Полиморфные варианты генов фолатного цикла у больных раком легкого

Рак легкого (РЛ) – распространенное онкологическое заболевание и ведущая причина смертности от рака во всем мире. Особенности метаболизма фолатов в организме могут влиять на процессы метилирования и репарации ДНК и играть важную роль в процессах канцерогенеза.

Целью исследования стало обобщение имеющихся данных об ассоциации между полиморфными вариантами генов фолатного цикла (MTHFR С677Т (rs1801133), MTR A2756G (rs1805087), MTRR А66G (rs1801394)) и риском РЛ у человека.

Материал и методы. Поиск исследований проводился в базе данных pubmed, elibrary.ru. В обзор включали оригинальные, рандомизированные исследования за период с 2003 по 2018 г.

Результаты. Накоплено большое количество работ о роли гена MTHFR С677Ту больных РЛ. Данные же по полиморфным вариантам MTR A2756Gи MTRR A66Gу больных РЛ весьма ограничены. Полиморфизмы MTHFR C677Tи MTRR А66Gзначительно связаны с РЛ во многих исследованиях. Ассоциаций между геном MTR A2756Gи РЛ пока получено не было, однако в злокачественной транс-формации легкого зафиксирована значимость совместного действия MTR 2756A > Gand MTRR 66A > G. Ряд факторов, таких как национальность, курение, пол, точный диагноз, могут оказывать влияние на результаты и выводы исследований о роли генов фолатного цикла у больных РЛ.

Заключение. Дальнейшее изучение генетических полиморфизмов MTHFR С677Т (rs1801133), MTR A2756G (rs1805087), MTRR А66G (rs1801394)с учетом ген-средовых и ген-генных взаимодействий может объяснить индивидуальные различия риска РЛ.

1. Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer. 2015; 136 (5): 359-386. https://doi.org/10.1002/ijc.29210.

2. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Tobacco smoke and involuntary smoking. IARC Monogr Eval Carcinog Risks Hum. 2004; 83: 166-167.

3. Brownson R.C., Alavanja M.C., Caporaso N., Berger E., Chang J.C. Family history of cancer and risk of lung cancer in lifetime non-smokers and long-term ex-smokers. Int J Epidemiol. 1997; 26: 256-263.

4. Wang Y., Broderick P., Webb E., Wu X., Vijayakrishnan J., Matakidou A., Qureshi M., Dong Q., Gu X., Chen W.V., Spitz M.R., Eisen T., Amos C.I., Houlston R.S.Common 5p15.33 and 6p21.33 variants influence lung cancer risk. Nat Genet. 2008 Dec; 40 (12): 1407-9. https://doi.org/10.1038/ng.273.

5. Broderick P., Wang Y., Vijayakrishnan J., Matakidou A., Spitz M.R., Eisen T., Amos C.I., Houlston R.S. Deciphering the impact of common genetic variation on lung cancer risk: a genome-wide association study. Cancer Res. 2009 Aug 15; 69 (16): 6633-41. https://doi.org/10.1158/0008-5472.CAN-09-0680.

6. Hung R.J., McKay J.D., Gaborieau V., Boffetta P., Hashibe M., Zaridze D., Mukeria A., Szeszenia-Dabrowska N., Lissowska J., Rudnai P., Fabianova E., Mates D., Bencko V., Foretova L., Janout V., Chen C., Goodman G., Field J.K., Liloglou T., Xinarianos G., Cassidy A., McLaughlin J., Liu G., Narod S., Krokan H.E., Skorpen F., Elvestad M.B., Hveem K., Vatten L., Linseisen J., Clavel-Chapelon F., Vineis P., Bueno-de-Mesquita H.B., Lund E., Martinez C., Bingham S., Rasmuson T., Hainaut P., Riboli E., Ahrens W., Benhamou S., Lagiou P., Trichopoulos D., Holcátová I., Merletti F., Kjaerheim K., Agudo A., Macfarlane G., Talamini R., Simonato L., Lowry R., Conway D.I., Znaor A., Healy C., Zelenika D., Boland A., Delepine M., Foglio M., Lechner D., Matsuda F., Blanche H., Gut I., Heath S., Lathrop M., Brennan P. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature. 2008; 452: 633-637. https://doi.org/10.1038/nature06885.

