Abstract B57: Inherited alterations of Transforming Growth Factor Beta signaling components in Appalachian Cervical Cancers
Authors: Knobloch Thomas J. , Oghumu Steve , Sears Marta , Zhang Zhaoxia , Ogbemudia Blessing , Perrault Joe , Cohn David , DeGraffinreid Cecilia R. , Lu Bo , Peng Juan , Hade Erinn M. , Schiano Michael A. , Calhoun Byron C. , McBee William , Lesnock Jamie , Gallion Holly , Pollock Jondavid , Ruffin Mack T. , Weghorst Christopher M. , Paskett Electra D. 
Published: March 2017

Abstract
Introduction: Invasive cancer of the uterine cervix (ICC) is a leading cause of cancer death in women worldwide. ICC incidence and mortality rates are especially high among women from Appalachia. In addition to lifestyle and social-behavioral factors and HPV infections, hereditary predispositions may mediate cervical cancer risk. Polymorphic alleles within the Transforming Growth Factor Beta (TGFB) signaling cascade, an important regulator of epithelial cell growth, have been implicated in modifying cancer susceptibility. The contributions of these factors within a gene-environment model have not been well characterized in Appalachian ICC patients. Hypothesis: High-risk genomic variants of TGFB signaling pathway components will be overrepresented in Appalachian women diagnosed with ICC compared to their healthy Appalachian counterparts. Methods: A case-control study was conducted with 163 cases, women diagnosed with ICC, and 842 controls, women with normal Pap tests from Appalachia Ohio, West Virginia, and Kentucky. Inclusion criteria were (i) women residing in Appalachian counties who were ≥18 years, (ii) spoke English, (ii) not cognitively impaired, (iii) able to provide informed consent. Three distinct groups were considered, representing (i) prevalent invasive cervical cancer cases, (ii) newly diagnosed invasive cervical cancer cases, and (iii) healthy controls. Targeted genomic variance analysis of 9 SNPs (rs1800469, rs1800470, rs3917200, rs7034462, rs11568785, rs868, rs1042522, rs750749, rs1800566) and a polymorphic repeat variant was conducted on blood DNA. Behavioral and environmental factors were collected using a comprehensive, self-administered questionnaire completed at the time of enrollment. Characteristics between cases and controls were compared by a two sample t-test, assuming unequal variance for continuous variables and by Fisher's exact test for categorical variables. Associations between disease status, polymorphism and behavioral or environmental characteristics were estimated via multivariable logistic regression. Results: Never smokers with TGFB1 rs1800469 overdominant allele types A/A-G/G had 0.4 (95% CI: 0.22-0.73, p=0.003) times the odds of cervical cancer compared to never smokers with A/G genotype. This effect was not observed in ever smokers (interaction p=0.02). While there was a suggestion of an increased risk of cervical cancer for never smokers with TGFB1 rs1800469 recessive A/G-A/A genotypes compared to G/G non9A genotype CD83 dominant T/T compared to C/C-C/T, or overdominant C/C -T/T compared to C/T alleles, there were no strong interaction effects identified. The effect of dominant TP53 rs1042522 allele type (C/C C/G versus G/G) differed by smoking status. There was a significant 3-fold increase in the odds of cervical cancer (aOR: 3.1, 95% CI: 1.1-8.5, p=0.03) for never smokers with TP53 rs1042522 G/G compared to never smokers with C/C-C/G genotypes. A similar increase was not observed in ever-smokers (smoking status by genotype interaction effect p=0.02). In codominant types, there was a similar increased adjusted odds (aOR: 3.65, 95% CI: 1.21-11.0, p=0.021) of cervical cancer for never smokers with G/G genotypes compared to never smokers with C/G genotypes. This effect was not observed in ever smokers (interaction effect p=0.06). Conclusions: Genetic susceptibility may contribute to the overall cervical cancer risk associated with the Appalachian population, especially among non-smokers. Inclusion of additional demographic and social-behavioral features, as well as other genetic events, may further define this evolving cervical cancer risk model.
Citation Format: Thomas J. Knobloch, Steve Oghumu, Marta Sears, Zhaoxia Zhang, Blessing Ogbemudia, Joe Perrault, David Cohn, Cecilia R. DeGraffinreid, Bo Lu, Juan Peng, Erinn M. Hade, Michael A. Schiano, Byron C. Calhoun, William McBee, Jr., Jamie Lesnock, Holly Gallion, Jondavid Pollock, Mack T. Ruffin, IV, Christopher M. Weghorst, Electra D. Paskett. Inherited alterations of Transforming Growth Factor Beta signaling components in Appalachian Cervical Cancers. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B57.