Yingtai Chen

The Risk of Second Cancers After Diagnosis of Primary Thyroid Cancer Is Elevated in Thyroid Microcarcinomas

BACKGROUND Thyroid cancers have increased dramatically over the past few decades. Comorbidities may be important, and previous studies have indicated elevated second cancer risk after initial primary thyroid cancers. This study examined the risk of second cancers after development of a thyroid cancer, primary utilizing the Surveillance, Epidemiology, and End Results (SEER) program database. METHODS The cohort consisted of men and women diagnosed with first primary thyroid cancer who were reported to a SEER database in 1973-2008 (n=52,103). Standardized incidence ratios (SIR) were calculated for all secondary cancers. Confidence intervals and p-values are at 0.05 significance alpha level and are two-sided based on Poisson exact methods. RESULTS In this cohort, 4457 individuals developed second cancers. The risk of developing second cancers after a primary thyroid cancer varied from 10% to 150% depending on different cancer types. Cancers in all sites, breast, skin, prostate, kidney, brain, salivary gland, second thyroid, lymphoma, myeloma, and leukemia were elevated. The magnitude of the risk varied by histology, tumor size, calendar year of first primary thyroid cancer diagnosis, and the treatment of the primary thyroid cancer. The risk of a second cancer was elevated in patients whose first primary thyroid carcinomas were small, or were diagnosed after 1994, or in whom some form of radiation treatment was administered. CONCLUSIONS This large population-based analysis of second cancers among thyroid cancer patients suggests that there was an increase of second cancers in all sites, and the most commonly elevated second cancers were the salivary gland and kidney. Additionally, the increase in second cancers in patients with recently diagnosed thyroid microcarcinomas (<10 mm) suggests that aggressive radiation treatment of the first primary thyroid cancer, the environment, and genetic susceptibility, may increase the risk of a second cancer.

Cytokine polymorphisms in Th1/Th2 pathway genes, body mass index, and risk of non-Hodgkin lymphoma

We conducted a population-based, case-control study in Connecticut women to test the hypothesis that genetic variations in Th1 and Th2 cytokine genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL). Compared with those with BMI less than 25 kg/m(2), women with BMI more than or equal to 25 kg/m(2) had 50% to 90% increased risk of NHL among women who carried IFNGR2 (rs9808753) AA, IL5 (rs2069812) CT/TT, IL7R (rs1494555) AA, and TNF (rs1799724) CC genotypes, but no increased risk among women with IFNGR2 AG/GG, IL5 CC, IL7R AG/GG, and TNF CT/TT genotypes. A significant interaction with BMI was only observed for IFNGR2 (rs9808753 P(forinteraction) = .034) and IL7R (rs1494555 P(forinteraction) = .016) for NHL overall; IL7R (rs1494555 P(forinteraction) = .016) and TNF (1799724 P(forinteraction) = .031) for B-cell lymphoma; and IL5 (rs2069812 P(forinteraction) = .034) for T-cell lymphoma. After stratification by common B-cell lymphoma subtypes, a significant interaction was observed for IFNGR2 (rs9808753 P(forinteraction) = .006), IL13 (rs20541 P(forinteraction) = .019), and IL7R (rs1494555 P(forinteraction) = .012) for marginal zone B-cell lymphoma; IL7R (rs1494555 P(forinteraction) = .017) for small lymphocytic lymphoma/chronic lymphocytic leukemia; and IL12A (rs568408 P(forinteraction) = .013) and TNF (1799724 P(forinteraction) = .04) for follicular lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between BMI and NHL risk.

Diagnostic radiography exposure increases the risk for thyroid microcarcinoma: a population-based case-control study.

