Supportive Care in Cancer

, Volume 27, Issue 2, pp 351–371 | Cite as

Systematic review of genetic polymorphisms associated with psychoneurological symptoms in breast cancer survivors

  • Gee Su YangEmail author
  • Sreelakshmy Kumar
  • Susan G. Dorsey
  • Angela R. Starkweather
  • Debra Lynch Kelly
  • Debra E. Lyon
Review Article



Psychoneurological (PN) symptoms, such as anxiety, cognitive impairment, depression, fatigue, sleep disturbances, and pain, are highly prevalent in breast cancer patients undergoing cancer treatment. Emerging evidence suggests that genetic polymorphisms may contribute to differential symptom susceptibility. We aimed to systematically review associations between genetic polymorphisms and PN symptoms during or after cancer treatment for early-stage breast cancer.


Twenty-six eligible articles published until October 2017 were identified in PubMed, PsycINFO, Web of Science, and additional records. Information on study characteristics, genetic polymorphisms, and PN symptoms was extracted. Study quality was evaluated by the STrengthening the REporting of Genetic Association (STREGA) guideline. Genes included in the analysis were categorized by biological pathways based on the Reactome database.


A total of 54 single nucleotide polymorphisms and haplotypes that are significantly associated with PN symptoms were identified; half of them were associated with increased severity of PN symptoms, while the other half contributed to the decrease of PN symptoms. Pain has the known highest number of associated genetic polymorphisms reported, followed by fatigue, cognitive impairment, depressive symptoms, sleep disturbances, and anxiety. The majority of genetic polymorphisms were involved in immune system and neuronal system pathways. Most studies were unsuccessful in meeting the STREGA guideline, which requires transparent reporting of methods and results.


This review provides comprehensive evidence of genetic polymorphisms underlying PN symptoms, which may pave the way for the development of personalized therapeutics targeting these symptoms. More well-designed genome-wide association studies are required to validate and replicate these findings.


Breast cancer Psychoneurological symptoms Genetic polymorphism Single nucleotide polymorphism Systematic review 



We would like to thank Ms. Debra McDonald for proofreading.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.


