In this thesis, the results showed that genetic variations of FKBP 5 and patients’ coping patterns to cancer were potent predictive factors for anxiety and depression in patients with advanced cancer. In particular, our findings indicate that genetic components such FKBP5 gene polymorphisms play a crucial role in anxiety and depression following prolonged stress exposure. A better understanding of genetic influences on stress responses might provide insight into the vulnerability of stress-related psychiatric disorders. Although the sample size is small to draw any firm conclusions on this issue, our results are meaningful in that we included relatively homogenous population exposed to real life stressors with similar level and used a prospective design. To confirm genetic influence of FKBP5 on psychological morbidity following prolonged stress, further investigation is required with a larger population.
REFERENCES
1. Andreassi JL. Heart activity and behavior II: Stress, emotions, motivation, personality, social factors, brain interactions, and conditioning. In: Psychophysiology: human behavior and physiological response. 5th ed. New Jersey: Lawrence Erlbaun Associates; 2007. p. 438-9.
2. Jovanovic T, Ressler KJ. How the neurocircuitry and genetics of fear inhibition may inform our understanding of PTSD. Am J Psychiatry 2010;167(6):648-62.
3. Zubin J, Spring B. Vulnerability - a new view of schizophrenia. J Abnorm Psychol 1977;86(2):103-26.
4. Stein MB, Jang KL, Livesley WJ. Heritability of anxiety sensitivity: a twin study. Am J Psychiatry 1999;156(2):246-51.
5. Kendler KS. Genetic epidemiology in psychiatry. Taking both genes and environment seriously. Arch Gen Psychiatry 1995;52(11):895-9.
6. Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: review and meta-analysis. Am J Psychiatry 2000;157(10):1552-62.
7. Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 1992;267(9):1244-52.
8. Johnson EO, Kamilaris TC, Chrousos GP, Gold PW. Mechanisms of stress: a dynamic overview of hormonal and behavioral homeostasis.
Neurosci Biobehav Rev 1992;16(2):115-30.
9. Herman JP, Ostrander MM, Mueller NK, Figueiredo H. Limbic system mechanisms of stress regulation: hypothalamo-pituitary- adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 2005;29(8):1201-13.
10. Jankord R, Herman JP. Limbic regulation of hypothalamo-pituitary-adrenocortical function during acute and chronic stress. Ann N Y Acad Sci 2008;1148:64-73.
11. Derijk RH, van Leeuwen N, Klok MD, Zitman FG. Corticosteroid receptor-gene variants: modulators of the stress-response and implications for mental health. Eur J Pharmacol 2008;585(2-3):
492-501.
12. Claes S. Glucocorticoid receptor polymorphisms in major depression.
Ann N Y Acad Sci 2009;1179:216-28.
13. Pace TW, Hu F, Miller AH. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain Behav Immun 2007;21(1):9-19.
14. Conrad CD. Chronic stress-induced hippocampal vulnerability: the glucocorticoid vulnerability hypothesis. Rev Neurosci 2008;19(6):
395-411.
15. Kendler KS, Gatz M, Gardner CO, Pedersen NL. A Swedish national twin study of lifetime major depression. Am J Psychiatry. Jan 2006;163(1):109-114.
16. Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology 2004;29(10):1765-81.
17. Xie P, Kranzler HR, Poling J, Stein MB, Anton RF, Brady K, et al.
Interactive effect of stressful life events and the serotonin transporter 5-HTTLPR genotype on posttraumatic stress disorder diagnosis in 2 independent populations. Arch Gen Psychiatry 2009;66(11):1201-9.
18. Redei EE. Molecular genetics of the stress-responsive adrenocortical axis. Ann Med 2008;40(2):139-48.
19. Yehuda R, Cai G, Golier JA, Sarapas C, Galea S, Ising M, et al. Gene
expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks. Biol Psychiatry 2009;66(7):708-11.
20. Binder EB. The role of FKBP5, a co-chaperone of the glucocorticoid receptor in the pathogenesis and therapy of affective and anxiety disorders. Psychoneuroendocrinology 2009;34 Suppl 1:186-95.
21. Lekman M, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ, et al.
The FKBP5-gene in depression and treatment response--an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort. Biol Psychiatry 2008;63(12):1103-10.
22. Roy A, Gorodetsky E, Yuan Q, Goldman D, Enoch MA. Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide. Neuropsychopharmacology 2010;35(8):
1674-83.
23. Scammell JG, Denny WB, Valentine DL, Smith DF. Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates. Gen Comp Endocrinol 2001;124(2):152-65.
24. Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B, et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004;36(12):1319-25.
25. Binder EB, Bradley RG, Liu W, Epstein MP, Deveau TC, Mercer KB, et al. Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 2008;299(11):1291-305.
26. Ronson A. Psychiatric disorders in oncology: recent therapeutic advances and new conceptual frameworks. Curr Opin Oncol 2004;16(4):318-23.
27. Derogatis LR, Morrow GR, Fetting J, Penman D, Piasetsky S, Schmale AM, et al. The prevalence of psychiatric disorders among cancer patients. JAMA 1983;249(6):751-7.
28. Courtens AM, Stevens FC, Crebolder HF, Philipsen H. Longitudinal study on quality of life and social support in cancer patients. Cancer Nurs 1996;19(3):162-9.
