Genetic Polymorphism of Thr241Met and Other Risk Factors Related with Gastric Cancer in Iranian Military Population: A Pilot Case Control Study

AUTHORS

Hassan Khanzadeh 1 , Ali Reza Khoshdel 2 , * , Shahrokh Irvani 3 , Keivan Majidzadeh-A 4 , Mohammad Soleimani 5

AUTHORS INFORMATION

1 AJA University of Medical Sciences, Tehran, Iran

2 Modern Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran

3 AJA Cancer Epidemiology Research and Treatment Center, AJA University of Medical Sciences, Tehran, Iran

4 Breast Cancer Research Center, Motamed Cancer Institute, ACECR, Tehran, Iran

5 Tasnim Biotechnology Research Center (TBRC), AJA University of Medical Sciences, Tehran, Iran

ARTICLE INFORMATION

Journal of Archives in Military Medicine: 7 (1-2); e92673
Published Online: June 12, 2019
Article Type: Research Article
Received: April 28, 2019
Revised: June 7, 2019
Accepted: June 7, 2019
Crossmark

Crossmark

CHEKING

READ FULL TEXT
Abstract

Background: Gastric cancer (GC) is a result of interaction between genetic and environmental factors. The recognition of GC risk factors is very important for early diagnostic and prevention from this cancer.

Objectives: The objective of this study was to investigate the effects of some factors such as Thr241Met polymorphism on GC occurrence in Iranian military population.

Methods: Investigated samples in the present study were 53 tissue samples from patients with pathologically proven GC and 91 sex-age matched blood samples from healthy controls. Data for cases and controls were obtained through registered files and questionnaires, respectively. Genomic DNA was extracted and PCR-RFLP was used for genotyping of Thr241Met polymorphism. Chi-square and odds ratio (OR) were used to determine the factors affecting the incidence of GC.

Results: The Thr\Met genotype of Thr241Met polymorphism of the XRCC3 gene (P = 0.04 and OR = 2.99) and blood type B (P = 0.04 and OR = 2.99) significantly affected the incidence of GC. This study did not prove the significant effect of smoking (P = 0.08 and OR = 2.47) and positive family history (P = 0.13 and OR = 2.25) on GC risk.

Conclusions: These findings may be helpful in early identification of high-risk individuals, especially in military population and prevention from GC.

Keywords

Gastric Cancer Risk Factor Genetic Marker PCR RFLP Thr241Met.

Copyright © 2019, Journal of Archives in Military Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Background

A considerable incidence, weak prognosis, and limited treatment strategies make GC a major health problem (1). The trend of GC is increasing with a mild trend among the Iranian military population (2). The cancer risk factors and pattern in military population may differ from the general population (3). The effective treatment of GC is needed for early diagnostic strategies (4). Thus, people at risk for developing GC in the military population as well as their families must be detected. The identification of GC risk factors can be effective in screening, early diagnosis, and treatment.

GC is a multifactorial disease that results from the interaction of genetic sensitivity and environmental factors (5). GC has a higher incidence rate in males and older populations (6). Multiple factors such as race (7, 8), Helicobacter pylori infection (9), gastro-esophageal reflux disease (10), dietary factors such as salty (11) and smoked food (12), low consumption of fruits and vegetables (11), smoking (13), family history (14), low socioeconomic groups (15), and blood type A (16) are thought to play a role in the incidence of GC.

Various studies have been mentioned in the genetic predisposition as an important factor in the etiology of GC (17). X-ray repair cross-complementing group 3 (XRCC3) is one of the DNA repair genes, and a sequence variation exists in exon 7 of this gene, which leads to an amino acid change (threonine with methionine) in codon 241 (17, 18). This polymorphism is mentioned as Thr241Met. Several studies have evaluated the association between Thr241Met polymorphisms and GC susceptibility (17, 19-21). There are controversies and diversities in the effect of Thr241Met polymorphism on GC, especially in Asian countries. For example, this polymorphism was not associated with GC risk in the Kashmiri population (22), while it was connected to GC in the Chinese population (23).

