Age, gender and type 2 diabetes contribute to the risk of gastric cancer: a retrospective single institution analysis           
Zeng Wang1, Xinjun Cai3, Mengjuan Liu1, Hongyang Lu2, Nengming Lin1,4*
1.Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou 310022, China
2.Zhejiang Key Lab of Diagnosis & Treatment Technology on Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou 310022, China
3. Department of Pharmacy, Integrated Chinese and Western Medicine Hospital of Zhejiang Province, Hangzhou 310003, China
4. Institute for Individualized Medicine, Hangzhou First People’s Hospital, Hangzhou 310006, China

Abstract: Diabetes is involved in the development of several cancers. However, whether type 2 diabetes mellitus (T2DM) as well as other potential risk factors are related to gastric cancer (GC) remains unclear. In this study, 1320 patients with gastric cancer (gastric cancer group) and 1252 thyroid nodule patients (control group), who were admitted in our hospital from Jan 2010 to Dec 2012, were analyzed in a case-control study. Logistic regression analysis was applied to evaluate the risk of diabetes condition, gender, age, body-mass index (BMI) level and other factors for GC. There were 416 patients with DM in the gastric cancer group (31.5%) and 120 patients with DM in the control group (9.6%). The differences between the two groups were significant (P = 0.000). Compared with the control group, the logistic regression analyses suggested that male patients had a higher risk of GC. Moreover, older individuals (especially over 65 years) were more susceptible to GC, and as for T2DM, it was found to be associated with GC, that is, the incidence in the gastric cancer group was significantly higher than in the control group. The OR values of age, T2DM, gender and BMI were 16.951, 15.130, 2.658 and 0.224, respectively. In conclusion, age, gender and T2DM are the risk factors of gastric cancer. Furthermore, male patient over 65 years with T2DM is susceptible to GC, and T2DM is the risk factor only second to age, and there might be synergistic effects among these factors.                      
Keywords: T2DM, Age, Gender, Gastric cancer, Risk factor
CLC number: R969                Document code: A                 Article ID: 10031057(2014)1179905
1. Introduction
Diabetes mellitus (DM) currently becomes a commondisease around the world. The WHO currently estimates that type 2 diabetes mellitus (T2DM) affects approximately 171 million people worldwide[1]. Meanwhile, DM patients are also increasing rapidly in China, DM people aged 35 to 64 has amounted to 20.8/100 000, ranking the second in the world[2]. Recently, DM has been recognized as one of the important risk factors for several malignancies. The most common type of diabetesmellitus, type 2, is also reported to be associated with the risk of breast cancer and several gastrointestinal cancers including liver, pancreas, colon and rectum cancers[3–7].
Gastric cancer (GC) is the fourth most common cancer and the second leading cause of death due to cancer in the world[8].Surgical resection is still the primary curativetreatment choice in early-stage GC, with a 5-year survival rate less than 30% in patients with resected GC[9].Therefore, early intervention on risk factors of GC is very important.
With respect to the relationship of diabetes with GC development, especially for the GC population, inconsistent results have been reported. Jee et al. found an increased risk of GC in patients with diabetes[10], La Vecchia et al. found an inverse association between the risk of GC and diabetes[11], and Inoue et al. found a null relationship between DM and GC risk[12]. Additionally, type 2 diabetes and GC share many risk factors, such as age, sex, alcohol consumption, BMI, tobacco smoking and so on, but the potential links between the two diseases are not exactly understood, and quantification of this association in various populations remains to be addressed. Therefore, in this research, we evaluated whether gender, age, BMI, alcohol consumption, tobacco smoking, type 2 diabetes and family history of cancer patients are associated with GC in China in a case-control study.
2. Materials and methods
2.1. Study population
A total of 1320 patients with gastric cancer (gastric cancer group) and 1252 thyroid nodule patients (controlgroup), who were admitted in our hospital from Jan 2010 to Dec 2012, were analyzed in a case-control study. This study is a retrospective single hospital-basedinvestigation. Patients in the gastric cancer group were treated in our hospital with newly diagnosed gastric cancer. The inclusion criteria for the patients were as follows: pathologically confirmed diagnosis of gastric cancer; laboratory data available for plasma glucose and detailed record of disease course and history. The exclusion criteria were the presence of other types of digestive diseases (such as neuroendocrine tumors, adenomas, cysts or unknown primary tumors) and the absence of laboratory data on plasma glucose. Control group (without cancer) were the patients treated in our hospital for thyroid nodule. The inclusion criteria for the controls were the same as those for cancer patients, but without the cancer. The cases and controls were selected at the same period, with integrated laboratory data on plasma glucose to reduce the bias in the study.
Pathologically confirmed diagnosis of gastric cancer, detailed information of patients’ age, gender, weight, height, presence of T2DM, alcohol, smoking status and family history of gastric cancer were obtained from the medical records.
Based on the body weight, BMI is calculated as weight (kg)/height squared (m)2.
2.2. Statistical methods
Software SPSS (version 15) was used for data management and statistical analysis. We compared the proportions of potential risk factors among cases. Student’s t test was used to compare mean age between cases and controls. The χ2 test was used to compare proportions. Logistic regression analyses were performed in the risk factor evaluation.
3. Results
A total of 1320 gastric cancer patients and 1252 thyroid nodule patients were included in the study. Of the 2572 patients, 1390 were male with average age of 55.1±12.3, and 1182 were female with average age of 47.6±27.1. The prevalence of T2DM in the gastric cancer group and control groups were 31.5% and 9.6%, respectively (P<0.001, χ2 = 187.3). The characteristics of the two groups are summarized in Table 1.

