr and Thr/Thr) with reduced risk of NHL (OR = 0.66, 95% CI: 0.51–0.85, p = 0.001), especially B‐cell lymphoma (OR = 0.61, 95% CI: 0.47–0.80, p ≤≤ 0.0001). These findings provide the first molecular epidemiologic evidence supporting a role of circadian genes in lymphomagenesis, which suggests that genetic variations in circadian genes might be a novel panel of promising biomarkers for NHL and warrants further investigation.

Lymphoma survival patterns by WHO subtype in the United States, 1973-2003.

With the incidence and prevalence of lymphoid neoplasms increasing, a comparison of survival patterns by subtype may provide critical clues for improving the disease burden. We conducted a comprehensive survival analysis for 254,702 lymphoid neoplasm cases diagnosed during 1973–2003 at 17 Surveillance, Epidemiology and End Results (SEER) registries according to the World Health Organization (WHO) classification introduced in 2001. The best survival was observed for Hodgkin lymphoma among young patients, and the worst survival was observed among cases with plasma cell neoplasms, particularly plasma cell leukemia, in all racial groups. Being diagnosed at a lower stage without B-symptoms and a non-HIV/AIDS status favored survival for each type of lymphoma. Males typically had lower survival rates than females, but the opposite was observed for Burkitt lymphoma/leukemia among non-whites and multiple myeloma among non-Hispanic whites. Non-Hispanic whites typically had higher survival rates than blacks with the exception of multiple myeloma. Survival rates decline with age at diagnosis among elders, while the patterns were diverse by subtype among younger cases. The differences in lymphoma survival patterns suggest that distinct prognostic risk factors impact survival by subtype and that future research and public health interventions should address racial disparities in lymphoma survivorship.

Vegetable and fruit intake and non-Hodgkin lymphoma survival in Connecticut women

We investigated whether an increased intake of vegetables and fruits favors NHL survival. A cohort of 568 female cases of incident NHL diagnosed during 1996–2000 in Connecticut was followed up for a median of 7.7 years. Adjusted hazard ratios (HRs) were estimated by Cox proportional hazard models. Our results show that a pre-diagnostic high intake of vegetables appeared to favor overall survival (HR = 0.74, 95% CI 0.57–0.98) among patients with NHL who survived longer than 6 months. In particular, pre-diagnostic high intakes of green leafy vegetables and citrus fruits were associated with 29% (95% CI 0.51–0.98) and 27% (95% CI 0.54–0.99) reduced risk of death, respectively. When different types of vegetables and fruits were investigated separately, their impacts were found to vary in NHL subtypes. Our study suggests that increasing vegetable and citrus fruit consumption could be a useful strategy to improve survival in NHL patients.

Genetic polymorphisms in the metabolic pathway and non-Hodgkin lymphoma survival†

Metabolic pathway enzymes, such as Cytochrome P450 (CYP), glutathione S‐transferase (GST), and N‐acetyltransferases (NAT) are involved in activation and detoxification of environmental carcinogens as well as drug metabolism. We hypothesized that the genetic variations in such metabolic pathways may affect NHL prognosis and survival. Follow‐up information of 496 female NHL incident cases diagnosed during 1996–2000 in Connecticut were abstracted from the Connecticut Tumor Registry in 2008; survival analyses were conducted by comparing the Kaplan‐Meier curves, and hazard ratios (HR) were computed from the Cox Proportional Hazard models adjusting for demographic and tumor characteristics which were suggested by previous studies to be determinants of NHL survival. We identified six SNPs from four metabolism genes (CYP2E1, GSTP1, GSTT1, and NAT1) that were associated with NHL survival. Specifically, polymorphisms in GSTT1 were associated with follicular lymphoma survival; and polymorphisms in CYP2E1, GSTP1, and NAT1 were associated with survival of chronic lymphocytic leukemia/small lymphocytic lymphoma. Our study suggests that genetic polymorphisms in metabolic pathways may help improve the prediction of NHL survival and prognosis. Am. J. Hematol., 2010.

