Synergistic Effects of Genetic Variants of Glucose Homeostasis and Lifelong Exposures to Cigarette Smoking, Female Hormones, and Dietary Fat Intake on Primary Colorectal Cancer Development in African and Hispanic/Latino American Women

Su Yon Jung; Eric M Sobel; Matteo Pellegrini; Herbert Yu; Jeanette C Papp

doi:10.3389/fonc.2021.760243

Synergistic Effects of Genetic Variants of Glucose Homeostasis and Lifelong Exposures to Cigarette Smoking, Female Hormones, and Dietary Fat Intake on Primary Colorectal Cancer Development in African and Hispanic/Latino American Women

Front Oncol. 2021 Oct 7:11:760243. doi: 10.3389/fonc.2021.760243. eCollection 2021.

Authors

Su Yon Jung¹, Eric M Sobel^{2

3}, Matteo Pellegrini⁴, Herbert Yu⁵, Jeanette C Papp²

Affiliations

¹ Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, Los Angeles, CA, United States.
² Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
³ Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.
⁴ Department of Molecular, Cell and Developmental Biology, Life Sciences Division, University of California, Los Angeles, Los Angeles, CA, United States.
⁵ Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, United States.

Abstract

Background: Disparities in cancer genomic science exist among racial/ethnic minorities. Particularly, African American (AA) and Hispanic/Latino American (HA) women, the 2 largest minorities, are underrepresented in genetic/genome-wide studies for cancers and their risk factors. We conducted on AA and HA postmenopausal women a genomic study for insulin resistance (IR), the main biologic mechanism underlying colorectal cancer (CRC) carcinogenesis owing to obesity.

Methods: With 780 genome-wide IR-specific single-nucleotide polymorphisms (SNPs) among 4,692 AA and 1,986 HA women, we constructed a CRC-risk prediction model. Along with these SNPs, we incorporated CRC-associated lifestyles in the model of each group and detected the topmost influential genetic and lifestyle factors. Further, we estimated the attributable risk of the topmost risk factors shared by the groups to explore potential factors that differentiate CRC risk between these groups.

Results: In both groups, we detected IR-SNPs in PCSK1 (in AA) and IFT172, GCKR, and NRBP1 (in HA) and risk lifestyles, including long lifetime exposures to cigarette smoking and endogenous female hormones and daily intake of polyunsaturated fatty acids (PFA), as the topmost predictive variables for CRC risk. Combinations of those top genetic- and lifestyle-markers synergistically increased CRC risk. Of those risk factors, dietary PFA intake and long lifetime exposure to female hormones may play a key role in mediating racial disparity of CRC incidence between AA and HA women.

Conclusions: Our results may improve CRC risk prediction performance in those medically/scientifically underrepresented groups and lead to the development of genetically informed interventions for cancer prevention and therapeutic effort, thus contributing to reduced cancer disparities in those minority subpopulations.

Keywords: African and Hispanic/Latino American women; attributable risk; colorectal cancer; endogenous estrogen; glucose homeostasis; polyunsaturated fatty acid; random survival forest; smoking.

Abstract

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