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Decreased digit ratio (2D:4D) and gastric cancer in Chinese men
Early Human Development 103 (2016) 109–112
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Decreased digit ratio (2D:4D) and gastric cancer in Chinese men☆ Youjing Sheng a, Wenli Qian a, Lu Wang b, Zhenghao Huo a, Hong Lu a,⁎, Haochen Yu a, Zhi Geng a, Ping Cheng c a Ningxia Medical University, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education/Key Laboratory of Reproduction and Genetics/Department of Medical Genetics and Cell Biology, Yinchuan 750004, PR China b Clinical Medicine Science, Peking University Health Science Center, Beijing 100191, PR China c Surgical Oncology of General Hospital of Ningxia Medical University, Yinchuan 750004, PR China.
a r t i c l e
i n f o
Article history: Received 16 May 2016 Received in revised form 27 July 2016 Accepted 9 August 2016 Available online xxxx Keywords: Digit ratio (2D:4D) Sexual hormones Gastric cancer (GCA)
a b s t r a c t Background: The development of finger length is influenced by the level of hormones during pregnancy in the womb. The relative length of 2nd to 4th digit (2D:4D) is considered as a putative marker for prenatal hormone exposure and may represent an individual susceptibility to certain diseases, particularly those hormonerelated cancers (e.g., gastric cancer). Aims: The aim of this study is to investigate whether there is a possible relationship between 2D:4D ratio and gastric cancer (GCA) in Chinese men. Methods: 94 male patients with GCA and 91 controls were chosen to participate in this study. Photographs of both hands were collected and then the lengths of second and fourth digits of both hands were measured. Left hand, right hand, mean hand, and right minus left hand (ΔR-L) 2D:4D ratios were analyzed and compared. Results: In GCA group, 2D:4D ratios were significantly lower (right hand: p b 0.01; left hand, mean hand: p b 0.001) than controls. No association was observed between 2D:4D ratio and tumor staging (neither in tumor size (T) nor in lymph node involvement (N) or distant metastases (M)). There was also no correlation between 2D:4D ratio and age of onset. Conclusions: Decreased 2D:4D ratio may be an indicator for forecasting the susceptibility to develop GCA. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Digit ratio refers to the ratio of human finger length. It is determined during embryonic development and then changes little after sexual maturation [1]. The ratio which is known as the 2nd to 4th digit ratio (2D:4D) is a sexually dimorphic trait. Previous studies have reported that 2nd digit is usually shorter than 4th digit in males than in females, which results in a relatively lower 2D:4D ratio [2]. Several studies have shown that the development of finger length is influenced by the level of hormones during pregnancy in the womb [1]. Malas et al. [3] suggested that the 2D:4D ratio was probably fixed when fetus started to produce testosterone in week 8 and testosterone peaks in weeks 11 or 12 to 14. It has been demonstrated that 2D:4D ratio is negatively related to prenatal testosterone (PT) and positively related to prenatal estrogen (PE). Furthermore, there is evidence that 2D:4D measures are unrelated to the concentrations of adult circulating sex steroids [4]. So, recent years, 2D:4D ratio is considered as a useful
☆ Foundation item: This study was supported by grants from National Natural Science Foundation of China (Grant Nos. 31460272; 30960154; 31360257). ⁎ Corresponding author at: Department of Medical Genetics and Cell Biology, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, PR China. Tel.: +860951 6980110 E-mail address: [email protected] (H. Lu).
http://dx.doi.org/10.1016/j.earlhumdev.2016.08.004 0378-3782/© 2016 Elsevier Ireland Ltd. All rights reserved.
biomarker for prenatal hormone exposure or sensitivity to testosterone and estrogen. Up to now, there are a number of researches investigating the correlation between 2D:4D ratio and sex steroids related diseases, such as some cancers, coronary artery disease (CAD) and infertility. Jung et al. [5] found that 2D:4D ratio was related to the level of prostate specific antigen (PSA) and the patients with lower 2D:4D ratio had higher risk of prostate cancer. Muller et al. [6] reported a direct association between left hand, ΔR-L 2D:4D ratios and the breast cancer. They suggested that lower exposure or sensitivity to PT might be associated with lower risk of breast cancer. Wu et al. [7] observed that the male patients with CAD had significantly higher 2D:4D ratios than controls in both hands. Similar with earlier studies, Lu et al. [8] also found that the patients with infertility had higher 2D:4D ratios than controls. All above evidence implied that the 2D:4D ratio may be correlated with the risk of many hormone-related diseases. Gastric cancer (GCA) is one of the most common cancers in China, and it is the leading causes of cancer-related mortality in malignant tumor [9]. Several epidemiologic studies have suggested that prenatal sex hormones (PE and PT) may play an important role in gastric carcinogenesis [10–12]. The earlier finding in a Brazilian sample (mainly men but some women) by Nicolas et al. [13] gave mixed results, such that (a) the patients with GCA had lower Δ R–L 2D:4D ratio compared to controls suggesting they had been exposed to higher PT than PE, and (b) the patients had higher left 2D:4D ratio suggesting that they had
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Y. Sheng et al. / Early Human Development 103 (2016) 109–112
been exposed to low PT, particularly so for males. Their findings predict that 2D:4D may be a biological marker for the screening of patients' susceptibility to GCA. Based on the findings mentioned above, here we speculate that there may also be a link between 2D:4D ratio and GCA from Chinese populations. As GCA is more frequent in males than in females, so, in this study, only men were chosen for investigating the relationship between 2D:4D ratio and GCA. 2. Subjects and methods 2.1. Participants All individuals were Han nationality including 185 adult males (age: 25–77 years). The present study was performed at Yinchuan city which located in the Ningxia Region, China. Patients: 94 male patients with GCA (age: 25–77 years, mean age ± S.D. = 55.22 ± 9.59 years) were recruited from the general tumor hospital affiliated to Ningxia Medical University. All of them were diagnosed by clinical and histological analysis. Controls: 91 resident natives (age: 35–76 years, mean age ± S.D. = 52.78 ± 10.48 years) were invited to participate in this research, and all were presented healthy physical and mental states. 2.2. Ethical statements This study was approved by the Ningxia Medical University Committee for the Protection of Human Subjects. The participants had informed written consent before the experiment.