Identification of Predictive Pathways for Non-Hodgkin Lymphoma Prognosis

Despite decades of intensive research, NHL (non-Hodgkin lymphoma) still remains poorly understood and is largely incurable. Recent molecular studies suggest that genomic variants measured with SNPs (single nucleotide polymorphisms) in genes may have additional predictive power for NHL prognosis beyond clinical risk factors. We analyzed a genetic association study. The prognostic cohort consisted of 346 patients, among whom 138 had DLBCL (diffuse large B-cell lymphoma) and 101 had FL (follicular lymphoma). For DLBCL, we analyzed 1229 SNPs which represented 122 KEGG pathways. For FL, we analyzed 1228 SNPs which represented 122 KEGG pathways. Unlike in existing studies, we targeted at identifying pathways with significant additional predictive power beyond clinical factors. In addition, we accounted for the joint effects of multiple SNPs within pathways, whereas some existing studies drew pathway-level conclusions based on separate analysis of individual SNPs. For DLBCL, we identified four pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 2.535, 2.220, 2.094, 2.453, and 2.512, respectively. As a comparison, the clinical factors had a median of the prediction logrank statistics around 0.552. For FL, we identified two pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 4.320 and 3.532, respectively. As a comparison, the clinical factors had a median of the prediction logrank statistics around 1.212. For NHL overall, we identified three pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 5.722, 5.314, and 5.441, respective. As a comparison, the clinical factors had a median of the prediction logrank statistics around 4.411. The identified pathways have sound biological bases. In addition, they are different from those identified using existing approaches. They may provide further insights into the biological mechanisms underlying the prognosis of NHL.

Polymorphisms in immune function genes and non-Hodgkin lymphoma survival

IntroductionCytokines play a critical role in regulating the immune system. In the tumor microenvironment, they influence survival, proliferation, differentiation, and movement of both tumor and stromal cells, and regulate tumor interactions with the extracellular matrix. Given these biologic properties, there is reason to hypothesize that cytokine activity influences the pathogenesis of non-Hodgkin lymphoma (NHL).MethodsWe investigated the effect of genetic variation in cytokine genes on NHL prognosis and survival by evaluating genetic variation in individual SNPs as well as the combined effect of multiple deleterious genotypes. Survival information from 496 female incident NHL cases diagnosed during 1996–2000 in Connecticut were abstracted from Connecticut Tumor Registry in 2008. Survival analyses were conducted by comparing Kaplan-Meier curves and hazard ratios (HR) were computed using Cox proportional hazard models adjusting for demographic and tumor characteristics for genes that were suggested by previous studies to be associated with NHL survival.ResultsWe found that the variant IL6 genotype is significantly associated (HR = 0.42; 95%CI: 0.23–0.77) with a decreased risk of death, as well as relapse and secondary cancer occurrence, among those with NHL. We also found that risk of death, relapse, and secondary cancers varied by specific SNPs for the follicular, DLBCL, and CLL/SLL histologic types. We identified combinations of polymorphisms whose combined deleterious effect significantly alter overall NHL survival and disease-free survival.ConclusionOur study provides evidence that the identification of genetic polymorphisms in cytokine genes may help improve the prediction of NHL survival and prognosis.

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 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 histologic subtypes in women from Connecticut, 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 and follicular lymphoma. Two single nucleotide polymorphisms 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. When vegetables, bean vegetables, cruciferous vegetables, green leafy vegetables, red vegetables, yellow/orange vegetables, fruit, and citrus fruits were examined separately, strong interaction effects were narrowed to vegetable intake among patients with diffuse large B-cell lymphoma. Our results suggest that genetic polymorphisms in oxidative stress pathway genes, especially in the NOS genes, modify the association between vegetable and fruit intake and risk of NHL. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1429–38)

Genetic polymorphisms in glutathione S-transferases and cytochrome P450s, tobacco smoking, and risk of non-Hodgkin lymphoma

We investigated variation in glutathione S‐transferases (GSTs) and cytochrome P450s (CYPs), and smoking in a population‐based case‐control study of NHL including 1,115 women. Although risk of NHL was not altered by variant polymorphisms in GSTs or CYPs, it was significantly changed for DLBCL when considered in conjunction with smoking behavior, though only in nonsmokers. An increased risk of DLBCL in nonsmokers was associated with the variant G allele for GSTP1 (OR = 1.6, 95% CI 1.0–2.3) and CYP1A1 (OR = 2.4; 95% CI 1.0–5.7), but a decreased risk for the variant G allele for CYP1B1 (OR = 0.6, 95% CI 0.4–1.0). Our results confer support investigation of the gene‐environment interaction in a larger study population of DLBCL. Am. J. Hematol. 2009.