  1. 1.
    Alfaro E, Dhruva A, Langford DJ, Koetters T, Merriman JD, West C, Dunn LB, Paul SM, Cooper B, Cataldo J, Hamolsky D, Elboim C, Kober K, Aouizerat BE, Miaskowski C (2014) Associations between cytokine gene variations and self-reported sleep disturbance in women following breast cancer surgery. Eur J Oncol Nurs 18:85–93. CrossRefPubMedGoogle Scholar
  2. 2.
    Belfer I, Segall S (2011) COMT genetic variants and pain. Drugs Today (Barc) 47:457–467. CrossRefGoogle Scholar
  3. 3.
    Berry DA, Cronin KA, Plevritis SK, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353:1784–1792CrossRefGoogle Scholar
  4. 4.
    Bower JE, Ganz PA, Irwin MR, Castellon S, Arevalo J, Cole SW (2013) Cytokine genetic variations and fatigue among patients with breast cancer. J Clin Oncol 31:1656–1661. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Buchanan ND, Dasari S, Rodriguez JL, Lee Smith J, Hodgson ME, Weinberg CR, Sandler DP (2015) Post-treatment neurocognition and psychosocial care among breast cancer survivors. Am J Prev Med 49:S498–S508. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cajanus K, Holmstrom EJ, Wessman M, Anttila V, Kaunisto MA, Kalso E (2016) Effect of endocannabinoid degradation on pain: role of FAAH polymorphisms in experimental and postoperative pain in women treated for breast cancer. Pain 157:361–369. CrossRefPubMedGoogle Scholar
  7. 7.
    Cheng H, Li W, Gan C, Zhang B, Jia Q, Wang K (2016) The COMT (rs165599) gene polymorphism contributes to chemotherapy-induced cognitive impairment in breast cancer patients. Am J Transl Res 8:5087–5097PubMedPubMedCentralGoogle Scholar
  8. 8.
    Clayton DG, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM, Smink LJ, Lam AC, Ovington NR, Stevens HE, Nutland S, Howson JM, Faham M, Moorhead M, Jones HB, Falkowski M, Hardenbol P, Willis TD, Todd JA (2005) Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet 37:1243–1246CrossRefGoogle Scholar
  9. 9.
    Collado-Hidalgo A, Bower JE, Ganz PA, Irwin MR, Cole SW (2008) Cytokine gene polymorphisms and fatigue in breast cancer survivors: early findings. Brain Behav Immun 22:1197–1200. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Dantzer R, Kelley KW (2007) Twenty years of research on cytokine-induced sickness behavior. Brain Behav Immun 21:153–160CrossRefGoogle Scholar
  11. 11.
    Dodd MJ, Cho MH, Cooper BA, Miaskowski C (2010) The effect of symptom clusters on functional status and quality of life in women with breast cancer. Eur J Oncol Nurs 14:101–110. CrossRefPubMedGoogle Scholar
  12. 12.
    Dooley LN, Ganz PA, Cole SW, Crespi CM, Bower JE (2016) Val66Met BDNF polymorphism as a vulnerability factor for inflammation-associated depressive symptoms in women with breast cancer. J Affect Disord 197:43–50. CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR (2010) Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 68:748–754. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Eshragh J, Dhruva A, Paul SM, Cooper BA, Mastick J, Hamolsky D, Levine JD, Miaskowski C, Kober KM (2017) Associations between neurotransmitter genes and fatigue and energy levels in women after breast cancer surgery. J Pain Symptom Manag 53:67–84 e67. CrossRefGoogle Scholar
  15. 15.
    Fernandez-de-las-Peñas C, Fernandez-Lao C, Cantarero-Villanueva I, Ambite-Quesada S, Rivas-Martinez I, del Moral-Avila R, Arroyo-Morales M (2012) Catechol-O-methyltransferase genotype (Val158met) modulates cancer-related fatigue and pain sensitivity in breast cancer survivors. Breast Cancer Res Treat 133:405–412. CrossRefPubMedGoogle Scholar
  16. 16.
    Fu OS, Crew KD, Jacobson JS, Greenlee H, Yu G, Campbell J, Ortiz Y, Hershman DL (2009) Ethnicity and persistent symptom burden in breast cancer survivors. J Cancer Surviv 3:241–250. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Garcia-Giralt N, Rodriguez-Sanz M, Prieto-Alhambra D, Servitja S, Torres-Del Pliego E, Balcells S, Albanell J, Grinberg D, Diez-Perez A, Tusquets I, Nogues X (2013) Genetic determinants of aromatase inhibitor-related arthralgia: the B-ABLE cohort study. Breast Cancer Res Treat 140:385–395. CrossRefPubMedGoogle Scholar
  18. 18.
    Gilbertson-White S, Aouizerat BE, Miaskowski C (2011) Methodologic issues in the measurement of cytokines to elucidate the biological basis for cancer symptoms. Biol Res Nurs 13:15–24. CrossRefPubMedGoogle Scholar
  19. 19.
    Kambur O, Kaunisto MA, Tikkanen E, Leal SM, Ripatti S, Kalso EA (2013) Effect of catechol-o-methyltransferase-gene (COMT) variants on experimental and acute postoperative pain in 1,000 women undergoing surgery for breast cancer. Anesthesiology 119:1422–1433. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Kim HJ, Barsevick AM, Fang CY, Miaskowski C (2012) Common biological pathways underlying the psychoneurological symptom cluster in cancer patients. Cancer Nurs 35:E1–E20. CrossRefPubMedGoogle Scholar
