Xuezhong Chen

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.

Early Recurrence and Death After Esophagectomy in Patients With Esophageal Squamous Cell Carcinoma

BACKGROUNDnThe aim of this retrospective study is to analyze recurrence and death within 1 year after esophagectomy in patients with esophageal carcinoma.nnnMETHODSnThe records of 533 consecutive patients with esophageal squamous cell carcinoma who underwent surgery from January 2002 to January 2005 were reviewed. Patients who died of recurrence within 1 year after operation (group A) were compared with patients who survived more than 5 years without any recurrence (group B). Their clinicopathologic characteristics were evaluated by univariate and multivariate analyses.nnnRESULTSnThe overall 1-year and 5-year survival rates for the entire cohort were 76.1% and 32.3%, respectively, with the follow-up rate of 93.4%. Of the 119 patients who died within 1 year after the esophagectomy, local recurrence or distant metastasis or both were documented in 62 patients (52.1%). The radicality of resection, size of tumor, radicality of resection, grade of differentiation, depth of invasion, status of lymph node metastasis, number of lymph node metastases, and marginal status were shown by univariate analysis to be the significant prognostic factors. By multivariate analysis, they were also the independent prognostic factors, except for the size of tumor and the radicality of resection.nnnCONCLUSIONSnMore than half of early death in esophageal squamous cell carcinoma patients after esophagectomy were still tumor recurrence related, especially hematogeneous spreading. The grade of differentiation, depth of invasion, lymph node metastasis, number of lymph node metastases, and marginal status are valuable prognostic factors in predicting early death.

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 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; Pu2009=u20090.004) for T‐cell lymphoma and ERCC2 (rs13181; Pu2009=u20090.002) 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.

Genetic polymorphisms in oxidative stress pathway genes and modification of BMI and risk of non-Hodgkin lymphoma

Background: Being overweight and obese increases oxidative stress in the body. To test the hypothesis that genetic variations in oxidative stress pathway genes modify the relationship between body mass index (BMI) and risk of non-Hodgkin lymphoma (NHL), we conducted a population-based case–control study in Connecticut women. Methods: Individuals who were overweight/obese (BMI ≥ 25) were compared with normal and underweight individuals (BMI < 25), and their risk of NHL stratified assuming a dominant allele model for each oxidative stress pathway single-nucleotide polymorphism. Results: Polymorphisms in AKR1A1, AKR1C1, AKR1C3, CYBA, GPX1, MPO, NCF2, NCF4, NOS1, NOS2A NOS3, OGG1, ATG9B, SOD1, SOD2, SOD3, RAC1, and RAC2 genes after false discovery rate adjustment did not modify the association between BMI and risk of NHL overall and histologic subtypes. Conclusions: The results suggest that common genetic variations in oxidative stress genes do not modify the relationship between BMI and risk of NHL. Impact: Studies of BMI and oxidative stress independently may elevate NHL risk, but this study suggests no interaction of the two risk factors. Future studies with larger study populations may reveal interactions. Cancer Epidemiol Biomarkers Prev; 21(5); 866–8. ©2012 AACR.

Polymorphisms in Th1/Th2 cytokine genes, hormone replacement therapy, 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 hormone replacement therapy (HRT) and risk of non-Hodgkin lymphoma (NHL). Compared to women without a history of HRT use, women with a history of HRT use had a significantly decreased risk of NHL if they carried IFNGR2 (rs1059293) CT/TT genotypes (ORu2009=u20090.5, 95%CI: 0.3–0.9), IL13 (rs20541) GG genotype (ORu2009=u20090.6, 95%CI: 0.4–0.9), and IL13 (rs1295686) CC genotype (ORu2009=u20090.6, 95%CI: 0.4–0.8), but not among women who carried IFNGR2 CC, IL13 AG/AA, and IL13CT/TT genotypes. A similar pattern was also observed for B-cell lymphoma but not for T-cell lymphoma. A statistically significant interaction was observed for IFNGR2 (rs1059293 Pfor interactionu2009=u20090.024), IL13(rs20541 Pfor interactionu2009=u20090.005), IL13 (rs1295686 Pfor interactionu2009=u20090.008), and IL15RA (rs2296135 Pfor interactionu2009=u20090.049) for NHL overall; IL13 (rs20541 Pfor interactionu2009=u20090.0009), IL13(rs1295686 Pfor interactionu2009=u20090.0002), and IL15RA (rs2296135 Pfor interactionu2009=u20090.041) for B-cell lymphoma. The results suggest that common genetic variation in Th1/Th2 pathway genes may modify the association between HRT and NHL risk.

