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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

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.

Keywords

Cervical cancer Gene–environment interaction Genetic association Polymorphic allele Appalachia 

Notes

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).

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)

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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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