7. Wu C., Hu Z., Yu D., Huang L., Jin G., Liang J., Guo H., Tan W., Zhang M., Qian J., Lu D., Wu T., Lin D., Shen H.Genetic variants on chromosome 15q25 associated with lung cancer risk in Chinese populations. Cancer Res. 2009; 69: 5065-5072. https://doi.org/10.1158/0008-5472.CAN-09-0081.

8. Shiraishi K., Kunitoh H., Daigo Y., Takahashi A., Goto K., Sakamoto H., Ohnami S., Shimada Y., Ashikawa K., Saito A., Watanabe S., Tsuta K., Kamatani N., Yoshida T., Nakamura Y., Yokota J., Kubo M., KohnoT. A genome-wide association study identifies two new susceptibility loci for lung adenocarcinoma in the Japanese population. Nat. Genet. 2012; 44: 900-903. https://doi.org/10.1038/ng.2353.

9. Yoon K.A., Park J.H., Han J., Park S., Lee G.K., Han J.Y., Zo J.I., Kim J., Lee J.E., Takahashi A., Kubo M., Nakamura Y., Lee J.S. A genomewide association study reveals susceptibility variants for non-small cell lung cancer in the Korean population. Hum Mol Genet. 2010 Dec 15; 19 (24): 4948-54. https://doi.org/10.1093/hmg/ddq421.

10. Wang M., Liu H., Liu Z., Yi X., Bickeboller H., Hung R.J., Brennan P., Landi M.T., Caporaso N., Christiani D.C., Doherty J.A., TRICL Research Team, Amos C.I., Wei Q. Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium. Carcinogenesis. 2016 Sep; 37 (9): 888-896. https://doi.org/10.1093/carcin/bgw070.

11. Siemianowicz K., Gminski J., Garczorz W., Slabiak N., Goss M., Machalski M., Magiera-Molendowska H. Methylenetetrahydrofolate reductase gene C677T and A1298C polymorphisms in patients with small cell and non-small cell lung cancer.Oncol Rep. 2003; 10 (5): 1341-4.

12. Shen M., Rothman N., Berndt S.I., He X., Yeager M., Welch R., Chanock S., Caporaso N., Lan Q.Polymorphisms in folate metabolic genes and lung cancer risk in Xuan Wei, China. Lung Cancer. 2005 Sep; 49 (3): 299-309. https://doi.org/10.1016/j.lungcan.2005.04.002.

13. Shi Q., Zhang Z., Li G., Pillow P.C., Hernandez L.M., Spitz M.R., Wei Q. Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis. Pharmacogenet Genomics. 2005 Aug; 15 (8): 547-55.

14. Hung R.J., Hashibe M., McKay J., Gaborieau V., SzeszeniaDabrowska N., Zaridze D., Lissowska J., Rudnai P., Fabianova E., Mates I., Foretova L., Janout V., Bencko V., Chabrier A., Moullan N., Canzian F., Hall J., Boffetta P., Brennan P. Folate-related genes and the risk of tobacco-related cancers in Central Europe.Carcinogenesis. 2007 Jun; 28 (6): 1334-1340. https://doi.org/10.1093/carcin/bgm067.

15. Vineis P., Veglia F., Garte S., Malaveille C., Matullo G., Dunning A., Peluso M., Airoldi L., Overvad K., Raaschou-Nielsen O., Clavel-Chapelon F., Linseisen J.P., Kaaks R., Boeing H., Trichopoulou A., Palli D., Crosignani P., Tumino R., Panico S., Bueno-De-Mesquita H.B., Peeters P.H., Lund E., Gonzalez C.A., Martinez C., Dorronsoro M., Barricarte A., Navarro C., Quiros J.R., Berglund G., Jarvholm B., Day N.E., Key T.J., Saracci R., Riboli E., Autrup H.Genetic susceptibility according to three metabolic pathways in cancers of the lung and bladder and in myeloid leukemias in nonsmokers. Ann Oncol. 2007 Jul; 18 (7): 1230-42. https://doi.org/10.1093/annonc/mdm109.

