Translating Gene-Calcium Interactions to Precision Medicine for Colorectal Cancer

The study design is case/control, where the cases are participants with colorectal adenoma, and the controls are colonoscopy-confirmed to be adenoma free.]]>
Despite a reduction in both incidence and mortality of colorectal cancer (CRC), partially due to rapidly increased use of endoscopy, CRC still remains the 4th most common incident cancer and the 2nd most common cause of cancer death in the United States. Thus, it is critical to develop new primary prevention strategies. High consumption of calcium (Ca) has been linked to reduced risks of colorectal adenoma and CRC, however, results have been inconsistent. NKCC2, encoded by SLC12A1, is the direct downstream effector of ROMK encoded by KCNJ1. Both NKCC2 and ROMK serve as driving forces for reabsorption of Ca and magnesium (Mg). Our previous studies showed that the corresponding reduction in risk with advanced or multiple adenomas was 89% among those with variant alleles in both genes (KCNJ1 and SLC12A1). A large portion (38%) of the US population has at least 1 variant allele in any 2 of 3 genes (KCNJ1, SLC12A1 and SLC8A1), among whom high Ca intake was associated with a 70% reduced adenoma risk. However, we only examined tagging SNPs in these three genes with a minor allele frequency (MAF) ≥ 5%; rare mutations in these genes are causally linked to diseases with Ca homeostasis dysfunction. It is unknown if these interactions are associated with incident CRC or adenoma recurrence or confer additional protection in individuals receiving endoscopic screenings. We propose to conduct targeted deep resequencing in these 3 genes to unravel functional variants and identify new rare variants and then prospectively evaluate if Ca-gene interactions affect different stages of carcinogenesis, confer protection beyond endoscopic screening, and discover the underlying mechanism(s) for these interactions. PLCO provides a very unique and unparalleled opportunity to prospectively examine these hypotheses. This study will be essential for translating these novel findings to personalized prevention strategies for CRC by identifying high risk populations, thus, maximizing the benefits and minimizing potential adverse effects (advanced and fatal prostate cancer, kidney stones, and myocardial infarction) associated with high Ca intake.]]>