2. Objectives

Therefore, having a small study from Iran may enhance the information in regards to the impact of Thr241Met polymorphism on GC in conjunction with environmental factors. Furthermore, there are very few studies on GC in the Iranian military population. Thus, the objective of the current study is surveying the relation between some demographic and environmental factors and Thr241Met polymorphism with GC risk in the Iranian military population.

3. Methods

The present study was a pilot case-control study. Investigated samples were 53 gastrectomy samples of patients with GC from the Imam Reza (501) hospital of Iran army and 91 blood samples from age-sex matched healthy controls. Control subjects were selected from among those who were referred to the 501 hospital, and were free from any type of cancer. Age and gender rate of the cases were considered, and the control group was selected to be in the age range and gender rate of the patients.

Data for cases were obtained from patients registered files and data for controls were collected through questionnaires. Genomic DNA was extracted by SinaClon company DNA extraction kits (EX6041 for tissue and EX6001 for blood), according to the manufacturer's instructions. The extracted DNA was stored at -20ºC until subsequent experiments.

The Thr241Met polymorphism was genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Primers of 5’-GCTGTCTCGGGGCATGGCTC-3’ (forward) and 5’-ACGAGCTCAGGGGTGCAACC-3’ (reverse) were used to amplify a 208-bp fragment of XRCC3 gene. The amplification cycle was 95ºC for 5 minutes, 30 cycles at 95ºC for 30 seconds, 59ºC for 35 seconds, and 72ºC for 1 minute, and final extension for 10 minutes at 72ºC (17). Amplification of 208-bp fragment was confirmed by electrophoresis on 2% agarose gel. Then, eight microliters of PCR product overnight digested with two units of Nla III restriction endonuclease at 37ºC and separated on 2.5% agarose gel stained with ethidium bromide. Thr/Thr homozygotes presents one fragment of 208 bp, Thr/Met heterozygotes presents three fragments of 208, 120, and 88 bp and Met/Met homozygotes presents two fragments of 120 and 88 bp on the gel image.

The results of Thr241Met polymorphism and demographic and environmental information were analyzed by the SAS 9.3.1 software (24) LOGISTIC procedure to determine the factors affecting GC risk. Associations are assessed using odds ratios (OR) and 95% confidence intervals (CIs).

4. Results

Characteristics of the age and sex ratios for participants are summarized in Table 1. The ratio of males was higher than females in both cases and controls. Also, the mean, maximum, and minimum age were similar for cases and controls. Statistical analysis was performed for age and sex and non-significant differentiation observed for age (P = 0.64 OR = 0.99 (95% CI: 0.96 - 1.03)) and sex (P = 0.92 OR = 1.04 (95% CI: 0.49 - 2.19)) between cases and controls.

Table 1. Descriptive Statistics for Age and Sex of Participants
PopulationNumberAgeSex, No. (%)
Mean ± SDMinimumMaximumMenWomen
Case5365.06 ± 11.53428634 (64.15)19 (35.85)
Control9164.25 ± 9.21438658 (63.74)33 (36.26)
Total14464.55 ± 10.10428692 (63.89)52 (36.11)

Statistical properties of surveyed factors and OR and P value for GC occurrence are presented in Table 2. As shown in Table 2, the results of the present study indicated that the effects of birthplace and smoking (P = 0.08) on GC were not significant. However the percentage of smokers among patients was higher than healthy individuals, and OR for smoking was high (OR = 3.03).