correlations between 2D:4D ratio and age, the TNM staging (tumor size [T], lymph node metastasis [N], distant metastasis [M]). Data were all conducted by using SPSS software (Version 19.0), with a significance level of p b 0.05. 3. Result All controls and most patients (66%) didn't have familial history of malignancy. The rates of alcohol consumption were similar between controls (33%) and patients (32%). Tobacco consumption was significantly higher in the GCA group (62%) than in controls (47%) (χ2 = 3.894, p = 0.048). Most patients were diagnosed as low-differentiated adenocarcinoma, while few were gastric mucinous adenocarcinoma. Signet-ring cell carcinoma of gastric was also included. Related hormone therapy was not reported. The ranges of 2D:4D ratio between patients (left 2D:4D: 0.870– 1.044; right 2D:4D: 0.855–1.038; mean 2D:4D: 0.874–1.027; Δ R-L 2D:4D: − 0.079–0.163) and controls (left 2D:4D: 0.899–1.028; right 2D:4D: 0.905–1.001; mean 2D:4D: 0.905–1.000; Δ R-L 2D:4D: −0.062–0.103) were similar. There was no significant difference between left and right 2D:4D ratios in both patients and controls (p N 0.05). 3.1. Mean values of 2D:4D ratio and age The mean values of age and 2D:4D ratio of both hands between controls and patients were shown in Table 1. We found that the age was similar between GCA patients and controls. Mean values of 2D:4D ratio were significantly lower in patients compared to that of controls (right hand: Cohen's effect size d = 0.45, p b 0.01; left hand: d = 0.56, p b 0.001; mean hand: d = 0.61, p b 0.001).
2.3. Digit measurement According to the methodology proposed by Nicolás and Jorge [14], each Individual's images of both hands were obtained by a digital camera (Canon M3, Japan). Photographs were collected under the same camera configuration to avoid discrepancies between images. When taking photos, the participants were required to keep their wrists, hand palms and fingers extended and placed on a horizontal table; and the experimenter was required to keep the camera perpendicular to the palms side under the same height. The subjects with finger injured or uncompleted were excluded. All images were input into the computer and checked to insure the creases of the fingers were visible clearly. The lengths of the second and fourth digits of both hands were measured by the image analysis software (Image-Pro plus 6.0) and accurate to 0.01 mm. As described in the previous study [14], the digit length was measured from the most proximal crease up to the tip of the finger. To minimize measurement errors, each digit was measured twice and the average value was calculated as the last result. 2D:4D ratio was computed by dividing the length of the second finger by that of the fourth finger. The mean 2D:4D shown the average value of left 2D:4D and right 2D:4D, Δ R-L 2D:4D was obtained by the right 2D:4D minus left 2D:4D.
3.2. The relationship between 2D:4D ratio and TNM staging, age of onset Correlations between 2D:4D ratio and TNM staging, age of onset in GCA group were shown in Table 2. 2D:4D ratio did not show any correlation with tumor staging (neither in tumor size (T) nor in lymph node involvement (N) or distant metastases (M)) (p N 0.05). There was also no relationship between the age of onset and 2D:4D ratio (p N 0.05) (Table 2). 3.3. Relationships between lower/higher 2D:4D ratio and TNM staging, age of onset In order to extend to explore whether there is a link between 2D:4D ratio and GCA, we divided 2D:4D ratio of GCA patients into two groups (lower 2D:4D and higher 2D:4D) by median (Table 3). And then tested the relationships between lower/higher 2D:4D ratio and TNM staging, age of onset respectively again (Table 4). There were significant differences between lower 2D:4D ratio and higher 2D:4D ratio in both hands (p b 0.001). Whatever lower and higher 2D:4D ratio, there was still no correlation observed between 2D:4D ratio and TNM staging and age of onset (all p N 0.05).
2.4. Statistical analysis We use the following methods for statistical analysis: Remeasurement reliability was high for the first and second 2D:4D ratios (intraclass correlation coefficients (ICC), patients: left 2D:4D: r = 0.955, F(93) = 21.996, p b 0.001; right 2D:4D: r = 0.962, F(93) = 26.254, p b 0.001; controls: left 2D:4D: r = 0.993, F(90) = 148.873, p b 0.001; right 2D:4D: r = 0.986, F(90) = 71.314, p b 0.001). Differences of 2D:4D ratio and ages between the patients with GCA and controls were analyzed by independent sample t-test. The Pearson correlation coefficient test was used to investigate the
Table 1 Mean values of 2D:4D ratio and age in GCA and controls (mean, SD).