29. Glass RM. Psychiatric disorders among cancer patients. JAMA 1983;249(6):782-3.
30. Andersen BL, Kiecolt-Glaser JK, Glaser R. A biobehavioral model of cancer stress and disease course. Am Psychol 1994;49(5):389-404.
31. Tavoli A, Mohagheghi MA, Montazeri A, Roshan R, Tavoli Z, Omidvari S. Anxiety and depression in patients with gastrointestinal cancer: does knowledge of cancer diagnosis matter? BMC Gastroenterol 2007;7:28.
32. National database of cancer (1999-2002): Annual report of statistisc of death causes. Seoul: : Korea National Statistical Office; 2005.
33. Cervantes A, Rosello S, Roda D, Rodriguez-Braun E. The treatment of advanced gastric cancer: current strategies and future perspectives.
Ann Oncol 2008;19 Suppl 5:v103-7.
34. Zigmond AS, Snaith RP. The hospital anxiety and depression scale.
Acta Psychiatr Scand 1983;67(6):361-70.
35. Oh SM MK, Park DB. A Study on the Standardization of the Hospital Anxiety and Depression Scale for Koreans: A Comparison of Normal, Depressed and Anxious Groups. J Korean Neuropsychiatr Assoc 1999;38(2):289-96.
36. Watson M, PhD, , Matthew Law M, Maria dos Santos M, Steven Greer M, John Baruch M, Judith Bliss M. The Mini-MAC: Further development of the Mental Adjustment to Cancer Scale. Journal of Psychosocial Oncology 1994;12(3):33-46.
37. Kang JI, Chung HC, Kim SJ, Choi HJ, Ahn JB, Jeung HC, et al.
Standardization of the Korean version of Mini-Mental Adjustment to Cancer (K-Mini-MAC) scale: factor structure, reliability and validity.
Psychooncology 2008;17(6):592-7.
38. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-55.
39. Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005;21(2):263-5.
40. Ising M, Depping AM, Siebertz A, Lucae S, Unschuld PG, Kloiber S, et al. Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls. Eur J Neurosci 2008;28(2):389-98.
41. Luijk MP, Velders FP, Tharner A, van Ijzendoorn MH, Bakermans-Kranenburg MJ, Jaddoe VW, et al. FKBP5 and resistant attachment predict cortisol reactivity in infants: Gene-environment interaction. Psychoneuroendocrinology 2010. doi:10.1016/j.psyneuen.
2010.04.012
42. Ayres A, Hoon PW, Franzoni JB, Matheny KB, Cotanch PH, Takayanagi S. Influence of mood and adjustment to cancer on compliance with chemotherapy among breast cancer patients. J Psychosom Res 1994;38(5):393-402.
43. Costanzo ES, Lutgendorf SK, Rothrock NE, Anderson B. Coping and quality of life among women extensively treated for gynecologic cancer. Psychooncology 2006;15(2):132-42.
44. McCaul KD, Sandgren AK, King B, O'Donnell S, Branstetter A, Foreman G. Coping and adjustment to breast cancer. Psychooncology 1999;8(3):230-6.
< ABSTRACT (IN KOREAN)>
유전적 특성이 암환자의 스트레스 반응에 미치는 영향
<지도교수 남궁기>
연세대학교 대학원 의학과
강 지 인
암환자들은 암의 진단 및 치료과정에서 여러 스트레스를 겪으면서 다양한 스트레스 반응을 나타낸다. 유전적 요인은 개개인의 스트레스 반응의 차이와 정신 질환의 취약성에 영향을 줄 것이다. 본 연구는 시상하부-뇌하수체-부신 축을 조절하는 FKBP5 유전자 다형성이 암으로 고통 받고 있는 환자의 불안, 우울과 같은 스트레스 반응에 미치는 영향을 살펴보고자 하였다.
진행성 위암을 새롭게 진단받고 항암치료를 처음 받기로 예정되어 있는 환자를 대상으로 전향적 연구 설계로 진행하였다.
진행성 위암으로 확진된 130명의 암환자(남자 90명, 여자 40명)를 모집하여 진단받은 지 1개월 이내에 기초 평가를 실시하였다. 이들 중 6주 후에 평가 가능했던 93명의 환자(남자 63명, 여자 30명)에 대하여 추적 평가를 실시하였다. Hospital Anxiety and Depression Scale 과 Mini-Mental Adjustment to Cancer Scale 등을 이용하여
FKBP5 유전자의 세 가지 단일염기다형성 rs1360780, rs9296158, rs9470080 을 조사하였다.
FKBP5 유전적 특성과 6주 후의 불안 및 우울 점수의 변화를 분석했을 때 rs9296158 와 rs9470080 은 유전형에 따른 그룹과 시간과의 교호작용효과를 보였다. 또한 단계적 회기 분석 결과, FKBP5 유전자 및 대처방식은 불안, 우울 정도를 예측하였다. 특히, rs9296158 와 rs9470080 은 시간의 경과에 따른 불안 및 우울 점수 변화의 유의한 예측인자로 나타났다.
본 연구결과는 FKBP5 유전자 다형성과 같은 유전적 특성이 암 치료과정에서 스트레스 반응으로 나타나는 불안 및 우울 증상에 중요한 역할을 할 것임을 시사한다.
--- 핵심되는 말: 암, 스트레스, 우울, 유전자, FKBP5, HPA 축