Table 2. Statistical Properties of Factors on Gastric Cancer
FactorsCase, No. (%)Control, No. (%)OR (95% CI)Chi-SquareP Value
Birth state
North9 (16.98)10 (10.99)1 (referent)
Northwest9 (16.98)19 (20.88)0.54 (0.15 - 0.20)0.830.36
Center21 (39.62)48 (52.75)0.41 (0.13 - 1.29)2.320.12
West9 (16.98)7 (7.69)1.28 (0.31 - 5.32)0.120.73
South5 (9.43)2 (2.20)3.49 (0.37 - 32.93)1.200.27
East0 (0)5 (3.47)---
Blood type
O14 (26.42)25 (27.47)1 (referent)
A19 (35.85)40 (43.96)1.33 (0.50 - 3.55)0.330.56
B18 (33.96)13 (14.29)2.99 (1.02 - 8.79)3.980.04a
AB2 (3.77)13 (14.29)0.31 (0.04 - 2.24)1.340.25
Cardiovascular diseases or hypertension
No39 (73.58)58 (63.74)1 (referent)
Yes14 (26.42)33 (36.26)0.63 (0.26 - 1.53)1.060.30
Smoking
No40 (75.47)78 (85.71)1 (referent)
Yes13 (24.53)13 (14.29)2.47 (0.89 - 6.87)3.030.08
Family history
No43 (81.13)80 (87.91)1 (referent)
Yes10 (18.87)11 (12.09)2.25 (0.79 - 6.42)2.290.13
XRCC3 (Thr241Met)
Thr\Thr37 (69.81)48 (52.75)1 (referent)
Thr\Met16 (30.19)41 (45.05)0.40 (0.17 - 0.95)4.360.04a
Met\Met0 (0)2 (2.20)---

aSignificant effect

The frequency of blood type B was significantly different between cases and controls (P = 0.04) and the incidence of GC was highest in individuals with blood type B (OR = 2.99). The incidence of GC was lowest in individuals with blood type AB (OR = 0.33). Although, the number of individuals with a family history of cancer in cases was higher than controls, non-significant differences were observed between cases and controls for family history (P = 0.13), as well as for cardiovascular disease or hypertension (P = 0.30).

The frequency of heterozygote genotype (Thr\Met) in the controls was higher than cases (P = 0.04). Due to the fact that the Met\Met genotype observed only in the controls and did not exist in cases, it was not possible to calculate OR and chi-square for this genotype.

5. Discussion

The impacts of gender and age on the incidence of GC have been confirmed in numerous studies (11). In the present study, for an accurate study of other risk factors, age and sex ratios were matched between cases and controls. GC is more common in the elderly individuals. In Europe, the average age of GC patients is 62 years (6). It is reported that in the south of Iran the average age of GC patients is 65.5 and 63.7 for males and females, respectively (25). Also, the risk of developing GC in men is more than women (8). Gender differences may be a reflection of physiological differences. Estrogens may prevent from the development of GC (11). On the other hand, environmental and behavior patterns differ for men and women, especially for the military population in Iran, and these patterns can play a positive role in the development of GC.

The present study did not prove a significant relation between birthplaces with GC risk. Studies reported higher occurrence of GC in the north and northwest of Iran (26). Note that in the previous studies, the place of residence has been considered, however, in the current study, the place of birth has been investigated. The high incidence of GC in north and northwest of Iran may be due to environmental factors such as lifestyle and nutrition.

Although the smoking ratio difference between cases and controls marginally was not significant, but based on OR, GC risk in smokers was three times greater than non-smokers. Previous studies reported different results regarding smoking and increased risk of GC. In a meta-analysis study in Asia and Caucasus (27) and a case-control study in India (28) a non-significant relation was observed between smoking and GC. Another meta-analysis study suggested that smoking increased the risk of both cardiac and non-cardiac GC (13). In addition, a case-control study identified smoking as a risk factor for GC (29). Although the exact mechanism of the relationship between smoking and cancer occurrence is unclear, it is likely that the formation of oxygen radicals and increasing cell death induce cancer causing changes in the lining of the stomach, and promote carcinogenesis (30). On the other hand, it has been reported that smoking increases the damage of the stomach and therefore, smokers have high rates of Helicobacter pylori infection and gastrointestinal inflammation (31).

The incidence of GC was high in individuals with blood type B (OR = 2.99). Previous studies mostly introduced blood type A as most sensitive blood type for GC (32). Blood type A was the second sensitive group to GC (OR = 1.33). However, there are studies that reported blood type B as a sensitive blood type for GC. A study among Chinese reported that blood type B associated with an increase of carcinoma and cardiac cancers (33). According to the results of the present study, it seems that the pattern of blood types impact on GC in Iranian military population is different with others, or the interaction between blood types and other factors is responsible for results inconsistency. The military population may have a different pattern for demographic and environmental factors and their impact on cancer development (34).