16. Cheng Z., Wang W., Dai L.L., Kang Y. MTHFR C667T polymorphism association with lung cancer risk in Henan province: a case-control study.Asian Pac J Cancer Prev. 2012; 13 (6): 2491-2494.

17. Arslan S., Karadayi S., Yildirim M.E., Ozdemir O., Akkurt I. The association between methylene-tetrahydrofolate reductase gene polymorphism and lung cancer risk.Mol Biol Rep. 2011; 38 (2): 991-6. https://doi.org/10.1007/s11033-010-0194-z.

18. Kiyohara C., Horiuchi T., Takayama K., Nakanishi Y. Methylenetetrahydrofolate reductase polymorphisms and interaction with smoking and alcohol consumption in lung cancer risk: a case-control study in a Japanese population.BMC Cancer. 2011 Oct 25; 11: 459. https://doi.org/10.1186/1471-2407-11-459.

19. Aksoy-Sagirli P., Erdenay A., Kaytan-Saglam E., Kizir A. Association of Three Single Nucleotide Polymorphisms in MTR and MTRR Genes with Lung Cancer in a Turkish Population.Genet Test Mol Biomarkers. 2017; 21 (7): 428-432. https://doi.org/10.1089/gtmb.2017.0062.

20. Goldbohm R.A., Voorrips L.E. Epidemiology of nutrition and lung cancer. Nestle Nutr Workshop Ser Clin Perform Programme. 2000; 4: 23-35.

21. Brennan P., Fortes C., Butler J., Agudo A., Benhamou S., Darby S., Gerken M., Jökel K.H., Kreuzer M., Mallone S., Nyberg F., Pohlabeln H., Ferro G., Boffetta P. A multicenter case-control study of diet and lung cancer among non-smokers. Cancer Causes Control. 2000; 11: 49-58.

22. Männistö S., Smith-Warner S.A., Spiegelman D., Albanes D., Anderson K., van den Brandt P.A., Cerhan J.R., Colditz G., Feskanich D., Freudenheim J.L., Giovannucci E., Goldbohm R.A., Graham S., Miller A.B., Rohan T.E., Virtamo J., Willett W.C., Hunter D.J.Dietary carotenoids and risk of lung cancer in a pooled analysis of seven cohort studies. Cancer Epidemiol Biomarkers Prev. 2004; 13: 40-48.

23. Darby S., Whitley E., Doll R., Key T., Silcocks P.Diet, smoking and lung cancer: a case-control study of 1000 cases and 1500 controls in South-West England. Br J Cancer. 2001; 84: 728-735. https://doi.org/10.1054/bjoc.2000.1668.

24. Wei Q., Shen H., Wang L.E., Duphorne C.M., Pillow P.C., Guo Z., Qiao Y., Spitz M.R.Association between low dietary folate intake and suboptimal cellular DNA repair capacity. Cancer Epidemiol Biomarkers Prev. 2003; 12: 963-969.

25. Wei Q., Cheng L., Amos C.I., Wang L.E., Guo Z., Hong W.K., Spitz M.R. Repair of tobacco carcinogen-induced DNA adducts and lung cancer risk: a molecular epidemiologic study. J Natl Cancer Inst. 2000; 92: 1764-1772.

26. Cui L.H., Shin M.H., Kim H.N., Song H.R., Piao J.M., Kweon S.S., Choi J.S., Yun W.J., Kim Y.C., Oh I.J., Kim K.S. Methylenetetrahydrofolate reductase C677T polymorphism in patients with lung cancer in a Korean population.BMC Med Genet. 2011; 12: 28. https://doi.org/10.1186/1471-2350-12-28.

27. Matakidou A., El Galta R., Rudd M.F., Webb E.L., Bridle H., Eisen T., Houlston R.S. Prognostic significance of folate metabolism polymorphisms for lung cancer.Br J Cancer. 2007; 97 (2): 247-252.