Age Right 2D:4D Left 2D:4D Mean 2D:4D ΔR–L 2D:4D
GCA (N = 94)
Controls (N = 91)
t
p
55.22 (9.59) 0.948 (0.038) 0.946 (0.036) 0.947 (0.031) 0.002 (0.040)
52.78 (10.48) 0.962 (0.022) 0.963 (0.024) 0.963 (0.020) −0.000 (0.022)
−1.656 3.157 3.792 4.070 −0.0541
0.100 0.002⁎ 0.000⁎⁎ 0.000⁎⁎ 0.589
⁎ p b 0.01 (difference of 2D:4D between GCA and controls). ⁎⁎ p b 0.001 (difference of 2D:4D between GCA and controls).
Y. Sheng et al. / Early Human Development 103 (2016) 109–112 Table 2 Correlations between 2D:4D ratio and TNM staging, age of onset in GCA group (r, p). 2D:4D
TNM staging T
Right Left Mean ΔR–L
Age of onset
N
−0.096 (0.378) −0.048 (0.662) −0.078 (0.475) −0.014 (0.901)
−0.013 (0.906) −0.046 (0.670) −0.044 (0.686) −0.015 (0.899)
0.004 (0.969) 0.108 (0.319) 0.061 (0.575) −0.136 (0.208)
0.065 (0.549) 0.104 (0.337) 0.101 (0.350) −0.016 (0.887)
4. Discussion Gastric cancer is rapidly increasing in prevalence all over the world and is one of the most common causes of cancer death in China. It is more frequent in men than women with presenting a characteristic of low diagnosis rate early. Most of them are advanced GCA, especially in 2–4 stage (TNM staging). There are different levels of eating disorders, emaciation, anemia, low protein disorder and the postoperative complications displayed. This study aimed to investigate the relationship between GCA and 2D:4D ratio which may reflect PT and PE levels in Chinese men. The present evidence shown that the left, right and mean 2D:4D ratios were significantly lower than that of controls. It is widely recognized that PT is inversely related to 2D:4D ratio, while PE is positively related to 2D:4D ratio. And previous studies have demonstrated that sexual hormones may play an important role on regulating growth and function of epithelial gastric tissue [10,11,15]. Thus, our results indicate that the patients with GCA may have had relatively higher PT or lower PE exposure during fetal development compared to controls. Although there was no difference in Δ R-L 2D:4D ratio between the patients and controls in the present study, the conclusion of ours support the finding of Nicolas et al. [13] who shown that the patients with GCA had lower Δ R-L 2D:4D compared to controls suggesting they had been exposed to higher PT. Moreover, it has been reported that testosterone is related to helicobacter pylori infections and is one of the main etiological factors for gastric carcinogenesis, while estrogen is a protective effect over helicobacter pylori infections [12,16]. It means the individual who has a higher exposure level or sensitivity to PT in his fetus will has the less ability to defense the helicobacter pylori infections and the higher risk of developing GCA later in life. Therefore, according to the previous studies and our results, we guess that the men with lower 2D:4D ratio (indicating higher PT) will have a higher risk of developing GCA, and 2D:4D ratio may be a possible indicator of GCA. In contrast, decreased 2D:4D ratios in patients with GCA in our study were different from the results of Nicolas et al. [13] who found that GCA group shown significantly higher left 2D:4D ratio and lower Δ R-L 2D:4D ratio than controls, especially in males. It has been reported that Δ R-L 2D:4D ratio seems to better reflect the prenatal hormone exposure or sensitivity than right 2D:4D ratio, but not left 2D:4D ratio [17]. However, our results shown there was no-significant difference on Δ R-L 2D:4D ratio as well as the difference on left 2D:4D ratio was stronger than right 2D:4D ratio between two groups. Therefore, we suggest that left 2D:4D ratio
Table 3 Mean values of lower and higher 2D:4D ratio in GCA group (mean, S.D.). 2D:4D Left 2D:4D Right 2D:4D Mean 2D:4D ΔR-L 2D:4D
Table 4 Correlations between lower/higher 2D:4D ratio and TNM staging, age of onset in GCA group (r, p). 2D:4D
M
Lower
Higher
t
p
0.9167 (0.0182) 0.9171 (0.0220) 0.9219 (0.0169) −0.0282 (0.0208)
0.9747 (0.0247) 0.9786 (0.0231) 0.9716 (0.0209) 0.0325 (0.0308)
−12.959 −13.210 −12.675 −11.180
0.000⁎ 0.000⁎ 0.000⁎ 0.000⁎
⁎ p b 0.001 (difference of 2D:4D between lower and higher group).
