Cancer Causes & Control

, Volume 30, Issue 10, pp 1087–1100 | Cite as

Inherited alterations of TGF beta signaling components in Appalachian cervical cancers

  • Thomas J. KnoblochEmail author
  • Juan Peng
  • Erinn M. Hade
  • David E. Cohn
  • Mack T. RuffinIV
  • Michael A. Schiano
  • Byron C. Calhoun
  • William C. McBeeJr.
  • Jamie L. Lesnock
  • Holly H. Gallion
  • Jondavid Pollock
  • Bo Lu
  • Steve Oghumu
  • Zhaoxia Zhang
  • Marta T. Sears
  • Blessing E. Ogbemudia
  • Joseph T. Perrault
  • Logan C. Weghorst
  • Erin Strawser
  • Cecilia R. DeGraffinreid
  • Electra D. Paskett
  • Christopher M. Weghorst
Original Paper



This study examined targeted genomic variants of transforming growth factor beta (TGFB) signaling in Appalachian women. Appalachian women with cervical cancer were compared to healthy Appalachian counterparts to determine whether these polymorphic alleles were over-represented within this high-risk cancer population, and whether lifestyle or environmental factors modified the aggregate genetic risk in these Appalachian women.


Appalachian women’s survey data and blood samples from the Community Awareness, Resources, and Education (CARE) CARE I and CARE II studies (n = 163 invasive cervical cancer cases, 842 controls) were used to assess gene–environment interactions and cancer risk. Polymorphic allele frequencies and socio-behavioral demographic measurements were compared using t tests and χ2 tests. Multivariable logistic regression was used to evaluate interaction effects between genomic variance and demographic, behavioral, and environmental characteristics.


Several alleles demonstrated significant interaction with smoking (TP53 rs1042522, TGFB1 rs1800469), alcohol consumption (NQO1 rs1800566), and sexual intercourse before the age of 18 (TGFBR1 rs11466445, TGFBR1 rs7034462, TGFBR1 rs11568785). Interestingly, we noted a significant interaction between “Appalachian self-identity” variables and NQO1 rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1 rs1800469/TGFBR1 rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1 rs1800469/TGFBR1 rs7034462 model in subjects who had no sexual intercourse before age 18.


This study reports novel associations between common low-penetrance alleles in the TGFB signaling cascade and modified risk of cervical cancer in Appalachian women. Furthermore, our unexpected findings associating Appalachian identity and NQO1 rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancer patients represent an emerging avenue of scientific exploration.


Cervical cancer Gene–environment interaction Genetic association Polymorphic allele Appalachia 



The study was supported by grants from the National Institutes of Health’s National Cancer Institute (P50 CA105632, P30 CA016058) and National Center for Advancing Translational Science (UL1TR001070).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

10552_2019_1221_MOESM1_ESM.docx (47 kb)
Supplementary material 1 (DOCX 47 kb)
10552_2019_1221_MOESM2_ESM.docx (396 kb)
Supplementary material 2 (DOCX 395 kb)
10552_2019_1221_MOESM3_ESM.docx (179 kb)
Supplementary material 3 (DOCX 179 kb)


  1. 1.
    Ervik M, Lam F, Ferlay J, Mery L, Soerjomataram I, Bray F (2018) Cancer today. International Agency for Research on Cancer. Accessed Feb 2019
  2. 2.
    Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. CrossRefGoogle Scholar
  3. 3.
    Bray F, Ren J-S, Masuyer E, Ferlay J (2013) Global estimates of cancer prevalence for 27 sites in the adult population in 2008. Int J Cancer 132(5):1133–1145. CrossRefGoogle Scholar
  4. 4.
    Appalachian Community Cancer Network (2010) Addressing the cancer burden in Appalachian communitiesGoogle Scholar
  5. 5.
    Appalachian Regional Commission (2015) Appalachia then and now: examining changes to the Appalachian region since 1965Google Scholar
  6. 6.
    Appalachian Regional Commission (2019) Appalachian Regional Commission. Accessed Feb 2019
  7. 7.
    Behringer B, Friedell GH (2006) Appalachia: where place matters in health. Prev Chronic Dis. 3(4):A113Google Scholar
  8. 8.
    Behringer B, Friedell GH, Dorgan KA et al (2007) Understanding the challenges of reducing cancer in Appalachia: addressing a place-based health disparity population. Californian J Heal Promot Disparities Soc Justice. 5:40–49CrossRefGoogle Scholar
  9. 9.
    Wewers ME, Katz M, Fickle D, Paskett ED (2006) Risky behaviors among Ohio Appalachian adults. Prev Chronic Dis. 3(4):A127Google Scholar
  10. 10.
    Lengerich EJ, Tucker TC, Powell RK et al (2005) Cancer incidence in Kentucky, Pennsylvania, and West Virginia: disparities in Appalachia. J Rural Health. 21(1):39–47CrossRefGoogle Scholar
  11. 11.
    Pickup M, Novitskiy S, Moses HL (2013) The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 13(11):788–799. CrossRefGoogle Scholar
  12. 12.
    Pasche B, Pennison MJ, Jimenez H, Wang M (2014) TGFBR1 and cancer susceptibility. Trans Am Clin Climatol Assoc 125:300–312Google Scholar
  13. 13.
    Martelossi Cebinelli GC, Paiva Trugilo K, Badaró Garcia S, Brajão de Oliveira K (2016) TGF-β1 functional polymorphisms: a review. Eur Cytokine Netw 27(4):81–89. Google Scholar
  14. 14.
    Levovitz C, Chen D, Ivansson E, Gyllensten U, Finnigan JP, Alshawish S, Zhang W, Schadt EE, Posner MR, Genden EM, Boffetta P, Sikora AG (2014) TGFβ receptor 1: an immune susceptibility gene in HPV-associated cancer. Cancer Res 74(23):6833–6844. Epub 2014 Oct 1 CrossRefGoogle Scholar
  15. 15.
    Boone SD, Baumgartner KB, Baumgartner RN, Connor AE, Pinkston CM, John EM, Hines LM, Stern MC, Giuliano AR, Torres-Mejia G, Brock GN, Groves FD, Kerber RA, Wolff RK, Slattery ML (2013) Associations between genetic variants in the TGF-β signaling pathway and breast cancer risk among Hispanic and non-Hispanic white women. Breast Cancer Res Treat 141(2):287–297. (Epub 2013 Sep 14)CrossRefGoogle Scholar
  16. 16.
    Bellam N, Pasche B (2010) Tgf-beta signaling alterations and colon cancer. Cancer Treat Res 155:85–103. CrossRefGoogle Scholar
  17. 17.
    Di QG, Sun BH, Jiang MM, Du JF, Mai ZT, Zhang X, Zhou LR, Chi YM, Lv J (2017) Polymorphisms of -800G/A and +915G/C in TGF-β1 gene and lung cancer susceptibility. Oncol Lett. 14(1):733–736. (Epub 2017 May 16)CrossRefGoogle Scholar
  18. 18.
    Wan PQ, Wu JZ, Huang LY, Wu JL, Wei YH, Ning QY (2015) TGF-β1 polymorphisms and familial aggregation of liver cancer in Guangxi, China. Genet Mol Res 14(3):8147–8160. CrossRefGoogle Scholar
  19. 19.
    Shi Q, Wang X, Cai C, Yang S, Huo N, Liu H (2017) Association between TGF-β1 polymorphisms and head and neck cancer risk: a meta-analysis. Front Genet. 8:169. CrossRefGoogle Scholar
  20. 20.
    Hampras SS, Sucheston-Campbell LE, Cannioto R, Chang-Claude J, Modugno F, Dörk T, Hillemanns P, Preus L, Knutson KL, Wallace PK et al (2016) Assessment of variation in immunosuppressive pathway genes reveals TGFBR2 to be associated with risk of clear cell ovarian cancer. Oncotarget. 7(43):69097–69110. CrossRefGoogle Scholar
  21. 21.
    Yang L, Wang YJ, Zheng LY, Jia YM, Chen YL, Chen L, Liu DG, Li XH, Guo HY, Sun YL, Tian XX, Fang WG (2016) Genetic polymorphisms of TGFB1, TGFBR1, SNAI1 and TWIST1 are associated with endometrial cancer susceptibility in Chinese han women. PLoS ONE 11(5):e0155270. CrossRefGoogle Scholar
  22. 22.
    Singh H, Jain M, Mittal B (2009) Role of TGF-beta1 (-509C > T) promoter polymorphism in susceptibility to cervical cancer. Oncol Res 18(1):41–45CrossRefGoogle Scholar
  23. 23.
    Al-Harbi NM, Bin Judia SS, Mishra KN, Shoukri MM, Alsbeih GA (2017) Genetic predisposition to cervical cancer and the association with XRCC1 and TGFB1 polymorphisms. Int J Gynecol Cancer. 27(9):1949–1956. CrossRefGoogle Scholar
  24. 24.
    Gautam KA, Pooja S, Sankhwar SN, Sankhwar PL, Goel A, Rajender S (2015) c.29C > T polymorphism in the transforming growth factor-β1 (TGFB1) gene correlates with increased risk of urinary bladder cancer. Cytokine 75(2):344–348. CrossRefGoogle Scholar
  25. 25.
    Pasche B, Knobloch TJ, Bian Y et al (2005) Somatic acquisition and signaling of TGFBR1*6A in cancer. J Am Med Assoc 294(13):1634–1646. CrossRefGoogle Scholar
  26. 26.
    Zhang H-T, Zhao J, Zheng S-Y, Chen X-F (2005) Is TGFBR1 *6A really associated with increased risk of cancer? J Clin Oncol 23(30):7743–7744. CrossRefGoogle Scholar
  27. 27.
    Bian Y, Knobloch TJ, Sadim M et al (2007) Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development. Hum Mol Genet 16(24):3128–3135. CrossRefGoogle Scholar
  28. 28. community awareness, resources and education (CARE I): NCT02113514 (2018).
  29. 29. Community awareness, resources and education (CARE II): NCT01299714 (2018).
  30. 30.
    Reiter PL, Katz ML, Ruffin MT et al (2013) HPV prevalence among women from Appalachia: results from the CARE project. PLoS ONE 8(8):e74276. CrossRefGoogle Scholar
  31. 31.
    Weaver R (2016) Appalachia, USA: an empirical note and agenda for future research. J Rural Soc Sci. 31(1):23–52Google Scholar
  32. 32.
    Reiter PL, Katz ML, Ferketich AK, Ruffin MT, Paskett ED (2009) Appalachian self-identity among women in Ohio appalachia. J Rural Commun Psychol E12(1)Google Scholar
  33. 33.
    Wilson RJ, Ryerson AB, Singh SD, King JB (2016) Cancer incidence in Appalachia, 2004–2011. Cancer Epidemiol Biomarkers Prev 25(2):250–258. CrossRefGoogle Scholar
  34. 34.
    Erichsen HC, Chanock SJ (2004) SNPs in cancer research and treatment. Br J Cancer 90(4):747–751. CrossRefGoogle Scholar
  35. 35.
    Guengerich FP (1998) The environmental genome project: functional analysis of polymorphisms. Environ Health Perspect 106(7):365–368CrossRefGoogle Scholar
  36. 36.
    dbSNP: database for short genetic variations scope and access searching for and displaying SNP recordsGoogle Scholar
  37. 37.
    Silverman ES, Palmer LJ, Subramaniam V et al (2004) Transforming growth factor-β 1 promoter polymorphism C–509T Is associated with asthma. Am J Respir Crit Care Med 169(2):214–219. CrossRefGoogle Scholar
  38. 38.
    Afify RAA, Salama N (2013) Correlation of transforming growth factor beta-1 gene polymorphisms C-509T and aplastic anemia. Comp Clin Path. 22(4):755–760. CrossRefGoogle Scholar
  39. 39.
    Grainger DJ, Heathcote K, Chiano M et al (1999) Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 8(1):93–97CrossRefGoogle Scholar
  40. 40.
    Jin G, Wang L, Chen W et al (2007) Variant alleles of TGFB1 and TGFBR2 are associated with a decreased risk of gastric cancer in a Chinese population. Int J Cancer 120(6):1330–1335. CrossRefGoogle Scholar
  41. 41.
    García-Rocha R, Moreno-Lafont M, Mora-García ML et al (2015) Mesenchymal stromal cells derived from cervical cancer tumors induce TGF-β1 expression and IL-10 expression and secretion in the cervical cancer cells, resulting in protection from cytotoxic T cell activity. Cytokine 76(2):382–390. CrossRefGoogle Scholar
  42. 42.
    Lane DP (1992) p53, guardian of the genome. Nature 358(6381):15–16. CrossRefGoogle Scholar
  43. 43.
    Gracy G, Sadhna K, Jacqueline J, Deepika K (2014) Highlights of p53 mutation and it’s role in cervical cancer metastasis. Int J Biol Med Res 5(1):3772–3779Google Scholar
  44. 44.
    Chen R, Liu S, Ye H et al (2015) Association of p53 rs1042522, MDM2 rs2279744 and p21 rs1801270 polymorphisms with retinoblastoma risk and invasion in a Chinese population. Sci Rep. 5(1):13300. CrossRefGoogle Scholar
  45. 45.
    Jee SH, Won SY, Yun JE, Lee JE, Park JS, Ji SS (2004) Polymorphism p53 codon-72 and invasive cervical cancer: a meta-analysis. Int J Gynecol Obstet. 85(3):301–308. CrossRefGoogle Scholar
  46. 46.
    Klug SJ, Ressing M, Koenig J et al (2009) TP53 codon 72 polymorphism and cervical cancer: a pooled analysis of individual data from 49 studies. Lancet Oncol. 10(8):772–784. CrossRefGoogle Scholar
  47. 47.
    Stumbar SE, Stevens M, Feld Z (2019) Cervical cancer and its precursors: a preventative approach to screening, diagnosis, and management. Prim Care 46(1):117–134. (Epub 2018 Dec 22)CrossRefGoogle Scholar
  48. 48.
    Wang X, Huang X, Zhang Y (2018) Involvement of human papillomaviruses in cervical cancer. Front Microbiol. 9:2896. CrossRefGoogle Scholar
  49. 49.
    Khani Y, Pourgholam-Amiji N, Afshar M, Otroshi O, Sharifi-Esfahani M, Sadeghi-Gandomani H, Vejdani M, Salehiniya H (2018) Tobacco smoking and cancer types: a review. Biomed Res Ther 5(4):2142–2159. CrossRefGoogle Scholar
  50. 50.
    Johnson CA, James D, Marzan A, Armaos M (2019) Cervical cancer: an overview of pathophysiology and management. Semin Oncol Nurs. Google Scholar
  51. 51.
    Su B, Qin W, Xue F, Wei X, Guan Q, Jiang W, Wang S, Xu M, Yu S (2018) The relation of passive smoking with cervical cancer: a systematic review and meta-analysis. Medicine 97(46):e13061. CrossRefGoogle Scholar
  52. 52.
    Collins S, Rollason TP, Young LS, Woodman CB (2010) Cigarette smoking is an independent risk factor for cervical intraepithelial neoplasia in young women: a longitudinal study. Eur J Cancer 46(2):405–411. (Epub 2009 Oct 12)CrossRefGoogle Scholar
  53. 53.
    International Agency for Research on Cancer (2012) IARC monographs on the evaluation of carcinogenic risks to humans. Personal habits and indoor combustions: tobacco smoking, vol 100E. IARC, LyonGoogle Scholar
  54. 54.
    Fonseca-Moutinho JA (2011) Smoking and cervical cancer. ISRN Obstet Gynecol. 2011:1–6. CrossRefGoogle Scholar
  55. 55.
    Hecht SS (2014) It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco. Cancer Prev Res. 7(7):639–647. CrossRefGoogle Scholar
  56. 56.
    Xue J, Yang S, Seng S (2014) Mechanisms of cancer induction by tobacco-specific NNK and NNN. Cancer 6(2):1138–1156CrossRefGoogle Scholar
  57. 57.
    Wieringa HW, van der Zee AG, de Vries EG, van Vugt MA (2016) Breaking the DNA damage response to improve cervical cancer treatment. Cancer Treat Rev 42:30–40. (Epub 2015 Nov 24)CrossRefGoogle Scholar
  58. 58.
    Plummer M, Herrero R, Franceschi S et al (2003) Smoking and cervical cancer: pooled analysis of the IARC multi-centric case–control study. Cancer Causes Control 14(9):805–814CrossRefGoogle Scholar
  59. 59.
    Gibson G (2012) Rare and common variants: twenty arguments. Nat Rev Genet 13(2):135–145. CrossRefGoogle Scholar
  60. 60.
    Saint Pierre A, Génin E (2014) How important are rare variants in common disease? Brief Funct Genomics. 13(5):353–361. CrossRefGoogle Scholar
  61. 61.
    Woychik R (2014) Where exposure science and citizen science meet. Research Triangle Environmental Health Collaborative. Environ Heal Summit @BULLET Recomm from Res Triangle Environ Heal Collab Environ Heal SummitGoogle Scholar
  62. 62.
    Langston MA, Levine RS, Kilbourne BJ et al (2014) Scalable combinatorial tools for health disparities research. Int J Environ Res Public Health. 11(10):10419–10443. CrossRefGoogle Scholar
  63. 63.
    Juarez PD, Matthews-Juarez P, Hood DB et al (2014) The public health exposome: a population-based, exposure science approach to health disparities research. Int J Environ Res Public Health. 11(12):12866–12895. CrossRefGoogle Scholar
  64. 64.
    U.S. Department of Health and Human Services (USDHHS), National Institute of Health (NIH) NI of EHS (NIEHS) (2017) Advancing science, improving health: a plan for environmental health research. NIEHS 2012–2017. Accessed 25 Jun 2018
  65. 65.
    Post DM, Gehlert S, Hade EM, Reiter PL, Ruffin M, Paskett ED (2013) Depression and SES in women from Appalachia. J Rural Ment Heal. 37(1):2–15. CrossRefGoogle Scholar
  66. 66.
    Oyana TJ, Matthews-Juarez P, Cormier SA, Xu X, Juarez PD (2015) Using an external exposome framework to examine pregnancy-related morbidities and mortalities: implications for health disparities research. Int J Environ Res Public Health. 13(1):ijerph13010013. CrossRefGoogle Scholar
  67. 67.
    Schootman M, Gomez SL, Henry KA et al (2017) Geospatial approaches to cancer control and population sciences. Cancer Epidemiol Biomark Prev 26(4):472–475. CrossRefGoogle Scholar
  68. 68.
    Korycinski RW, Tennant BL, Cawley MA, Bloodgood B, Oh AY, Berrigan D (2018) Geospatial approaches to cancer control and population sciences at the United States cancer centers. Cancer Causes Control 29(3):371–377. CrossRefGoogle Scholar
  69. 69.
    Smith BE (2015) Representing Appalachia: the impossible necessity of Appalachian studies. In: Berry C, Obermiller PJ, Scott SL (eds) Studying Appalachian studies: making the path by walking. University of Illinois Press, Urbana, ILGoogle Scholar
  70. 70.
    Yang S, Jin T, Su H-X et al (2015) The association between NQO1 Pro187Ser polymorphism and bladder cancer susceptibility: a meta-analysis of 15 studies. PLoS ONE 10(1):e0116500. CrossRefGoogle Scholar
  71. 71.
    Yu H, Liu H, Wang L-E, Wei Q (2012) A functional NQO1 609C > T polymorphism and risk of gastrointestinal cancers: a meta-analysis. PLoS ONE 7(1):e30566. CrossRefGoogle Scholar
  72. 72.
    Oh E-T, Park HJ (2015) Implications of NQO1 in cancer therapy. BMB Rep. 48(11):609–617CrossRefGoogle Scholar
  73. 73.
    Atia A, Alrawaiq N, Abdullah A (2014) A review of NAD(P)H: quinone oxidoreductase 1 (NQO1); a multifunctional antioxidant enzyme. J Appl Pharm Sci. 4(12):118–122. Google Scholar
  74. 74.
    Peng Q, Lu Y, Lao X et al (2014) The NQO1 Pro187Ser polymorphism and breast cancer susceptibility: evidence from an updated meta-analysis. Diagn Pathol. 9(1):100. CrossRefGoogle Scholar
  75. 75.
    Asher G, Lotem J, Sachs L, Kahana C, Shaul Y (2002) Mdm-2 and ubiquitin-independent p53 proteasomal degradation regulated by NQO1. Proc Natl Acad Sci USA 99(20):13125–13130. CrossRefGoogle Scholar
  76. 76.
    Asher G, Lotem J, Kama R, Sachs L, Shaul Y (2002) NQO1 stabilizes p53 through a distinct pathway. Proc Natl Acad Sci USA 99(5):3099–3104. CrossRefGoogle Scholar
  77. 77.
    Vrijheid M (2014) The exposome: a new paradigm to study the impact of environment on health. Thorax 69(9):876–878. CrossRefGoogle Scholar
  78. 78.
    Wild CP, Scalbert A, Herceg Z (2013) Measuring the exposome: a powerful basis for evaluating environmental exposures and cancer risk. Environ Mol Mutagen 54(7):480–499. CrossRefGoogle Scholar
  79. 79.
    Hu X, Zhang Z, Ma D, Huettner PC, Massad LS, Nguyen L, Borecki I, Rader JS (2010) TP53, MDM2, NQO1, and susceptibility to cervical cancer. Cancer Epidemiol Biomark Prev 19(3):755–761. (Epub 2010 Mar 3)CrossRefGoogle Scholar
  80. 80.
    Radloff LS (1977) The CES-D scale. Appl Psychol Meas 1(3):385–401. CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Thomas J. Knobloch
    • 1
    • 11
    Email author
  • Juan Peng
    • 2
  • Erinn M. Hade
    • 2
  • David E. Cohn
    • 3
    • 11
  • Mack T. RuffinIV
    • 4
  • Michael A. Schiano
    • 5
    • 6
  • Byron C. Calhoun
    • 5
    • 6
  • William C. McBeeJr.
    • 7
  • Jamie L. Lesnock
    • 7
  • Holly H. Gallion
    • 8
  • Jondavid Pollock
    • 9
  • Bo Lu
    • 1
  • Steve Oghumu
    • 1
    • 11
  • Zhaoxia Zhang
    • 1
  • Marta T. Sears
    • 1
  • Blessing E. Ogbemudia
    • 1
  • Joseph T. Perrault
    • 10
  • Logan C. Weghorst
    • 1
  • Erin Strawser
    • 1
  • Cecilia R. DeGraffinreid
    • 10
  • Electra D. Paskett
    • 1
    • 10
    • 11
  • Christopher M. Weghorst
    • 1
    • 11
  1. 1.College of Public HealthThe Ohio State UniversityColumbusUSA
  2. 2.Department of Biomedical Informatics, Center for Biostatistics, College of MedicineThe Ohio State UniversityColumbusUSA
  3. 3.Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wexner Medical Center, College of MedicineThe Ohio State University ColumbusColumbusUSA
  4. 4.Department of Family and Community Medicine, Milton S. Hershey Medical CenterPenn State UniversityHerseyUSA
  5. 5.Department of Obstetrics & GynecologyWest Virginia UniversityCharlestonUSA
  6. 6.Charleston Area Medical Center Health SystemCharlestonUSA
  7. 7.Mon General Health SystemMorgantownUSA
  8. 8.Pikeville Medical CenterPikevilleUSA
  9. 9.Wheeling HospitalSchiffler Cancer CenterWheelingUSA
  10. 10.Division of Cancer Prevention and Control, Wexner Medical Center, College of MedicineThe Ohio State University ColumbusColumbusUSA
  11. 11.The Ohio State University Comprehensive Cancer CenterColumbusUSA

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