Early Effects of Low Dose 12C6+ Ion or X-Ray Irradiation on Peripheral Blood Lymphocytes of Patients with Alimentary Tract Cancer:

The aim of this study was to examine the early effects of low dose 12C6+ irradiation or X-ray on peripheral blood lymphocytes (PBL) of patients with alimentary tract cancer and to explore mechanisms that may be involved in an antitumor immune response. We found that the percentage of T lymphocyte subsets, the mRNA expression levels of IL-2 and IFN-γ in PBL, and their protein levels in supernatant were significantly increased 24 hours after exposure to low dose radiation. The effects were more pronounced in the group receiving 0.05Gy 12C6+ ion irradiation than the group receiving X-ray irradiation. There was no significant change in the percentage of NK cell subsets and TNF-α production of PBL. Our study suggests that low dose irradiation could alleviate immune suppression caused by tumor burden and that the effect was more pronounced for 0.05Gy high linear energy transfer (LET) 12C6+ irradiation.

Abstract P1-01-17: Characterization of novel ESR1 (c.749T>C; p.Met250Thr) mutation in enhancing cellular invasiveness of breast cancer

Emerging evidence has revealed that the mutations in estrogen receptor alpha (ERα) gene (ESR1) is frequently observed in ER+ metastatic breast cancer, and is associated with the aggressively invasive and metastatic phenotype in advanced breast cancer due to the resistance of endocrine therapy. In our previous study, we have identified three novel mutations of ESR1, including ESR1 G74R, D230H and M250T, in the untreated patients with early breast cancer. However, the functional roles for these novel mutations in the cellular biology of breast cancer remain to be elucidated. In this study, we described the molecular mechanism underlying potential roles for the novel mutation ESR1 p.Met250Thr (c.749T>C) in regulating the cellular invasiveness of breast cancer. Firstly, we found, as compared with wild-type (WT) HA-ESR1, forced expression of HA-ESR1 M250T enhanced the invasive capacity of breast cancer MCF-7 cells by using Transwell assay. Moreover, we found that the levels of miR-190 were significantly up-regulated in the MCF-7 (HA-ESR1 M250T) cells, and further verified that miR-190 played an important role in ESR1 M250T-mediated induction of cellular invasiveness by using specific shRNA to knock down miR-190 levels in MCF-7 (HA-ESR1 M250T) cells. Further bioinformatics analysis showed that there were several half Estrogen Response Elements (EREs) in the promoter region of Talin-2, as the host gene of miR-190. Talin-2-driven luciferase reporter assay indicated ESR1 M250T resulted in a higher increase in the luciferase activity than ESR1 WT. Chromatin-immunoprecipitation (ChIP) assay identified a higher binding ability with Talin-2 promoter for ESR1 M250T than ESR1 WT. Collectively, our mechanistic study revealed that the ESR1 M250T mutation, located in the DNA-binding domain, increased the invasive capacity of breast cancer cells via the transcriptional induction of Talin-2 and miR-190. The potential role for ESR1 M250T in affecting the efficacy of endocrine therapy has been under the investigation in our laboratory, and the result from which will help us better elucidate the clinical relevance for novel ESR1 mutations in affecting the sensitivity of endocrine therapy. This study was supported in part by National Natural Science Foundation of China (8160111571) and Guangdong Natural Science Foundation (2016A030313768). Citation Format: Liao N, Zhang G-C, Wang Y, Cao L, Li K, Ren C-Y, Wen L-Z, Shi Y, Zhu W, Chen X. Characterization of novel ESR1 (c.749T>C; p.Met250Thr) mutation in enhancing cellular invasiveness of breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-01-17.

Abstract 860: Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CAnnAbstractnnBackground: Basal cell carcinoma (BCC) is the most common malignant skin carcinoma. Although mortality is low as BCC rarely metastasizes, this malignancy has a tendency for local recurrence. As such, it is of great practical utility to assess which is the best therapeutic choice in the management of BCC recurring after different treatments. Here, we describe six cases of recurrent BCC treated with carbon ion radiotherapy and review the cases previously reported in the literature.nnMethods: Case records of six patients with biopsy-proved, recurrent BCC, who were given total doses of 60-70 GyE, administered in 6-11 fractions over 6-11 days, with a fraction dose of 7-10 GyE in the therapy terminal at Heavy Ion Research Facility in Lanzhou (HIRFL) at the Institute of Modern Physics, Chinese Academy of Sciences (IMP-CAS), China, were retrospectively reviewed.nnResults: Tumor response rate was 100%, including 6 CR, at 12 months after completion of carbon ion radiation. In a minimum follow-up period of 55 months, overall survival and no recurrence were achieved. No grade 3 or higher toxicity and complication occurred.nnConclusions: Carbon ion radiotherapy is well tolerated and should be considered as a potential salvage modality for recurrent BCC in certain cases.nnNote: This abstract was not presented at the meeting.nnCitation Format: Yingtai Chen, Feng Dong, Yantao Tian, Chengfeng Wang, Liang Cui, Xuezhong Chen. Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 860. doi:10.1158/1538-7445.AM2014-860