Thyroid cancer incidence and diagnostic radiography exposures, particularly computed tomography (CT) scanning and nuclear medicine examinations, have increased substantially in the USA. However, very few epidemiologic studies have directly investigated their associations. A population-based case–control study was conducted in Connecticut in 2010–2011, including 462 histologically confirmed incident thyroid cancer cases and 498 population-based controls. Multivariate unconditional logistic regression models were used to estimate the associations between diagnostic radiography and the risk of thyroid cancer, controlling for potential confounding factors. Exposure to any form of diagnostic radiography was associated with an increased risk of well-differentiated thyroid microcarcinoma [tumor size⩽10 mm, odds ratio (OR)=2.76, 95% confidence interval (CI): 1.31–5.81]. The highest risk increase occurred with nuclear medicine examinations (excluding cardiology tests and thyroid uptake studies; OR=5.47, 95% CI: 2.10–14.23), followed by chest CT scanning (OR=4.30, 95% CI: 1.66–11.14), head and neck CT scanning (OR=3.88, 95% CI: 1.75–8.63), upper gastrointestinal series (OR=3.56, 95% CI: 1.54–8.21), lower gastrointestinal series (OR=3.29, 95% CI: 1.41–7.66), kidney radiography involving dye injection into a vein or artery (OR=3.21, 95% CI: 1.20–8.54), mammography (OR=2.95, 95% CI: 1.14–7.61), chest radiography (OR=2.93, 95% CI: 1.37–6.29), and abdomen CT scanning (OR=2.54, 95% CI: 1.02–6.30). No significant associations were found between these imaging modalities and thyroid tumors larger than 10 mm. This study provides the first direct evidence that CT scanning and nuclear medicine examinations are associated with an increased risk of thyroid cancer. The novel finding that an array of diagnostic radiography procedures are associated with thyroid microcarcinomas warrants further investigation.

Time trend of female breast carcinoma In Situ by race and histology in Connecticut, U.S.A.

A rapid increase of female breast cancer has been reported in many areas of the world and the reasons are not fully understood. While some have attributed the increase to the increasing detection of early stage breast cancer through mammography screening, few studies have directly examined the time trend of in situ breast cancer specifically. This study included all incident cases of female breast carcinoma in situ reported to the Connecticut Tumor Registry between 1973 and 1992. The age-adjusted incidence rates and age-specific incidence rates were calculated by histology and by race. The age-adjusted incidence rates were standardised to the 1970 United States standard million population. The study found that the overall age-adjusted incidence rate of in situ breast cancer has increased dramatically, from 3.53/100000 in 1973-1975 to 17.51/100000 in 1991-1992. The increase was not uniform during the past two decades of cancer registration. In fact, most of the observed rise has occurred since the early 1980s. This increase was found in both Caucasians and Blacks. The results by histology indicate that the dramatic increase in carcinoma in situ is mostly attributable to an increase in ductal carcinoma in situ. The increase was also observed in all age groups 40 years and over. These results are consistent with the use pattern and the reported effect of mammography screening. Therefore, these results are qualitatively consistent with the idea that mammography screening is largely responsible for the recent upsurge in female breast cancer incidence in this population. The study also found that the age group 40-49 years in whites experienced a rapid increase in incidence that began in the same time period as the older age groups, but it has since levelled off. The potential impact of the highly publicized debate regarding the efficacy of mammography in this age group in recent years is discussed.

Occupational solvent exposure, genetic variation of DNA repair genes, and the risk of non-Hodgkin's lymphoma.

The main objective of this study was to test the hypothesis that genetic variations in DNA repair genes may modify the association between occupational exposure to solvents and the risk of non-Hodgkin’s lymphoma (NHL). A population-based case–control study was conducted on Connecticut women including 518 histologically confirmed incident NHL cases and 597 controls. Unconditional logistic regression models were used to estimate the odds ratios and effect modification from the 30 single nucleotide polymorphisms in 16 DNA repair genes of the association between solvent exposure and the risk of NHL overall and subtypes. Single nucleotide polymorphisms in MGMT (rs12917) and NBS1 (rs1805794) significantly modified the association between exposure to chlorinated solvents and the risk of NHL (Pfor interaction=0.0003 and 0.0048, respectively). After stratification by major NHL histological subtypes, MGMT (rs12917) modified the association between chlorinated solvents and the risk of diffuse large B-cell lymphoma (Pfor interaction=0.0027) and follicular lymphoma (Pfor interaction=0.0024). A significant interaction was also observed between occupational exposure to benzene and BRCA2 (rs144848) for NHL overall (Pfor interaction=0.0042). Our study results suggest that genetic variations in DNA repair genes modify the association between occupational exposure to solvents and the risk of NHL.

Risk of second primary cancer after treatment for esophageal cancer: a pooled analysis of nine cancer registries