28. Harmon D.L., Shields D.C., Woodside J.V., McMaster D., Yarnell J.W., Young I.S., Peng K., Shane B., Evans A.E., Whitehead A.S. Methionine synthase D919G polymorphism is a significant but modest determinant of circulating homocysteineconcentrations. Genet Epidemiol.1999 Nov; 17 (4): 298-309.

29. Ma J., Stampfer M.J., Christensen B., Giovannucci E., Hunter D.J., Chen J., Willett W.C., Selhub J., Hennekens C.H., Gravel R., Rozen R. A polymorphism of the methionine synthase gene: association with plasma folate, vitamin B12, homocyst(e)ine, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 1999 Sep; 8 (9): 825-829.

30. Dmitrieva A.I., Novitskii V.V., Sevost'yanova N.V., Frei-din M.B., Puzyrev V.P., Kolomiets S.A., Cheremisina O.V., Nerush E.V., Ten I.A. Izuchenie polimorfizma genov GSTT1 i GSTM1 u bol'nykh rakom legkikh. Byulleten' Sibirskogo otdeleniya Rossiiskoi akademii meditsinskikh nauk. 2004; 24 (1): 60-62. [Dmitrieva A.I., Novitski V.V., Sevostjanova N.V., Freidin M.B., Pusyrev V.P., Kolomiets S.A., Cheremisina O.V., Nerush E.V., Ten L.A. Study of polymorphism of GSTTl and GSTMl genes in lung cancer patients. Herald of Siberian Branch of Russian Academy Medical Sciences. 2004; 24 (1): 60-62. (in Russian)].

31. Bakanova M.L., Soboleva O.A., Minina V.I., Savchenko Ya.A., Ryzhkova A.V., Titov, R.A., Titov V.A., Boyarskikh U.A., Voronina E.N., Glushkov A.N. Vklad polimorfnykh variantov genov folatnogo tsikla v tsitogeneticheskuyu nestabil'nost' kletok krovi bol'nykh rakom legkogo. Meditsinskaya genetika. 2017; 16 (3): 12-19. [Bakanova M.L., Soboleva O.A., Minina V.I., Savchenko Y.A., Ryzhkova A.V., Titov R.A., Titov V.A., Boyarskih U.A., Voronina E.N., Glushkov A.N. Association of polymorphism of folate metabolism genes and chromosomal aberrations in blood cells of lung cancer patients. Medical Genetics. 2017; 16 (3): 12-19. (in Russian)].

32. Weiner A.S., Boyarskikh U.A., Voronina E.N., Mishukova O.V., Filipenko M.L.Methylenetetrahydrofolate reductase C677T and methionine synthase A2756G polymorphisms influence on leukocyte genomic DNA methylation level. Gene. 2014 Jan 1; 533 (1): 168-72. https://doi.org/10.1016/j.gene.2013.09.098.

33. Henao O.L., Piyathilake C.J., Waterbor J.W., Funkhouser E., Johanning G.L., Heimburger D.C., Partridge E.E.Women with polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MS) are less likely to have cervical intraepithelial neoplasia (CIN) 2 or 3. Int J Cancer. 2005; 113: 991-997. https://doi.org/10.1002/ijc.20695.

34. Lin J., Spitz M.R., Wang Y., Schabath M.B., Gorlov I.P., Hernandez L.M., Pillow P.C., Grossman H.B., Wu X.Polymorphisms of folate metabolic genes and susceptibility to bladder cancer: a case-control study. Carcinogenesis. 2004; 25: 1639-47. https://doi.org/10.1093/carcin/bgh175.

35. Skibola C.F., Forrest M.S., Coppedé F., Agana L., Hubbard A., Smith M.T., Bracci P.M., Holly E.A. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood. 2004; 104: 2155-2162. https://doi.org/10.1182/blood-2004-02-0557.

36. Olteanu H., Munson T., Banerjee R. Differences in the efficiency of reductive activation of methionine synthase and exogenous electron acceptors between the common polymorphic variants of human methionine synthase reductase. Biochemistry. 2002; 41: 13378-85.