Table 1. Clinical findings of the gastric cancer group and control group (n or mean±SD)

NA: Not applicable. 
There was no significant difference in age, gender, alcohol consumption, BMI index, tobacco smoking, family history of gastric cancer between the two groups. Since the data about the history of gastritis were not completely recorded in the medical records, they couldn’t be precisely analyzed. However, the diabetes mellitus treatment status between the two groups was significantly different (P<0.001).
Old age is shown to be an important factor in the occurrence of gastric cancer[15,16], so we reanalyzed the data of the 2572 patients by setting a new demarcation point using the logistic regression analyses. Firstly, people aged below or over 65 were set as 0, or 1, respectively. Then, other factors (variables) were numerically assigned as follows: male as 1, female as 0; patients with BMI below or over than 25 kg/m2 as 0 or 1; patients who drink alcohol or not set as 1 or 0; patients who smoked or not as 1 or 0; patients who had family history of gastric cancer or not as 1, or 0; patientswho were T2DM or not as 1 or 0. As a result, age, gender, BMI index and type 2-diabetes were associated with gastric cancer (P<0.05, Table 2). 

Table 2. Logistic regression analysis of risk factors in gastric cancer

o significant. OR>1 means males are more susceptible than females to GC, older patients (over 65 years of age) as well as patient with T2DM are more susceptible to GC. OR value was calculated using logistic regression. The regression analysis was performed vs controls without cancer. 