The previous study reported that people with cardiovascular disease have a low risk for GC due to the use of a series of drugs (35). This issue may be confirmed by low OR (OR = 0.63) obtained in the current study for cardiovascular disease, however, a marginally non-significant relationship was observed between cardiovascular disease and GC risk. It is possible that some genetic, hormonal, and environmental factors reversely affected the process of developing cardiovascular disease and GC.

The incidence of GC in people with a family history of cancer was higher than those without any family history of cancer (OR = 2.29). Having a first-degree relative with a history of GC is a proven risk factor for GC (14). Similarity of genetic susceptibility and lifestyle in families may be a reason of being high risk in individuals with a family history of cancer. In the present study, the history of all cancers is considered (not only history of GC) and this issue may be a reason for a non-significant relationship between family history and GC risk.

The frequency of Met\Met genotype was very low (two individuals in the studied population). The low frequency of Met\Met genotype also reported in previous studies (17, 19). The role of Thr241Met polymorphism in the GC etiology has been studied in several studies and different results have been reported. A case-control study in Chinese reported that this polymorphism may not be associated with GC (17). Cabral et al. (19), reported a significant association between Thr241Met polymorphism and GC. In that study, the frequency of Thr\Met genotype in patients was higher than the control group, which is in contrast with the results of the present study. In the other previous study (21), the frequency of Thr\Met genotype in controls was higher than patients, which is in accordance with the result of the present research. A meta-analysis confirmed that Thr241Met may be a GC risk factor among Asians (36). Insufficient number of samples may affect the results of the present study.

The incidence of GC has an increasing trend among the Iranian military population (2). The military population is a unique subset of the population, and some demographic and environmental factors differ between military and general population (34). Therefore, demographic and environmental factors affect the incidence of GC; thus, identified risk factors can be implemented in early diagnosis of cancer. Earlier stage at diagnosis leads to better prognosis and increased survival rates (37). These suggest that we need to have good screening programs to identify and prevent GC in our military population and their families using the risk factors and markers that are known in the current study and other similar studies.

5.1. Conclusions

Our study indicated a significant effect of Thr241Met polymorphism and blood type B on GC risk in the Iranian military population. We could not prove the statistically significant association of smoking and family history with GC in our study. The limited number of samples is a fundamental problem in our research and the results may be affected by chance. In general, according to confirming the risk factors of GC in this study and other similar studies, it is recommended to screen programs with gastroduodenoscopy and screening GC markers such as Thr241Met polymorphism and blood type to identify high-risk individuals in military population, and thus, prevent from GC occurrence and mortality.