The introduction of new treatments for esophageal cancer including surgery, chemotherapy, radiotherapy, or a combination of these modalities has not only improved patient survival, but may also increase the risk of the second primary cancers. The available evidence is conflicting with most risk estimates based on sparse numbers. Here we estimated standardized incidence ratios (SIRs) of second cancer among 24,557 esophageal cancer survivors (at least 2 months) in the Surveillance, Epidemiology, and End Results (SEER) Program between 1973 and 2007, who had been followed up for median 6.5 years (range 2 months-29.3 years). Second cancer risk was statistically significantly elevated (SIR = 1.34, 95% confidence interval [CI]= 1.25-1.42) among the survivors compared with the general population; the SIRs for cancers of oral and pharynx, stomach, small intestine, larynx, lung and bronchus, thyroid and prostate cancer were 8.64 (95% CI = 7.36-10.07), 2.87 (95% CI = 2.10-3.82), 3.80 (95% CI = 1.82-7.00), 3.19 (95% CI = 2.12-4.61), 1.68 (95% CI = 1.46-1.93), 2.50 (95% CI = 1.25-4.47), and 0.77 (95% CI = 0.65-0.90), respectively. Radiotherapy raised cancer risk of larynx (SIR = 3.98, 95% CI = 2.43-6.14) and thyroid (SIR = 3.57, 95% CI = 1.54-7.03) among all esophageal cancer survivors. For patients who had 5-9 years of follow up after radiotherapy, the SIR for lung cancer was 3.46 (95% CI = 2.41-4.82). Patients with esophageal cancer are at increased risks of second cancers of oral and pharynx, larynx, lung, and thyroid, while at a decreased risk for prostate cancer. These findings indicate that radiotherapy for esophageal cancer patients may increase risk of developing second cancers of larynx, lung, and thyroid. Thus, randomized clinical trials to address the association of radiotherapy and the risk of secondary cancer are warranted.

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.

Thyroid-Stimulating Hormone, Thyroid Hormones, and Risk of Papillary Thyroid Cancer: A Nested Case–Control Study

Background: The effects of thyroid-stimulating hormone (TSH) and thyroid hormones on the development of human papillary thyroid cancer (PTC) remain poorly understood. Methods: The study population consisted of 741 (341 women, 400 men) histologically confirmed PTC cases and 741 matched controls with prediagnostic serum samples stored in the Department of Defense Serum Repository. Concentrations of TSH, total T3, total T4, and free T4 were measured in serum samples. Conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI). Results: The median time between blood draw and PTC diagnosis was 1,454 days. Compared with the middle tertile of TSH levels within the normal range, serum TSH levels below the normal range were associated with an elevated risk of PTC among women (OR, 3.74; 95% CI, 1.53–9.19) but not men. TSH levels above the normal range were associated with an increased risk of PTC among men (OR, 1.96; 95% CI, 1.04–3.66) but not women. The risk of PTC decreased with increasing TSH levels within the normal range among both men and women (Ptrend = 0.0005 and 0.041, respectively). Conclusions: We found a significantly increased risk of PTC associated with TSH levels below the normal range among women and with TSH levels above the normal range among men. An inverse association between PTC and TSH levels within the normal range was observed among both men and women. Impact: These results could have significant clinical implications for physicians who are managing patients with abnormal thyroid functions and those with thyroidectomy. Cancer Epidemiol Biomarkers Prev; 26(8); 1209–18. ©2017 AACR.

Polymorphisms in DNA repair pathway genes, body mass index, and risk of non‐Hodgkin lymphoma

We conducted a population‐based case‐control study in Connecticut women to test the hypothesis that genetic variations in DNA repair pathway genes may modify the relationship between body mass index (BMI) and risk of non‐Hodgkin lymphoma (NHL). Compared to those with BMI <25, women with BMI ≥25 had significantly increased risk of NHL among women who carried BRCA1 (rs799917) CT/TT, ERCC2 (rs13181) AA, XRCC1 (rs1799782) CC, and WRN (rs1801195) GG genotypes, but no increase in NHL risk among women who carried BRCA1 CC, ERCC2 AC/CC, XRCC1 CT/TT, and WRN GT/TT genotypes. A significant interaction with BMI was only observed for WRN (rs1801195; P = 0.004) for T‐cell lymphoma and ERCC2 (rs13181; P = 0.002) for diffuse large B‐cell lymphoma. The results suggest that common genetic variation in DNA repair pathway genes may modify the association between BMI and NHL risk. Am. J. Hematol. 88:606–611, 2013.

Polymorphisms in JAK/STAT signaling pathway genes and risk of non-Hodgkin lymphoma

Impaired function of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway genes leads to immunodeficiency and various hematopoietic disorders. We evaluated the association between genetic polymorphisms (SNPs) in 12 JAK/STAT pathway genes (JAK3, STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6, SCOS1, SCOS2, SCOS3, and SCOS4) and NHL risk in a population-based case-control study of Connecticut women. We identified three SNPs in STAT3 (rs12949918 and rs6503695) and STAT4 (rs932169) associated with NHL risk after adjustment for multiple comparison. Our results suggest that genetic variation in JAK/STAT pathway genes may play a role in lymphomagenesis and warrants further investigation.