111
TNM staging T
Age of onset
N
M
Lower 2D:4D Right −0.140 (0.372) Left 0.044 (0.779) Mean −0.054 (0.730) ΔR–L 0.011 (0.946)
−0.083 (0.598) 0.093 (0.554) 0.014 (0.931) 0.035 (0.824)
−0.238 (0.124) −0.078 (0.620) −0.085 (0.589) −0.003 (0.983)
0.074 (0.639) 0.088 (0.573) 0.065 (0.677) −0.104 (0.507)
Higher 2D:4D Right −0.112 (0.467) Left −0.179 (0.246) Mean −0.069 (0.657) ΔR-L 0.023 (0.881)
0.185 (0.230) −0.243 (0.113) −0.140 (0.366) 0.100 (0.518)
−0.021 (0.892) 0.079 (0.612) 0.100 (0.518) 0.083 (0.590)
0.001 (0.995) −0.106 (0.493) −0.074 (0.633) −0.015 (0.923)
may also be a better marker for reflecting the sensitivity and exposure to PT. The reason behind all the differences above may be that GCA is more common in East Asia populations [18], but Nicolas's sample was Brazilian (mainly men but some women) which belongs to the Western world [19]. In addition, differences in sample size and method selected for assessing 2D:4D ratio between the two studies may also contribute to the different results. And also, further work is needed to clarify the situation for women with GCA. Several reports have shown that 2D:4D ratio may be useful in the identification of high-risk groups in relation to some cancers. Muller et al. [6] conducted a study between 2D:4D ratio and breast cancer risk, and concluded that digit ratio measures might be associated with breast cancer risk and age of disease onset. Similarly, an exploratory analysis conducted by Stolten et al. [20] shown a relationship between alternative digit ratio and diagnosis age in prostate cancer. In agreement with their results, Jung et al. [5] also found a significantly negative correlation between 2D:4D ratio and PSA, in other words, the lower 2D:4D ratio, the higher risk of prostate cancer. Above information implied that 2D:4D ratio may be also related to the age of onset or diagnosis age of GCA. Furthermore, Sox 9 gene is believed to associate with gastric adenocarcinomas, which has also been established as one of the genes to act on the development of finger length [2]. It has been reported that the expression of Sox 9 gene is inversely related to tumor staging and Epstein Barr infections which is closely related to early carcinogenesis of GCA [21]. So we guess that there may also be some associations between 2D:4D ratio and GCA tumor staging and age of onset. Therefore, we conducted the further analysis. Unexpected, similar with the findings of Nicolás et al. [13], even the 2D:4D ratio was divided into lower and higher groups by the median; we still didn't found any correlation between 2D:4D ratio and TNM staging and age of onset in GCA group. Although we observed there was a weakly negative trend (but not significant) between ΔR-L 2D:4D ratio and age of onset, the data suggested to us that there may be some other important factors (not only the 2D:4D ratio) associated with the age of onset and tumor staging of GCA, such as tobacco consumption which is another important etiological factor for GCA. An early study conducted by Ladeiras et al. [22] shown smoking was significantly associated with GCA. And in our study, we also found the smokerratio was significantly higher in GCA group than in controls. Thus, we suggest that later study on GCA should regard 2D:4D ratio indicating hormonal factors (PT/PE) influence as well as tobacco consumption. In conclusion, this study supported the view that the GCA patients have low 2D:4D ratio which may be a putative indicator for the development of GCA. It should be noted that the development of GCA is a complicated process with the interaction of various etiological factors, including gene, environment, living habit, and so on. So, further research should be needed in the future. Conflict of interest All authors have no conflict of interest.
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Author contributions Conceived and designed the experiments: HL; performed the experiments: HL, ZHH; analyzed the data: WLQ, YJS, LW, HCY, ZG, PC; wrote the paper: YJS, WLQ, HL (YJS and WLQ contributed equally to this work). Acknowledgments This study was supported by grants from National Natural Science Foundation of China (Grant Nos. 31460272; 30960154; 31360257). We appreciate colleagues for their friendly help during data collection period. References [1] J.T. Manning, D. Scutt, J. Wilson, et al., The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen, Hum. Reprod. 13 (1998) 3000–3004. [2] Z. Zheng, M.J. Cohn, Developmental basis of sexually dimorphic digit ratios, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 16289–16294. [3] M.A. Malas, S. Dogan, E.H. Evcil, K. Desdicioglu, Fetal development of the hand, digits and digit ratio (2D:4D), Early Hum. Dev. 82 (2006) 469–475. [4] D.C. Muller, G.G. Giles, J. Bassett, H.A. Morris, J.T. Manning, J.L. Hopper, et al., Second to fourth digit ratio (2D:4D) and concentrations of circulating sex hormones in adulthood, Reprod. Biol. Endocrinol. 9 (2011) 57. [5] H. Jung, K.H. Kim, S.J. Yoon, T.B. Kim, Second to fourth digit ratio: a predictor of prostate-specific antigen level and the presence of prostate cancer, BJU Int. 107 (2011) 591–596. [6] D.C. Muller, L. Baglietto, J.T. Manning, C. McLean, J.L. Hopper, D.R. English, G.G. Giles, G. Severi, Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study, Br. J. Cancer 23 (107) (2012) 1631–1636. [7] X.L. Wu, D.Y. Yang, W.H. Chai, M.L. Jin, X.C. Zhou, L. Peng, Y.S. Zhao, The ratio of second to fourth digit length (2D:4D) and coronary artery disease in a Han Chinese population, Int. J. Med. Sci. 10 (2013) 1584–1588. [8] H. Lu, Z.H. Huo, Y.J. Liu, Z.Y. Shi, J.L. Zhao, Correlations between digit ratio and infertility in Chinese men, Early Hum. Dev. 88 (2012) 865–869.
