Project Abstract The incidence of colorectal cancer in young adults under age 50 (referred to as early onset colorectal cancer [eoCRC]) has been rising by a striking 2% per year in the United States since the 1990s. Even more notably, a significant increase in eoCRC is experienced by every 5-year age group from as young as age 20 years. The accompanying human toll should not be understated considering the mirroring rise of deaths due to eoCRC, and the loss in quality of life given that most eoCRC are diagnosed at advanced stages. Despite urgent needs to interrupt this trajectory, factors responsible for the rise of eoCRC are unknown, rendering the development of effective cancer control strategies difficult. This study seeks to shed light on eoCRC risk factors that may contribute to the rising incidence of this disease, directly addressing Provocative Question1 from RFA-CA-20- 004: “What are the underlying causes of the unexplained rising incidence in early-onset cancers?” Evidence suggests that eoCRC may be a distinct disease subset with differential key risk factors from late-onset CRC. To date, studies that investigated eoCRC etiology remain sparse, and they mostly focused on the role of established risk factors for late-onset CRC, such as obesity, diet and physical activities. There has been a general lack of studies that evaluate the role of alternative risk factors such as those that involve gut dysbiosis and early life exposures in eoCRC etiology. To fill this critical gap, we will test novel hypotheses on the roles of broad-spectrum antibiotic use and high birth weight in eoCRC etiology. Use of broad-spectrum antibiotics results in intense and long-lasting gut dysbiosis, which is strongly implicated in CRC carcinogenesis. Further, animal studies and recent epidemiologic evidence supports the role of broad-spectrum antibiotics as CRC carcinogens. High birth weight, likely reflecting altered in-utero programming of key hormone pathways such as the insulin-like growth factor system and higher number of stem cells at risk for carcinogenesis, has been linked to risk of other young-onset cancers and late-onset CRC. Further, both broad-spectrum antibiotic use and high birth weight have been on the rise for decades preceding the rise of eoCRC. We will use a population-based, nested case-control study design, including ~1,100 eoCRC cases diagnosed between 2009- 2021 at Kaiser Permanente Southern California (KPSC) to carry out the following Specific Aims: (SA1) Test the hypothesis that greater exposure to broad-spectrum antibiotics increases risk of eoCRC; and (SA2) Test the hypothesis that high birth weight increases risk of eoCRC. KPSC's unique strengths include large sample size, comprehensive electronic medical records, long-term membership retention, and great racial/ethnic diversity. At the completion of these aims, we expect to (1) offer new insights into the carcinogenesis of eoCRC; (2) facilitate the development of eoCRC risk prediction models; (3) inform targeted early screening strategies; and (3) inform novel prevention strategies to amend this devastating epidemic.

Project Narrative We propose to investigate the effects of broad-spectrum antibiotic use and high birth weight on risk of early- onset colorectal cancer (eoCRC) leveraging a large eoCRC case series, population-based controls, and comprehensive, longitudinal electronic medical records. We expect our findings to advance knowledge on eoCRC etiology and inform novel prevention and targeted screening strategies.