Thomas J Knobloch1,2, Juan Peng3, Erinn M Hade3, David E Cohn4,5, Mack T Ruffin6, Michael A Schiano7,8, Byron C Calhoun7,8, William C McBee9, Jamie L Lesnock9, Holly H Gallion10, Jondavid Pollock11, Bo Lu12, Steve Oghumu12,5, Zhaoxia Zhang12, Marta T Sears12, Blessing E Ogbemudia12, Joseph T Perrault13, Logan C Weghorst12, Erin Strawser12, Cecilia R DeGraffinreid13, Electra D Paskett12,13,5, Christopher M Weghorst12,5. 1. College of Public Health, The Ohio State University, Columbus, OH, 43210, USA. knobloch.1@osu.edu. 2. The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA. knobloch.1@osu.edu. 3. Department of Biomedical Informatics, Center for Biostatistics, College of Medicine, The Ohio State University, Columbus, OH, 43210, USA. 4. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Wexner Medical Center, College of Medicine, The Ohio State University Columbus, Columbus, OH, 43210, USA. 5. The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA. 6. Department of Family and Community Medicine, Milton S. Hershey Medical Center, Penn State University, Hersey, PA, 17033, USA. 7. Department of Obstetrics & Gynecology, West Virginia University, Charleston, WV, 26505, USA. 8. Charleston Area Medical Center Health System, Charleston, WV, 25302, USA. 9. Mon General Health System, Morgantown, WV, 26505, USA. 10. Pikeville Medical Center, Pikeville, KY, 41501, USA. 11. Wheeling Hospital, Schiffler Cancer Center, Wheeling, WV, 26003, USA. 12. College of Public Health, The Ohio State University, Columbus, OH, 43210, USA. 13. Division of Cancer Prevention and Control, Wexner Medical Center, College of Medicine, The Ohio State University Columbus, Columbus, OH, 43210, USA.
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.
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 (TP53rs1042522, TGFB1rs1800469), alcohol consumption (NQO1rs1800566), and sexual intercourse before the age of 18 (TGFBR1rs11466445, TGFBR1rs7034462, TGFBR1rs11568785). Interestingly, we noted a significant interaction between "Appalachian self-identity" variables and NQO1rs1800566. Multivariable logistic regression of cancer status in an over-dominant TGFB1rs1800469/TGFBR1rs11568785 model demonstrated a 3.03-fold reduction in cervical cancer odds. Similar decreased odds (2.78-fold) were observed in an over-dominant TGFB1rs1800469/TGFBR1rs7034462 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 NQO1rs1800566 suggests that the complex environmental exposures that contribute to Appalachian self-identity in Appalachian cervical cancerpatients represent an emerging avenue of scientific exploration.
Authors: Boris Pasche; Thomas J Knobloch; Yansong Bian; Junjian Liu; Sharbani Phukan; Diana Rosman; Virginia Kaklamani; Lisa Baddi; Farida S Siddiqui; Wendy Frankel; Thomas W Prior; David E Schuller; Amit Agrawal; Jas Lang; M Eileen Dolan; Everett E Vokes; William S Lane; Chiang-Ching Huang; Trinidad Caldes; Antonio Di Cristofano; Heather Hampel; IngMarie Nilsson; Gunnar von Heijne; Riccardo Fodde; V V V S Murty; Albert de la Chapelle; Christopher M Weghorst Journal: JAMA Date: 2005-10-05 Impact factor: 56.272
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