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Early Human Development journal homepage: www.elsevier.com/locate/earlhumdev
Decreased digit ratio (2D:4D) and gastric cancer in Chinese men☆ Youjing Sheng a, Wenli Qian a, Lu Wang b, Zhenghao Huo a, Hong Lu a,⁎, Haochen Yu a, Zhi Geng a, Ping Cheng c a Ningxia Medical University, Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education/Key Laboratory of Reproduction and Genetics/Department of Medical Genetics and Cell Biology, Yinchuan 750004, PR China b Clinical Medicine Science, Peking University Health Science Center, Beijing 100191, PR China c Surgical Oncology of General Hospital of Ningxia Medical University, Yinchuan 750004, PR China.
a r t i c l e
i n f o
Article history: Received 16 May 2016 Received in revised form 27 July 2016 Accepted 9 August 2016 Available online xxxx Keywords: Digit ratio (2D:4D) Sexual hormones Gastric cancer (GCA)
a b s t r a c t Background: The development of finger length is influenced by the level of hormones during pregnancy in the womb. The relative length of 2nd to 4th digit (2D:4D) is considered as a putative marker for prenatal hormone exposure and may represent an individual susceptibility to certain diseases, particularly those hormonerelated cancers (e.g., gastric cancer). Aims: The aim of this study is to investigate whether there is a possible relationship between 2D:4D ratio and gastric cancer (GCA) in Chinese men. Methods: 94 male patients with GCA and 91 controls were chosen to participate in this study. Photographs of both hands were collected and then the lengths of second and fourth digits of both hands were measured. Left hand, right hand, mean hand, and right minus left hand (ΔR-L) 2D:4D ratios were analyzed and compared. Results: In GCA group, 2D:4D ratios were significantly lower (right hand: p b 0.01; left hand, mean hand: p b 0.001) than controls. No association was observed between 2D:4D ratio and tumor staging (neither in tumor size (T) nor in lymph node involvement (N) or distant metastases (M)). There was also no correlation between 2D:4D ratio and age of onset. Conclusions: Decreased 2D:4D ratio may be an indicator for forecasting the susceptibility to develop GCA. © 2016 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Digit ratio refers to the ratio of human finger length. It is determined during embryonic development and then changes little after sexual maturation [1]. The ratio which is known as the 2nd to 4th digit ratio (2D:4D) is a sexually dimorphic trait. Previous studies have reported that 2nd digit is usually shorter than 4th digit in males than in females, which results in a relatively lower 2D:4D ratio [2]. Several studies have shown that the development of finger length is influenced by the level of hormones during pregnancy in the womb [1]. Malas et al. [3] suggested that the 2D:4D ratio was probably fixed when fetus started to produce testosterone in week 8 and testosterone peaks in weeks 11 or 12 to 14. It has been demonstrated that 2D:4D ratio is negatively related to prenatal testosterone (PT) and positively related to prenatal estrogen (PE). Furthermore, there is evidence that 2D:4D measures are unrelated to the concentrations of adult circulating sex steroids [4]. So, recent years, 2D:4D ratio is considered as a useful
☆ Foundation item: This study was supported by grants from National Natural Science Foundation of China (Grant Nos. 31460272; 30960154; 31360257). ⁎ Corresponding author at: Department of Medical Genetics and Cell Biology, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia 750004, PR China. Tel.: +860951 6980110 E-mail address: [email protected] (H. Lu).
http://dx.doi.org/10.1016/j.earlhumdev.2016.08.004 0378-3782/© 2016 Elsevier Ireland Ltd. All rights reserved.
biomarker for prenatal hormone exposure or sensitivity to testosterone and estrogen. Up to now, there are a number of researches investigating the correlation between 2D:4D ratio and sex steroids related diseases, such as some cancers, coronary artery disease (CAD) and infertility. Jung et al. [5] found that 2D:4D ratio was related to the level of prostate specific antigen (PSA) and the patients with lower 2D:4D ratio had higher risk of prostate cancer. Muller et al. [6] reported a direct association between left hand, ΔR-L 2D:4D ratios and the breast cancer. They suggested that lower exposure or sensitivity to PT might be associated with lower risk of breast cancer. Wu et al. [7] observed that the male patients with CAD had significantly higher 2D:4D ratios than controls in both hands. Similar with earlier studies, Lu et al. [8] also found that the patients with infertility had higher 2D:4D ratios than controls. All above evidence implied that the 2D:4D ratio may be correlated with the risk of many hormone-related diseases. Gastric cancer (GCA) is one of the most common cancers in China, and it is the leading causes of cancer-related mortality in malignant tumor [9]. Several epidemiologic studies have suggested that prenatal sex hormones (PE and PT) may play an important role in gastric carcinogenesis [10–12]. The earlier finding in a Brazilian sample (mainly men but some women) by Nicolas et al. [13] gave mixed results, such that (a) the patients with GCA had lower Δ R–L 2D:4D ratio compared to controls suggesting they had been exposed to higher PT than PE, and (b) the patients had higher left 2D:4D ratio suggesting that they had
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been exposed to low PT, particularly so for males. Their findings predict that 2D:4D may be a biological marker for the screening of patients' susceptibility to GCA. Based on the findings mentioned above, here we speculate that there may also be a link between 2D:4D ratio and GCA from Chinese populations. As GCA is more frequent in males than in females, so, in this study, only men were chosen for investigating the relationship between 2D:4D ratio and GCA. 2. Subjects and methods 2.1. Participants All individuals were Han nationality including 185 adult males (age: 25–77 years). The present study was performed at Yinchuan city which located in the Ningxia Region, China. Patients: 94 male patients with GCA (age: 25–77 years, mean age ± S.D. = 55.22 ± 9.59 years) were recruited from the general tumor hospital affiliated to Ningxia Medical University. All of them were diagnosed by clinical and histological analysis. Controls: 91 resident natives (age: 35–76 years, mean age ± S.D. = 52.78 ± 10.48 years) were invited to participate in this research, and all were presented healthy physical and mental states. 2.2. Ethical statements This study was approved by the Ningxia Medical University Committee for the Protection of Human Subjects. The participants had informed written consent before the experiment.