37. Jeng Y.L., Wu M.H., Huang H.B., Lin W.Y., You S.L, Chu T.Y., Chen C.J., Sun C.A.The methylenetetrahydrofolate reductase 677C-->T polymorphism and lung cancer risk in a Chinese population. Anticancer Res. 2003 Nov-Dec; 23 (6D): 5149-5152.

38. Suzuki T., Matsuo K., Hiraki A., Saito T., Sato S., Yatabe Y., Mitsudomi T., Hida T., Ueda R., Tajima K. Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study.Carcinogenesis. 2007; 28 (8): 1718-1725. https://doi.org/10.1093/carcin/bgm104.

39. Liu C.S., Tsai C.W., Hsia T.C., Wang R.F., Liu C.J., Hang L.W., Chiang S.Y., Wang C.H., Tsai R.Y., Lin C.C., Bau D.T. Interaction of methylenetetrahydrofolate reductase genotype and smoking habit in Taiwanese lung cancer patients.Cancer Genom Proteom. 2009; 6 (6): 325-329.

40. Ding H., Wang Y., Chen Y., Liu C., Qiu H., Kang M., Tang W. Methylenetetrahydrofolate reductase tagging polymorphisms are associated with risk of non-small cell lung cancer in eastern Chinese Han population. Oncotarget. 2017; 8 (66): 110326-110336. https://doi.org/10.18632/oncotarget.22887.

41. Heijmans B.T., Boer J.M., Suchiman H.E., Cornelisse C.J., Westendorp R.G., Kromhout D., Feskens E.J., Slagboom P.E.A common variant of the methylenetetrahydrofolate reductase gene (1p36) is associated with an increased risk of cancer. Cancer Res. 2003 Mar 15; 63 (6): 1249-1253.

42. Liu H., Jin G., Wang H., Wu W., Liu Y., Qian J., Fan W., Ma H., Miao R., Hu Z., Sun W., Wang Y., Jin L., Wei Q., Shen H., Huang W., Lu D. Association of polymorphisms in one-carbon metabolizing genes and lung cancer risk: a case-control study in Chinese population.Lung Cancer. 2008; 61 (1): 21-29. https://doi.org/10.1016/j.lungcan.2007.12.001.

43. Yilmaz M., Kacan T., Sari I., Kilickap S. Lack of association between the MTHFRC677T polymorphism and lung cancer in a Turkish population.Asian Pac J Cancer Prev. 2014; 15 (15): 6333-6337.

44. Al-Motassem Y., Shomaf M., Said I., Berger S., Ababneh N., Diab O., Obeidat N., Awidi A. Allele and Genotype Frequencies of the Polymorphic Methylenetetrahydrofolate Reductase and Lung Cancer in the Jordanian Population: a Case Control Study.Asian Pac J Cancer Prev. 2015; 16 (8): 3101-3109.

45. Shilova A.N., Shkoda O.S., Lomivorotov V.V., Shilova Yu.N. Assotsiatsiya polimorfnykh variantov genov metabolizma folievoi kisloty s riskom razvitiya raka legkogo, raka predstatel'noi zhelezy, raka molochnoi zhelezy i raka matki. Rossiiskii onkologicheskii zhurnal. 2017; 22 (4): 203-208. [Shilova A.N., Shkoda O.S., Lomivorotov V.V., Shilova J.N. Association of the folate metabolism genes with the risk for lung, prostate, breast and uterine cancer. Russian Journal of Oncology. 2017; 22 (4): 203-208. (in Russian)]. https://doi.org/10.18821/1028-9984-2017-22-4-203-208.

46. Durda K., Kąklewski K., Gupta S., Szydłowski M., Baszuk P., Jaworska-Bieniek K., Sukiennicki G., Kaczmarek K., Waloszczyk P., Narod S., Lubiński J., Jakubowska A. Serum folate concentration and the incidence of lung cancer.PLoSOne. 2017 May 11; 12 (5): e0177441. https://doi.org/10.1371/journal.pone.0177441.

47. Pérez-Ramírez C., Cañadas-Garre M., Alnatsha A., Villar E., Delgado J.R., Calleja-Hernández M.Á., Faus-Dáder M.J. Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer.Pathol Res Pract. 2018 Jan; 214 (1): 44-52. https://doi.org/10.1016/j.prp.2017.11.015.