  21. 21.
    Kim JM, Kim SW, Stewart R, Kim SY, Shin IS, Park MH, Yoon JH, Lee JS, Park SW, Kim YH, Yoon JS (2012) Serotonergic and BDNF genes associated with depression 1 week and 1 year after mastectomy for breast cancer. Psychosom Med 74:8–15. CrossRefPubMedGoogle Scholar
  22. 22.
    Kim JM, Stewart R, Kim SY, Kang HJ, Jang JE, Kim SW, Shin IS, Park MH, Yoon JH, Park SW, Kim YH, Yoon JS (2013) A one year longitudinal study of cytokine genes and depression in breast cancer. J Affect Disord 148:57–65. CrossRefPubMedGoogle Scholar
  23. 23.
    Kober KM, Smoot B, Paul SM, Cooper BA, Levine JD, Miaskowski C (2016) Polymorphisms in cytokine genes are associated with higher levels of fatigue and lower levels of energy in women after breast cancer surgery. J Pain Symptom Manag 52:695–708 e694. CrossRefGoogle Scholar
  24. 24.
    Koleck TA, Bender CM, Sereika SM, Ahrendt G, Jankowitz RC, McGuire KP, Ryan CM, Conley YP (2014) Apolipoprotein E genotype and cognitive function in postmenopausal women with early-stage breast cancer. Oncol Nurs Forum 41:E313–E325. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Langford DJ, Paul SM, West CM, Dunn LB, Levine JD, Kober KM, Dodd MJ, Miaskowski C, Aouizerat BE (2015) Variations in potassium channel genes are associated with distinct trajectories of persistent breast pain after breast cancer surgery. Pain 156:371–380. CrossRefPubMedGoogle Scholar
  26. 26.
    Lengacher CA, Reich RR, Post-White J, Moscoso M, Shelton MM, Barta M, Le N, Budhrani P (2012) Mindfulness based stress reduction in post-treatment breast cancer patients: an examination of symptoms and symptom clusters. J Behav Med 35:86–94. CrossRefPubMedGoogle Scholar
  27. 27.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–e34. CrossRefPubMedGoogle Scholar
  28. 28.
    Lintermans A, Van Asten K, Jongen L, Van Brussel T, Laenen A, Verhaeghe J, Vanderschueren D, Lambrechts D, Neven P (2016) Genetic variant in the osteoprotegerin gene is associated with aromatase inhibitor-related musculoskeletal toxicity in breast cancer patients. Eur J Cancer 56:31–36. CrossRefPubMedGoogle Scholar
  29. 29.
    Little J, Higgins JP, Ioannidis JP, Moher D, Gagnon F, von Elm E, Khoury MJ, Cohen B, Davey-Smith G, Grimshaw J, Scheet P, Gwinn M, Williamson RE, Zou GY, Hutchings K, Johnson CY, Tait V, Wiens M, Golding J, van Duijn C, McLaughlin J, Paterson A, Wells G, Fortier I, Freedman M, Zecevic M, King R, Infante-Rivard C, Stewart AF, Birkett N (2009) Strengthening the Reporting of Genetic Association Studies (STREGA): an extension of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement. J Clin Epidemiol 62:597–608 e594. CrossRefPubMedGoogle Scholar
  30. 30.
    Mannisto PT, Kaakkola S (1999) Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev 51:593–628PubMedGoogle Scholar
  31. 31.
    Merriman JD, Aouizerat BE, Cataldo JK, Dunn L, Cooper BA, West C, Paul SM, Baggott CR, Dhruva A, Kober K, Langford DJ, Leutwyler H, Ritchie CS, Abrams G, Dodd M, Elboim C, Hamolsky D, Melisko M, Miaskowski C (2014) Association between an interleukin 1 receptor, type I promoter polymorphism and self-reported attentional function in women with breast cancer. Cytokine 65:192–201. CrossRefPubMedGoogle Scholar
  32. 32.
    Miaskowski C, Aouizerat BE (2012) Biomarkers: symptoms, survivorship, and quality of life. Semin Oncol Nurs 28:129–138. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Miaskowski C, Conley YP, Mastick J, Paul SM, Cooper BA, Levine JD, Knisely M, Kober KM (2017) Cytokine gene polymorphisms associated with symptom clusters in oncology patients undergoing radiation therapy. J Pain Symptom Manag 54:305–316 e303. CrossRefGoogle Scholar
  34. 34.
    Miaskowski C, Elboim C, Paul SM, Mastick J, Cooper BA, Levine JD, Aouizerat BE (2016) Polymorphisms in tumor necrosis factor-alpha are associated with higher anxiety levels in women after breast cancer surgery. Clin Breast Cancer 16:63–71 e63. CrossRefPubMedGoogle Scholar
  35. 35.
    Miclaus K, Wolfinger R, Vega S, Chierici M, Furlanello C, Lambert C, Hong H, Zhang L, Yin S, Goodsaid F (2010) Batch effects in the BRLMM genotype calling algorithm influence GWAS results for the Affymetrix 500K array. Pharmacogenomics J 10:336–346. CrossRefPubMedGoogle Scholar
  36. 36.
    Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R, Jemal A (2016) Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin 66:271–289CrossRefGoogle Scholar
  37. 37.