correlations between 2D:4D ratio and age, the TNM staging (tumor size [T], lymph node metastasis [N], distant metastasis [M]). Data were all conducted by using SPSS software (Version 19.0), with a significance level of p b 0.05. 3. Result All controls and most patients (66%) didn't have familial history of malignancy. The rates of alcohol consumption were similar between controls (33%) and patients (32%). Tobacco consumption was significantly higher in the GCA group (62%) than in controls (47%) (χ2 = 3.894, p = 0.048). Most patients were diagnosed as low-differentiated adenocarcinoma, while few were gastric mucinous adenocarcinoma. Signet-ring cell carcinoma of gastric was also included. Related hormone therapy was not reported. The ranges of 2D:4D ratio between patients (left 2D:4D: 0.870– 1.044; right 2D:4D: 0.855–1.038; mean 2D:4D: 0.874–1.027; Δ R-L 2D:4D: − 0.079–0.163) and controls (left 2D:4D: 0.899–1.028; right 2D:4D: 0.905–1.001; mean 2D:4D: 0.905–1.000; Δ R-L 2D:4D: −0.062–0.103) were similar. There was no significant difference between left and right 2D:4D ratios in both patients and controls (p N 0.05). 3.1. Mean values of 2D:4D ratio and age The mean values of age and 2D:4D ratio of both hands between controls and patients were shown in Table 1. We found that the age was similar between GCA patients and controls. Mean values of 2D:4D ratio were significantly lower in patients compared to that of controls (right hand: Cohen's effect size d = 0.45, p b 0.01; left hand: d = 0.56, p b 0.001; mean hand: d = 0.61, p b 0.001).
2.3. Digit measurement According to the methodology proposed by Nicolás and Jorge [14], each Individual's images of both hands were obtained by a digital camera (Canon M3, Japan). Photographs were collected under the same camera configuration to avoid discrepancies between images. When taking photos, the participants were required to keep their wrists, hand palms and fingers extended and placed on a horizontal table; and the experimenter was required to keep the camera perpendicular to the palms side under the same height. The subjects with finger injured or uncompleted were excluded. All images were input into the computer and checked to insure the creases of the fingers were visible clearly. The lengths of the second and fourth digits of both hands were measured by the image analysis software (Image-Pro plus 6.0) and accurate to 0.01 mm. As described in the previous study [14], the digit length was measured from the most proximal crease up to the tip of the finger. To minimize measurement errors, each digit was measured twice and the average value was calculated as the last result. 2D:4D ratio was computed by dividing the length of the second finger by that of the fourth finger. The mean 2D:4D shown the average value of left 2D:4D and right 2D:4D, Δ R-L 2D:4D was obtained by the right 2D:4D minus left 2D:4D.
3.2. The relationship between 2D:4D ratio and TNM staging, age of onset Correlations between 2D:4D ratio and TNM staging, age of onset in GCA group were shown in Table 2. 2D:4D ratio did not show any correlation with tumor staging (neither in tumor size (T) nor in lymph node involvement (N) or distant metastases (M)) (p N 0.05). There was also no relationship between the age of onset and 2D:4D ratio (p N 0.05) (Table 2). 3.3. Relationships between lower/higher 2D:4D ratio and TNM staging, age of onset In order to extend to explore whether there is a link between 2D:4D ratio and GCA, we divided 2D:4D ratio of GCA patients into two groups (lower 2D:4D and higher 2D:4D) by median (Table 3). And then tested the relationships between lower/higher 2D:4D ratio and TNM staging, age of onset respectively again (Table 4). There were significant differences between lower 2D:4D ratio and higher 2D:4D ratio in both hands (p b 0.001). Whatever lower and higher 2D:4D ratio, there was still no correlation observed between 2D:4D ratio and TNM staging and age of onset (all p N 0.05).
2.4. Statistical analysis We use the following methods for statistical analysis: Remeasurement reliability was high for the first and second 2D:4D ratios (intraclass correlation coefficients (ICC), patients: left 2D:4D: r = 0.955, F(93) = 21.996, p b 0.001; right 2D:4D: r = 0.962, F(93) = 26.254, p b 0.001; controls: left 2D:4D: r = 0.993, F(90) = 148.873, p b 0.001; right 2D:4D: r = 0.986, F(90) = 71.314, p b 0.001). Differences of 2D:4D ratio and ages between the patients with GCA and controls were analyzed by independent sample t-test. The Pearson correlation coefficient test was used to investigate the
Table 1 Mean values of 2D:4D ratio and age in GCA and controls (mean, SD).
Age Right 2D:4D Left 2D:4D Mean 2D:4D ΔR–L 2D:4D
GCA (N = 94)
Controls (N = 91)
t
p
55.22 (9.59) 0.948 (0.038) 0.946 (0.036) 0.947 (0.031) 0.002 (0.040)
52.78 (10.48) 0.962 (0.022) 0.963 (0.024) 0.963 (0.020) −0.000 (0.022)
−1.656 3.157 3.792 4.070 −0.0541
0.100 0.002⁎ 0.000⁎⁎ 0.000⁎⁎ 0.589
⁎ p b 0.01 (difference of 2D:4D between GCA and controls). ⁎⁎ p b 0.001 (difference of 2D:4D between GCA and controls).
Y. Sheng et al. / Early Human Development 103 (2016) 109–112 Table 2 Correlations between 2D:4D ratio and TNM staging, age of onset in GCA group (r, p). 2D:4D
TNM staging T
Right Left Mean ΔR–L
Age of onset
N
−0.096 (0.378) −0.048 (0.662) −0.078 (0.475) −0.014 (0.901)
−0.013 (0.906) −0.046 (0.670) −0.044 (0.686) −0.015 (0.899)
0.004 (0.969) 0.108 (0.319) 0.061 (0.575) −0.136 (0.208)
0.065 (0.549) 0.104 (0.337) 0.101 (0.350) −0.016 (0.887)
4. Discussion Gastric cancer is rapidly increasing in prevalence all over the world and is one of the most common causes of cancer death in China. It is more frequent in men than women with presenting a characteristic of low diagnosis rate early. Most of them are advanced GCA, especially in 2–4 stage (TNM staging). There are different levels of eating disorders, emaciation, anemia, low protein disorder and the postoperative complications displayed. This study aimed to investigate the relationship between GCA and 2D:4D ratio which may reflect PT and PE levels in Chinese men. The present evidence shown that the left, right and mean 2D:4D ratios were significantly lower than that of controls. It is widely recognized that PT is inversely related to 2D:4D ratio, while PE is positively related to 2D:4D ratio. And previous studies have demonstrated that sexual hormones may play an important role on regulating growth and function of epithelial gastric tissue [10,11,15]. Thus, our results indicate that the patients with GCA may have had relatively higher PT or lower PE exposure during fetal development compared to controls. Although there was no difference in Δ R-L 2D:4D ratio between the patients and controls in the present study, the conclusion of ours support the finding of Nicolas et al. [13] who shown that the patients with GCA had lower Δ R-L 2D:4D compared to controls suggesting they had been exposed to higher PT. Moreover, it has been reported that testosterone is related to helicobacter pylori infections and is one of the main etiological factors for gastric carcinogenesis, while estrogen is a protective effect over helicobacter pylori infections [12,16]. It means the individual who has a higher exposure level or sensitivity to PT in his fetus will has the less ability to defense the helicobacter pylori infections and the higher risk of developing GCA later in life. Therefore, according to the previous studies and our results, we guess that the men with lower 2D:4D ratio (indicating higher PT) will have a higher risk of developing GCA, and 2D:4D ratio may be a possible indicator of GCA. In contrast, decreased 2D:4D ratios in patients with GCA in our study were different from the results of Nicolas et al. [13] who found that GCA group shown significantly higher left 2D:4D ratio and lower Δ R-L 2D:4D ratio than controls, especially in males. It has been reported that Δ R-L 2D:4D ratio seems to better reflect the prenatal hormone exposure or sensitivity than right 2D:4D ratio, but not left 2D:4D ratio [17]. However, our results shown there was no-significant difference on Δ R-L 2D:4D ratio as well as the difference on left 2D:4D ratio was stronger than right 2D:4D ratio between two groups. Therefore, we suggest that left 2D:4D ratio
Table 3 Mean values of lower and higher 2D:4D ratio in GCA group (mean, S.D.). 2D:4D Left 2D:4D Right 2D:4D Mean 2D:4D ΔR-L 2D:4D
Table 4 Correlations between lower/higher 2D:4D ratio and TNM staging, age of onset in GCA group (r, p). 2D:4D
M
Lower
Higher
t
p
0.9167 (0.0182) 0.9171 (0.0220) 0.9219 (0.0169) −0.0282 (0.0208)
0.9747 (0.0247) 0.9786 (0.0231) 0.9716 (0.0209) 0.0325 (0.0308)
−12.959 −13.210 −12.675 −11.180
0.000⁎ 0.000⁎ 0.000⁎ 0.000⁎
⁎ p b 0.001 (difference of 2D:4D between lower and higher group).