Acknowledgements
Footnotes
References
  • 1. Compare D, Rocco A, Nardone G. Risk factors in gastric cancer. Eur Rev Med Pharmacol Sci. 2010;14(4):302-8.
  • 2. Khoshdel AR, Ziaei M, Ghaffari HR, Azadi S, Alimohamadi Y. The prediction number of new cases and death of gastric cancer among Iranian military community during 2007-2019. Multidiscipl Cancer Invest. 2018;2(2):14-9. doi: 10.30699/acadpub.mci.2.2.14.
  • 3. Zhu K, Devesa SS, Wu H, Zahm SH, Jatoi I, Anderson WF, et al. Cancer incidence in the U.S. military population: Comparison with rates from the SEER program. Cancer Epidemiol Biomarkers Prev. 2009;18(6):1740-5. doi: 10.1158/1055-9965.EPI-09-0041. [PubMed: 19505907]. [PubMed Central: PMC2780333].
  • 4. Lee YY, Derakhshan MH. Environmental and lifestyle risk factors of gastric cancer. Arch Iran Med. 2013;16(6):358-65. [PubMed: 23725070].
  • 5. Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med. 1995;333(1):32-41. doi: 10.1056/NEJM199507063330107. [PubMed: 7776992].
  • 6. Roder DM. The epidemiology of gastric cancer. Gastric Cancer. 2002;5 Suppl 1:5-11. [PubMed: 12772880].
  • 7. El-Serag HB, Mason AC, Petersen N, Key CR. Epidemiological differences between adenocarcinoma of the oesophagus and adenocarcinoma of the gastric cardia in the USA. Gut. 2002;50(3):368-72. doi: 10.1136/gut.50.3.368. [PubMed: 11839716]. [PubMed Central: PMC1773122].
  • 8. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am. 2002;11(2):235-56. [PubMed: 12424848].
  • 9. Kamangar F, Sheikhattari P, Mohebtash M. Helicobacter pylori and its effects on human health and disease. Arch Iran Med. 2011;14(3):192-9. [PubMed: 21529109].
  • 10. Rubenstein JH, Taylor JB. Meta-analysis: The association of oesophageal adenocarcinoma with symptoms of gastro-oesophageal reflux. Aliment Pharmacol Ther. 2010;32(10):1222-7. doi: 10.1111/j.1365-2036.2010.04471.x. [PubMed: 20955441]. [PubMed Central: PMC3481544].
  • 11. Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention. Cancer Epidemiol Biomarkers Prev. 2014;23(5):700-13. doi: 10.1158/1055-9965.EPI-13-1057. [PubMed: 24618998]. [PubMed Central: PMC4019373].
  • 12. Dungal N. The special problem of stomach cancer in Iceland, with particular reference to dietary factors. JAMA. 1961;178:789-98. [PubMed: 13888467].
  • 13. Ladeiras-Lopes R, Pereira AK, Nogueira A, Pinheiro-Torres T, Pinto I, Santos-Pereira R, et al. Smoking and gastric cancer: Systematic review and meta-analysis of cohort studies. Cancer Causes Control. 2008;19(7):689-701. doi: 10.1007/s10552-008-9132-y. [PubMed: 18293090].
  • 14. Bernini M, Barbi S, Roviello F, Scarpa A, Moore P, Pedrazzani C, et al. Family history of gastric cancer: A correlation between epidemiologic findings and clinical data. Gastric Cancer. 2006;9(1):9-13. doi: 10.1007/s10120-005-0350-7. [PubMed: 16557430].
  • 15. Uthman OA, Jadidi E, Moradi T. Socioeconomic position and incidence of gastric cancer: A systematic review and meta-analysis. J Epidemiol Community Health. 2013;67(10):854-60. doi: 10.1136/jech-2012-201108. [PubMed: 23929615].
  • 16. Nakao M, Matsuo K, Ito H, Shitara K, Hosono S, Watanabe M, et al. ABO genotype and the risk of gastric cancer, atrophic gastritis, and Helicobacter pylori infection. Cancer Epidemiol Biomarkers Prev. 2011;20(8):1665-72. doi: 10.1158/1055-9965.EPI-11-0213. [PubMed: 21680535].
  • 17. Shen H, Wang X, Hu Z, Zhang Z, Xu Y, Hu X, et al. Polymorphisms of DNA repair gene XRCC3 Thr241Met and risk of gastric cancer in a Chinese population. Cancer Lett. 2004;206(1):51-8. doi: 10.1016/j.canlet.2003.09.003. [PubMed: 15019159].
  • 18. Matullo G, Palli D, Peluso M, Guarrera S, Carturan S, Celentano E, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis. 2001;22(9):1437-45. doi: 10.1093/carcin/22.9.1437. [PubMed: 11532866].
  • 19. Cabral S, Lobato L, Nascimento R, Júnior O, Rodrigues A. Association between XRCC3 thr241Met polymorphism and the risk of cancer in Northern Brazil. Br J Med Med Res. 2016;15(7):1-6. doi: 10.9734/bjmmr/2016/24667.