48. Mao R., Fan Y., Jin Y., Bai J., Fu S. Methylenetetrahydrofolate reductase gene polymorphisms and lung cancer: a meta-analysis.J Hum Genet. 2008; 53 (4): 340-348. https://doi.org/10.1007/s10038-008-0262-6.

49. Boccia S., Boffetta P., Brennan P., Ricciardi G., Gianfagna F., Matsuo K., van Duijn C.M., Hung R.J. Meta-analyses of the methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and risk of head and neck and lung cancer.Cancer Lett. 2009 Jan 8; 273 (1): 55-61. https://doi.org/10.1016/j.canlet.2008.07.026.

50. Hou X.H., Huang Y.M., Mi Y.Y. Methylenetetrahydrofolate reductase gene C677T polymorphism and lung cancer: an updated metaanalysis.Asian Pac J Cancer Prev. 2012; 13 (5): 2025-2029.

51. Zhang Y., Chen G.Q., Ji Y., Huang B., Shen W.S., Deng L.C., Xi L., Cao X.M. Quantitative assessment of the effect of MTHFR polymorphisms on the risk of lung carcinoma.Mol Biol Rep. 2012 May; 39 (5): 6203-6211. https://doi.org/10.1007/s11033-011-1439-1.

52. Liu Z.B., Wang L.P., Shu J., Jin C., Lou Z.X. Methylenetetrahydrofolate reductase 677TT genotype might be associated with an increased lung cancer risk in Asians.Gene. 2013; 515 (1): 214-219. https://doi.org/10.1016/j.gene.2012.11.036.

53. Liu N.B., Li J., Qi J.F., Zhang Z.Z., Wu X., Zhang H. Methylenetetrahydrofolate reductase 677TT genotype may be associated with an increased lung cancer risk in North China: an updated meta-analysis.Med Sci Monit. 2014 Dec 29; 20: 2817-23. https://doi.org/10.12659/MSM.892050.

54. Rai V. Folate pathway gene MTHFR C677T polymorphism and risk of lung cancer in Asian populations.Asian Pac J Cancer Prev. 2014; 15 (21): 9259-9264.

55. Yang Y., Yang L.J., Deng M.Z., Luo Y.Y., Wu S., Xiong L., Wang D., Liu Y., Liu H. MTHFR C677T and A1298C polymorphisms and risk of lung cancer: a comprehensive evaluation.Genet Mol Res. 2016; 15 (2). https://doi.org/10.4238/gmr.15027615.

56. Xie S.Z., Liu Z.Z., Yu J.H., Liu L., Wang W., Xie D.L., Qin J.B. Association between the MTHFR C677T polymorphism and risk of cancer: evidence from 446 case-control studies.Tumour Biol. 2015 Nov; 36 (11): 8953-72. https://doi.org/10.1007/s13277-015-3648-z.

57. Wang X., Yue K., Hao L. Meta-analysis of methylenetetrahydrofolate reductase polymorphism and lung cancer risk in Chinese.Int J Clin Exp Med. 2015 Jan 15; 8 (1): 1521-1525.

58. Zhang X.D., Li Y.T., Yang S.Y., Li W. Meta-analysis on MTHFR polymorphism and lung cancer susceptibility in East Asian populations. Biomed Rep. 2013; 1 (3): 440-446. https://doi.org/10.3892/br.2013.68.

59. Shi Q., Zhang Z., Li G., Pillow P.C., Hernandez L.M., Spitz M.R., Wei Q. Sex differences in risk of lung cancer associated with methylenetetrahydrofolate reductasepolymorphisms. Cancer Epidemiol Biomarkers Prev. 2005; 14 (6): 1477-84. https://doi.org/10.1158/1055-9965.EPI-04-0905.

60. Piskac-Collier A.L., Monroy C., Lopez M.S., Cortes A., Etzel C.J., Greisinger A.J., Spitz M.R., El-Zein R.A. Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. Genes Chromosomes Cancer. 2011 Jan; 50 (1): 1-12. https://doi.org/10.1002/gcc.20826.