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TNM staging T
Age of onset
N
M
Lower 2D:4D Right −0.140 (0.372) Left 0.044 (0.779) Mean −0.054 (0.730) ΔR–L 0.011 (0.946)
−0.083 (0.598) 0.093 (0.554) 0.014 (0.931) 0.035 (0.824)
−0.238 (0.124) −0.078 (0.620) −0.085 (0.589) −0.003 (0.983)
0.074 (0.639) 0.088 (0.573) 0.065 (0.677) −0.104 (0.507)
Higher 2D:4D Right −0.112 (0.467) Left −0.179 (0.246) Mean −0.069 (0.657) ΔR-L 0.023 (0.881)
0.185 (0.230) −0.243 (0.113) −0.140 (0.366) 0.100 (0.518)
−0.021 (0.892) 0.079 (0.612) 0.100 (0.518) 0.083 (0.590)
0.001 (0.995) −0.106 (0.493) −0.074 (0.633) −0.015 (0.923)
may also be a better marker for reflecting the sensitivity and exposure to PT. The reason behind all the differences above may be that GCA is more common in East Asia populations [18], but Nicolas's sample was Brazilian (mainly men but some women) which belongs to the Western world [19]. In addition, differences in sample size and method selected for assessing 2D:4D ratio between the two studies may also contribute to the different results. And also, further work is needed to clarify the situation for women with GCA. Several reports have shown that 2D:4D ratio may be useful in the identification of high-risk groups in relation to some cancers. Muller et al. [6] conducted a study between 2D:4D ratio and breast cancer risk, and concluded that digit ratio measures might be associated with breast cancer risk and age of disease onset. Similarly, an exploratory analysis conducted by Stolten et al. [20] shown a relationship between alternative digit ratio and diagnosis age in prostate cancer. In agreement with their results, Jung et al. [5] also found a significantly negative correlation between 2D:4D ratio and PSA, in other words, the lower 2D:4D ratio, the higher risk of prostate cancer. Above information implied that 2D:4D ratio may be also related to the age of onset or diagnosis age of GCA. Furthermore, Sox 9 gene is believed to associate with gastric adenocarcinomas, which has also been established as one of the genes to act on the development of finger length [2]. It has been reported that the expression of Sox 9 gene is inversely related to tumor staging and Epstein Barr infections which is closely related to early carcinogenesis of GCA [21]. So we guess that there may also be some associations between 2D:4D ratio and GCA tumor staging and age of onset. Therefore, we conducted the further analysis. Unexpected, similar with the findings of Nicolás et al. [13], even the 2D:4D ratio was divided into lower and higher groups by the median; we still didn't found any correlation between 2D:4D ratio and TNM staging and age of onset in GCA group. Although we observed there was a weakly negative trend (but not significant) between ΔR-L 2D:4D ratio and age of onset, the data suggested to us that there may be some other important factors (not only the 2D:4D ratio) associated with the age of onset and tumor staging of GCA, such as tobacco consumption which is another important etiological factor for GCA. An early study conducted by Ladeiras et al. [22] shown smoking was significantly associated with GCA. And in our study, we also found the smokerratio was significantly higher in GCA group than in controls. Thus, we suggest that later study on GCA should regard 2D:4D ratio indicating hormonal factors (PT/PE) influence as well as tobacco consumption. In conclusion, this study supported the view that the GCA patients have low 2D:4D ratio which may be a putative indicator for the development of GCA. It should be noted that the development of GCA is a complicated process with the interaction of various etiological factors, including gene, environment, living habit, and so on. So, further research should be needed in the future. Conflict of interest All authors have no conflict of interest.
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Author contributions Conceived and designed the experiments: HL; performed the experiments: HL, ZHH; analyzed the data: WLQ, YJS, LW, HCY, ZG, PC; wrote the paper: YJS, WLQ, HL (YJS and WLQ contributed equally to this work). Acknowledgments This study was supported by grants from National Natural Science Foundation of China (Grant Nos. 31460272; 30960154; 31360257). We appreciate colleagues for their friendly help during data collection period. References [1] J.T. Manning, D. Scutt, J. Wilson, et al., The ratio of 2nd to 4th digit length: a predictor of sperm numbers and concentrations of testosterone, luteinizing hormone and oestrogen, Hum. Reprod. 13 (1998) 3000–3004. [2] Z. Zheng, M.J. Cohn, Developmental basis of sexually dimorphic digit ratios, Proc. Natl. Acad. Sci. U. S. A. 108 (2011) 16289–16294. [3] M.A. Malas, S. Dogan, E.H. Evcil, K. Desdicioglu, Fetal development of the hand, digits and digit ratio (2D:4D), Early Hum. Dev. 82 (2006) 469–475. [4] D.C. Muller, G.G. Giles, J. Bassett, H.A. Morris, J.T. Manning, J.L. Hopper, et al., Second to fourth digit ratio (2D:4D) and concentrations of circulating sex hormones in adulthood, Reprod. Biol. Endocrinol. 9 (2011) 57. [5] H. Jung, K.H. Kim, S.J. Yoon, T.B. Kim, Second to fourth digit ratio: a predictor of prostate-specific antigen level and the presence of prostate cancer, BJU Int. 107 (2011) 591–596. [6] D.C. Muller, L. Baglietto, J.T. Manning, C. McLean, J.L. Hopper, D.R. English, G.G. Giles, G. Severi, Second to fourth digit ratio (2D:4D), breast cancer risk factors, and breast cancer risk: a prospective cohort study, Br. J. Cancer 23 (107) (2012) 1631–1636. [7] X.L. Wu, D.Y. Yang, W.H. Chai, M.L. Jin, X.C. Zhou, L. Peng, Y.S. Zhao, The ratio of second to fourth digit length (2D:4D) and coronary artery disease in a Han Chinese population, Int. J. Med. Sci. 10 (2013) 1584–1588. [8] H. Lu, Z.H. Huo, Y.J. Liu, Z.Y. Shi, J.L. Zhao, Correlations between digit ratio and infertility in Chinese men, Early Hum. Dev. 88 (2012) 865–869.
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