 Result showed that old age, gender, BMI index and type 2-diabetes had statistical differences, and their OR values were 16.951, 2.658, 0.224 and 15.130, respectively. This suggested that age, gender and type 2-diabetes might be the risk factors of GC, but BMI index might be not. The OR values of alcohol intake, smoking status and family history of gastric cancer were 0.544, 0.975 and 0.221, but not significantly different (P>0.05).
4. Discussion
Diabetes mellitus is a factor that has long been discussed for its relation with GC. The relevance of T2DM among the GC patients in this retrospective study was 31.5%. In comparison, diabetes was present in 9.6% of the patients in the control group. This difference was statistically significant, and it supports the role of DM in GC. The incidence of T2DM in the GC patients and control group seemed a little lower than that in other reports[13,14]. This may be because some of T2DM patients remained undiagnosed.
Multiple factors are known to involve in the development of GC. In this study, non-modifiable risk factors (gender, age, family history of gastric cancer) and modifiable risk factors (BMI level, tobacco smoking and alcohol, history of gastritis, diabetes) were investigated. The logistic regression analyses suggest that T2DM is one of the independent risk factors. When coexisted with other risk factors such as gender and older age, the synergistic carcinogenesis effect is obvious.
In the developed countries, 78% of all newly diagnosed cancer occurs among individuals aged 55 years and older[15].Diabetes also becomes increasingly common with age: the prevalence is 2.6% in adults between 20–39 years, 10.8% between 40–59 years, and increases to 23.8% in those who are 60 years of age or older[16]. In our study, older individuals (especially over 65 years old) were found to be more susceptible to GC. Moreover, the population of male patients over 65 has higher risk for GC, as compared with individuals without cancer.
Oncogenesis is a multifactorial and multigenetic event. Gender and DM are known as important factors in the incidence and prognosis of many cancers. In stratified analyses by sex, male patients had a higher risk of GC. In agreement with our results, Yan et al. found that GC was positively associated with male sex compared with healthy controls[17]. However, Ge et al. reported that diabetic women are found to have an 18% increased risk of GC development[18]. These differences might be related to the racial and diet differences of cases we collected.
As for T2DM, we found that it was found to be associated with GC and the incidence in the gastric cancer group was significantly higher than in the control group. With respect to the relationship of diabetes with GC development, consistent results havebeen reported[13,14,19,20]. The possible biologic links between diabetes and cancer risk might be associated with the insulin/insulin-like growth factor (IGF) axis, effect of hyperinsulinemia and so on. Multiple signaling pathways are activated after insulin receptors interact with their ligands. By phosphorylating the adaptor proteins, most notably from the insulin receptor substrate (IRS) family, the initial kinase event is linked to downstream signaling pathways[21]. Once activated, these signaling pathways may stimulate multiple cancer phenotypes including proliferation, protection from apoptotic stimuli, invasion, and metastasis, potentially enhancing the promotion and progression of many types of cancer cells. It is also clear that insulin/IGF may stimulate normal cells that are involved in cancer progression. Apart from direct effects of insulin on cancer cells, it is possible that hyperinsulinemia could promote carcinogenesis indirectly through its effects on IGF-I[22].
BMI was surprisingly found to be a protective factor: BMI greater than 25 kg/m2 (overweight) was a less risk factor contributing to GC compared with BMI of less than 25 kg/m2. Though this finding seems controversial to the current reports that suggest a link between obesity and GC[23], the specific point should be balanced by the fact that the majority of our patient population was under the threshold of obesity. Further, the digestion and absorption functions of patients with GC were poor, which led to more weight loss than other patients did. As for other factors, tobacco smoking and alcohol consumption as well as family history of gastric cancer didn’t show any obvious difference in the risk for GC. It might be related to the retrospective nature of our study.
In summary, this study indicates that age, gender and T2DM are the risk factors of gastric cancer. Male patient over 65 years of age with T2DM is susceptible to be GC, and T2DM is the risk factor only second to age, and there might be synergistic effects among these factors. Besides, the main limitation of our study is its retrospective nature. A prospective study to address whether age, gender and type 2 diabetes as well as other factors contribute to the risk of gastric cancer is therefore clearly needed.
This study was supported by a grant from the Zhejiang Provincial Science Program (Grant No. Y2110004) and sponsored in part by Zhejiang Provincial Program for the Cultivation of High-level Innovation Health Talents (Grant No. 2010-190-4).
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年龄、性别及2型糖尿病对于胃癌发生的风险: 一项单一机构的回顾性分析
王增1, 蔡鑫君3, 刘孟娟1, 卢红阳2, 林能明1,4*
1. 浙江省肿瘤医院 药剂科,浙江 杭州 310022
2. 浙江省肿瘤医院胸部肿瘤诊治实验中心,浙江 杭州 310022
3. 杭州市红十字会医院 药剂科,浙江 杭州 310005
4. 杭州市第一人民医院 个体化医学研究所, 浙江 杭州310006    
摘要: 糖尿病与多种肿瘤的发生发展有关。然而, 与胃癌发生相关的潜在风险因素, 包括合并2型糖尿病(T2DM)是否与胃癌发生相关, 仍不清楚。本研究搜集了20101~201212月我院收治的1320例胃癌患者(胃癌组)1252个甲状腺结节的患者(对照组)的基本信息, 采用病例对照研究方法分析。应用Logistic回归分析评估合并T2DM情况、性别、年龄、身体质量指数(BMI)等对胃癌发生的影响。结果表明, 胃癌组中416T2DM31.5%, 对照组120T2DM9.6%, 两组间具有极其显著差异(P = 0.000)。与对照组相比, Logistic回归分析显示男性患者以及老年人群(年龄大于65)有较高发生胃癌的风险。此外, T2DM人群发生胃癌的风险也更高。年龄、T2DM、性别和体重指数的OR值分别为16.951, 15.130, 2.6580.224。本研究表明年龄、性别和2型糖尿病是胃癌发生的危险因素之一, 即患有2型糖尿病且年龄在65岁以上的男性患者是胃癌的高发人群, 在这三个危险因素中, 患有2型糖尿病的风险值仅次于年龄, 也有可能是这些因素之间的共同作用导致胃癌的发生。
关键词:  T2DM; 年龄; 性别; 胃癌; 危险因素
Received: 2014-04-07, Revised: 2014-05-27, Accepted: 2014-06-10.
Foundation items: Zhejiang Provincial Science Program (Grant No. Y2110004) and Cultivation of High-level Innovation Health Talents (Grant No. 2010-190-4).
*Corresponding author. Tel.: 86-571-88122438, Fax: 86-571-88122202, E-mail: