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Inherited alterations of TGF beta signaling components in Appalachian cervical cancers

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Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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References

  1. Ervik M, Lam F, Ferlay J, Mery L, Soerjomataram I, Bray F (2018) Cancer today. International Agency for Research on Cancer. http://gco.iarc.fr/today/home. Accessed Feb 2019

  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. https://doi.org/10.1002/ijc.29210

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1002/ijc.27711

    Article  CAS  Google Scholar 

  4. Appalachian Community Cancer Network (2010) Addressing the cancer burden in Appalachian communities

  5. Appalachian Regional Commission (2015) Appalachia then and now: examining changes to the Appalachian region since 1965

  6. Appalachian Regional Commission (2019) Appalachian Regional Commission. https://www.arc.gov/index.asp. Accessed Feb 2019

  7. Behringer B, Friedell GH (2006) Appalachia: where place matters in health. Prev Chronic Dis. 3(4):A113

    PubMed  PubMed Central  Google Scholar 

  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. 5:40–49

    Article  Google Scholar 

  9. Wewers ME, Katz M, Fickle D, Paskett ED (2006) Risky behaviors among Ohio Appalachian adults. Prev Chronic Dis. 3(4):A127

    PubMed  PubMed Central  Google Scholar 

  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):39–47

    Article  PubMed  Google Scholar 

  11. Pickup M, Novitskiy S, Moses HL (2013) The roles of TGFβ in the tumour microenvironment. Nat Rev Cancer 13(11):788–799. https://doi.org/10.1038/nrc3603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pasche B, Pennison MJ, Jimenez H, Wang M (2014) TGFBR1 and cancer susceptibility. Trans Am Clin Climatol Assoc 125:300–312

    PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1684/ecn.2016.0382

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/0008-5472.CAN-14-0602-T Epub 2014 Oct 1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s10549-013-2690-z (Epub 2013 Sep 14)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bellam N, Pasche B (2010) Tgf-beta signaling alterations and colon cancer. Cancer Treat Res 155:85–103. https://doi.org/10.1007/978-1-4419-6033-7_5

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.3892/ol.2017.6173 (Epub 2017 May 16)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.4238/2015.July.27.3

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.3389/fgene.2017.00169

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.18632/oncotarget.10215

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0155270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):41–45

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1097/IGC.0000000000001103

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cyto.2015.05.017

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1001/jama.294.13.1634

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1200/JCO.2005.02.9108

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1093/hmg/ddm274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. ClinicalTrials.gov. community awareness, resources and education (CARE I): NCT02113514 (2018). https://www.clinicaltrials.gov/ct2/show/NCT02113514.

  29. ClinicalTrials.gov. Community awareness, resources and education (CARE II): NCT01299714 (2018). https://www.clinicaltrials.gov/ct2/show/NCT01299714.

  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. https://doi.org/10.1371/journal.pone.0074276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Weaver R (2016) Appalachia, USA: an empirical note and agenda for future research. J Rural Soc Sci. 31(1):23–52

    Google Scholar 

  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)

  33. Wilson RJ, Ryerson AB, Singh SD, King JB (2016) Cancer incidence in Appalachia, 2004–2011. Cancer Epidemiol Biomarkers Prev 25(2):250–258. https://doi.org/10.1158/1055-9965.EPI-15-0946

    Article  PubMed  PubMed Central  Google Scholar 

  34. Erichsen HC, Chanock SJ (2004) SNPs in cancer research and treatment. Br J Cancer 90(4):747–751. https://doi.org/10.1038/sj.bjc.6601574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Guengerich FP (1998) The environmental genome project: functional analysis of polymorphisms. Environ Health Perspect 106(7):365–368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. dbSNP: database for short genetic variations scope and access searching for and displaying SNP records

  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. https://doi.org/10.1164/rccm.200307-973OC

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00580-012-1478-6

    Article  CAS  Google Scholar 

  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):93–97

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1002/ijc.22443

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cyto.2015.09.001

    Article  CAS  PubMed  Google Scholar 

  42. Lane DP (1992) p53, guardian of the genome. Nature 358(6381):15–16. https://doi.org/10.1038/358015a0

    Article  CAS  PubMed  Google Scholar 

  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):3772–3779

    Google Scholar 

  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. https://doi.org/10.1038/srep13300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.ijgo.2003.08.017

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/S1470-2045(09)70187-1

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.pop.2018.10.011 (Epub 2018 Dec 22)

    Article  PubMed  Google Scholar 

  48. Wang X, Huang X, Zhang Y (2018) Involvement of human papillomaviruses in cervical cancer. Front Microbiol. 9:2896. https://doi.org/10.3389/fmicb.2018.02896

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.15419/bmrat.v5i4.428

    Article  Google Scholar 

  50. Johnson CA, James D, Marzan A, Armaos M (2019) Cervical cancer: an overview of pathophysiology and management. Semin Oncol Nurs. https://doi.org/10.1016/j.soncn.2019.02.003

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1097/MD.0000000000013061

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.ejca.2009.09.015 (Epub 2009 Oct 12)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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, Lyon

    Google Scholar 

  54. Fonseca-Moutinho JA (2011) Smoking and cervical cancer. ISRN Obstet Gynecol. 2011:1–6. https://doi.org/10.5402/2011/847684

    Article  Google Scholar 

  55. Hecht SS (2014) It is time to regulate carcinogenic tobacco-specific nitrosamines in cigarette tobacco. Cancer Prev Res. 7(7):639–647. https://doi.org/10.1158/1940-6207.CAPR-14-0095

    Article  CAS  Google Scholar 

  56. Xue J, Yang S, Seng S (2014) Mechanisms of cancer induction by tobacco-specific NNK and NNN. Cancer 6(2):1138–1156

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1016/j.ctrv.2015.11.008 (Epub 2015 Nov 24)

    Article  PubMed  Google Scholar 

  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):805–814

    Article  PubMed  Google Scholar 

  59. Gibson G (2012) Rare and common variants: twenty arguments. Nat Rev Genet 13(2):135–145. https://doi.org/10.1038/nrg3118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Saint Pierre A, Génin E (2014) How important are rare variants in common disease? Brief Funct Genomics. 13(5):353–361. https://doi.org/10.1093/bfgp/elu025

    Article  PubMed  Google Scholar 

  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 Summit

  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. https://doi.org/10.3390/ijerph111010419

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.3390/ijerph111212866

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://www.niehs.nih.gov/about/strategicplan/strategicplan2012/index.cfm. Accessed 25 Jun 2018

  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. https://doi.org/10.1037/rmh0000001

    Article  Google Scholar 

  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. https://doi.org/10.3390/ijerph13010013

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/1055-9965.EPI-17-0104

    Article  Google Scholar 

  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. https://doi.org/10.1007/s10552-018-1009-0

    Article  PubMed  PubMed Central  Google Scholar 

  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, IL

    Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0116500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0030566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Oh E-T, Park HJ (2015) Implications of NQO1 in cancer therapy. BMB Rep. 48(11):609–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.7324/JAPS.2014.41220

    Article  Google Scholar 

  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. https://doi.org/10.1186/1746-1596-9-100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1073/pnas.202480499

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1073/pnas.052706799

    Article  CAS  PubMed  Google Scholar 

  77. Vrijheid M (2014) The exposome: a new paradigm to study the impact of environment on health. Thorax 69(9):876–878. https://doi.org/10.1136/thoraxjnl-2013-204949

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1002/em.21777

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1158/1055-9965.EPI-09-0886 (Epub 2010 Mar 3)

    Article  CAS  Google Scholar 

  80. Radloff LS (1977) The CES-D scale. Appl Psychol Meas 1(3):385–401. https://doi.org/10.1177/014662167700100306

    Article  Google Scholar 

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Acknowledgments

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).

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Knobloch, T.J., Peng, J., Hade, E.M. et al. Inherited alterations of TGF beta signaling components in Appalachian cervical cancers. Cancer Causes Control 30, 1087–1100 (2019). https://doi.org/10.1007/s10552-019-01221-y

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