    Myers JS, Koleck TA, Sereika SM, Conley YP, Bender CM (2017) Perceived cognitive function for breast cancer survivors: association of genetic and behaviorally related variables for inflammation. Support Care Cancer 25:2475–2484. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Nasirinezhad F, Jergova S, Pearson JP, Sagen J (2015) Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy. Neuropharmacology 95:100–109. CrossRefPubMedGoogle Scholar
  39. 39.
    Ng T, Teo SM, Yeo HL, Shwe M, Gan YX, Cheung YT, Foo KM, Cham MT, Lee JA, Tan YP, Fan G, Yong WS, Preetha M, Loh WJ, Koo SL, Jain A, Lee GE, Wong M, Dent R, Yap YS, Ng R, Khor CC, Ho HK, Chan A (2016) Brain-derived neurotrophic factor genetic polymorphism (rs6265) is protective against chemotherapy-associated cognitive impairment in patients with early-stage breast cancer. Neuro-Oncology 18:244–251. CrossRefPubMedGoogle Scholar
  40. 40.
    Overholser BR, Foster DR (2011) Opioid pharmacokinetic drug-drug interactions. Am J Manag Care 17(Suppl 11):S276–S287PubMedGoogle Scholar
  41. 41.
    Pompanon F, Bonin A, Bellemain E, Taberlet P (2005) Genotyping errors: causes, consequences and solutions. Nat Rev Genet 6:847–859. CrossRefPubMedGoogle Scholar
  42. 42.
    Reyes-Gibby CC, Swartz MD, Yu X, Wu X, Yennurajalingam S, Anderson KO, Spitz MR, Shete S (2013) Symptom clusters of pain, depressed mood, and fatigue in lung cancer: assessing the role of cytokine genes. Support Care Cancer 21:3117–3125. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Saad S, Dunn LB, Koetters T, Dhruva A, Langford DJ, Merriman JD, West C, Paul SM, Cooper B, Cataldo J, Hamolsky D, Elboim C, Aouizerat BE, Miaskowski C (2014) Cytokine gene variations associated with subsyndromal depressive symptoms in patients with breast cancer. Eur J Oncol Nurs 18:397–404. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Schillani G, Era D, Cristante T, Mustacchi G, Richiardi M, Grassi L, Giraldi T (2012) 5-HTTLPR polymorphism and anxious preoccupation in early breast cancer patients. Radiol Oncol 46:321–327. CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Schreiber KL, Kehlet H, Belfer I, Edwards RR (2014) Predicting, preventing and managing persistent pain after breast cancer surgery: the importance of psychosocial factors. Pain Manag 4:445–459. CrossRefPubMedGoogle Scholar
  46. 46.
    Seruga B, Zhang H, Bernstein LJ, Tannock IF (2008) Cytokines and their relationship to the symptoms and outcome of cancer. Nat Rev Cancer 8:887–899. CrossRefPubMedGoogle Scholar
  47. 47.
    Small BJ, Rawson KS, Walsh E, Jim HS, Hughes TF, Iser L, Andrykowski MA, Jacobsen PB (2011) Catechol-O-methyltransferase genotype modulates cancer treatment-related cognitive deficits in breast cancer survivors. Cancer 117:1369–1376. CrossRefPubMedGoogle Scholar
  48. 48.
    Starkweather AR, Lyon DE, Elswick RK Jr, Montpetit AJ, Conley Y, McCain NL (2013) A conceptual model of psychoneurological symptom cluster variation in women with breast cancer: bringing nursing research to personalized medicine. Curr Pharmacogenomics Person Med 11:224–230. CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Stephens K, Cooper BA, West C, Paul SM, Baggott CR, Merriman JD, Dhruva A, Kober KM, Langford DJ, Leutwyler H, Luce JA, Schmidt BL, Abrams GM, Elboim C, Hamolsky D, Levine JD, Miaskowski C, Aouizerat BE (2014) Associations between cytokine gene variations and severe persistent breast pain in women following breast cancer surgery. J Pain 15:169–180. CrossRefPubMedGoogle Scholar
  50. 50.
    Stephens KE, Levine JD, Aouizerat BE, Paul SM, Abrams G, Conley YP, Miaskowski C (2017) Associations between genetic and epigenetic variations in cytokine genes and mild persistent breast pain in women following breast cancer surgery. Cytokine 99:203–213. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Syvanen AC (2001) Accessing genetic variation: genotyping single nucleotide polymorphisms. Nat Rev Genet 2:930–942CrossRefGoogle Scholar
  52. 52.
    Young EE, Kelly DL, Shim I, Baumbauer KM, Starkweather A, Lyon DE (2017) Variations in COMT and NTRK2 influence symptom burden in women undergoing breast cancer treatment. Biol Res Nurs 19:318–328. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Gee Su Yang
    • 1
    Email author
  • Sreelakshmy Kumar
    • 1
  • Susan G. Dorsey
    • 2
  • Angela R. Starkweather
    • 3
  • Debra Lynch Kelly
    • 1
  • Debra E. Lyon
    • 1
  1. 1.Department of Biobehavioral Nursing Science, College of NursingUniversity of FloridaGainesvilleUSA
  2. 2.Department of Pain and Translational Symptom Science, School of NursingUniversity of MarylandBaltimoreUSA
  3. 3.School of NursingUniversity of ConnecticutStorrsUSA

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