  • 20. Xu G, Wang M, Xie W, Bai X. DNA repair gene XRCC3 Thr241Met polymorphism and susceptibility to glioma: A case-control study. Oncol Lett. 2014;8(2):864-8. doi: 10.3892/ol.2014.2192. [PubMed: 25013509]. [PubMed Central: PMC4081356].
  • 21. Canbay E, Agachan B, Gulluoglu M, Isbir T, Balik E, Yamaner S, et al. Possible associations of APE1 polymorphism with susceptibility and HOGG1 polymorphism with prognosis in gastric cancer. Anticancer Res. 2010;30(4):1359-64. [PubMed: 20530453].
  • 22. Bashir H, Majid S, Hamid R, Farooq R, Wani HA, Shoib S, et al. Polymorphism of the XRCC3 gene and risk of gastric cancer in a Kashmiri population: A case-control study. Eur J Cancer Prev. 2015;24(3):167-75. doi: 10.1097/CEJ.0000000000000115. [PubMed: 25642794].
  • 23. Zhao L, Long XD, Yao JG, Wang C, Ma Y, Huang YZ, et al. Genetic polymorphism of XRCC3 codon 241 and Helicobacter pylori infection-related gastric antrum adenocarcinoma in Guangxi Population, China: A hospital-based case-control study. Cancer Epidemiol. 2011;35(6):564-8. doi: 10.1016/j.canep.2011.03.004. [PubMed: 21937297].
  • 24. Rodenhouse N, Best L, O'Connor R, Bollinger E. SAS Institute Inc. SAS; 2004.
  • 25. Hassanzade J, Molavi EH, Farahmand M, Rajaiifard AR. Incidence and mortality rate of common gastrointestinal cancers in south of Iran, a population based study. Iran J Cancer Prev. 2011;4(4):163-9. [PubMed: 26322193]. [PubMed Central: PMC4551286].
  • 26. Malekzadeh R, Derakhshan MH, Malekzadeh Z. Gastric cancer in Iran: Epidemiology and risk factors. Arch Iran Med. 2009;12(6):576-83. [PubMed: 19877751].
  • 27. La Torre G, Chiaradia G, Gianfagna F, De Lauretis A, Boccia S, Mannocci A, et al. Smoking status and gastric cancer risk: An updated meta-analysis of case-control studies published in the past ten years. Tumori. 2009;95(1):13-22. [PubMed: 19366050].
  • 28. Sumathi B, Ramalingam S, Navaneethan U, Jayanthi V. Risk factors for gastric cancer in south India. Singapore Med J. 2009;50(2):147-51. [PubMed: 19296029].
  • 29. Ponnala D, Madireddi S. Evaluation of risk factors for gastric cancer. Int J Appl Biol Pharm Technol. 2010;1(1):158-61.
  • 30. Wang H, Ma L, Li Y, Cho CH. Exposure to cigarette smoke increases apoptosis in the rat gastric mucosa through a reactive oxygen species-mediated and p53-independent pathway. Free Radic Biol Med. 2000;28(7):1125-31. [PubMed: 10832074].
  • 31. Gonzalez CA, Lopez-Carrillo L. Helicobacter pylori, nutrition and smoking interactions: Their impact in gastric carcinogenesis. Scand J Gastroenterol. 2010;45(1):6-14. doi: 10.3109/00365520903401959. [PubMed: 20030576].
  • 32. Wang Z, Liu L, Ji J, Zhang J, Yan M, Zhang J, et al. ABO blood group system and gastric cancer: A case-control study and meta-analysis. Int J Mol Sci. 2012;13(10):13308-21. doi: 10.3390/ijms131013308. [PubMed: 23202954]. [PubMed Central: PMC3497328].
  • 33. Su M, Lu SM, Tian DP, Zhao H, Li XY, Li DR, et al. Relationship between ABO blood groups and carcinoma of esophagus and cardia in Chaoshan inhabitants of China. World J Gastroenterol. 2001;7(5):657-61. doi: 10.3748/wjg.v7.i5.657. [PubMed: 11819849]. [PubMed Central: PMC4695569].
  • 34. Zullig LL, Jackson GL, Dorn RA, Provenzale DT, McNeil R, Thomas CM, et al. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System. Mil Med. 2012;177(6):693-701. doi: 10.7205/milmed-d-11-00434. [PubMed: 22730846]. [PubMed Central: PMC3531965].
  • 35. Kumar V, Abbas AK, Aster JC. Robbins basic pathology. Elsevier Health Sciences; 2017.
  • 36. Qin XP, Zhou Y, Chen Y, Li NN, Wu XT. XRCC3 Thr241Met polymorphism and gastric cancer susceptibility: A meta-analysis. Clin Res Hepatol Gastroenterol. 2014;38(2):226-34. doi: 10.1016/j.clinre.2013.10.011. [PubMed: 24315014].
  • 37. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43-66. [PubMed: 17237035].
  • COMMENTS

    LEAVE A COMMENT HERE: