Table 1.

Summary of the current state of knowledge for the epidemiology, tumor marker characterization, red flag symptoms and screening for early-onset CRC

	What is known?	What is new?	What is unknown?
Epidemiology	Early-onset CRC incidence has been increasing since the 1990s. CRC-related mortality is increasing among young adults 40–49 years of age. Early-onset CRC incidence patterns are fairly similar in men and women, but vary by site (predominantly distal and rectal cancer) and stage (mostly late-stage disease).	Early-onset CRC incidence varies by geography across the United States with the most rapid rise in western states, but highest incidence in southern states and rural areas. Conflicting results exist regarding whether obesity and diabetes are risk factors for early-onset CRC. Metabolic syndrome is associated with early-onset CRC. A Western diet is associated with early-onset high-risk adenomas.	Do antibiotics, perceived stress, red and processed meats, synthetic food coloring, and food additives impact the risk of early-onset CRC? Do exposures during gestation, childhood, and early adulthood impact the risk of early-onset CRC?
Tumor markers	MSI-high early-onset CRC is mostly due to Lynch Syndrome and accounts for <20% of all early-onset CRC. The molecular profile of sporadic early-onset CRC is distinct from late-onset CRC. Early-onset CRC is more likely to exhibit global hypomethylation and somatic CTNNB1 mutations and less likely to have somatic APC and BRAF mutations.	Inflammatory pathways may be particularly important to the development of early-onset CRC based on multiomics studies. Cartilage oligomeric matrix protein (COMP) is over-expressed in early-onset CRC, suggesting a potential target for treatment. Somatic POLE mutation is more common in early-onset CRC and may have implications for better response to immune checkpoint inhibitors due to association with higher tumor mutational burden.	Are specific early-onset CRC tumor molecular signatures associated with specific etiologic processes or risk factors? Can currently identified tumor markers help optimize treatment of early-onset CRC?
Red flag symptoms	Red flag signs/symptoms precede 70–95% of early-onset CRC diagnoses. Rectal bleeding is the most commonly reported initial symptom in early-onset CRC cases. Time delays to early-onset CRC diagnosis from symptom presentation average 6 months.	Compared to later-onset CRC, abdominal pain, rectal pain, change in bowel habits, rectal bleeding and weight loss were associated with an increased odds of early-onset CRC. Recent studies found time to diagnosis is not associated with worse early-onset CRC stage at presentation or survival.	What are the best strategies for increasing awareness of red flag signs and symptoms for early-onset CRC among individuals younger than age 50 and among providers? What are the best strategies for triage of individuals with red flags towards immediate colonoscopy vs. symptom and sign-specific work up and treatment? What are the short-term cumulative risks for CRC among individuals across the range of signs and symptoms potentially associated with early-onset CRC? What patient, provider, or health system-based factors, are associated with increased time to early-onset CRC diagnosis?
Screening	Primary approach to precision screening is offering early screening initiation based on family history guidelines. Traditionally, screening for individuals at average risk has been recommended to begin at age 50.	Recent research suggests models incorporating genetic risk scores, lifestyle, and other factors may identify candidates for early initiation of screening for individuals without a family history. New draft recommendations by the US Preventive Services Task Force support initiation of screening at age 45 instead of 50 for individuals at average risk. Starting screening at age 45 is supported by rising incidence, recent modeling studies, observation that neoplasia prevalence is similar for individuals ages 45 to 49 compared with 50 to 54 year-olds, and evidence that early initiation is cost-effective.	How can we improve adherence to family-history based guidelines for screening? For individuals without a family history, how can novel risk scores be implemented for precision screening? For average risk individuals, how can early initiation be informed by past experiences with implementation among 50 to 75 year-olds? For average risk individuals, how can early screening initiation be implemented with a multi-pronged approach that also continues to focus resources on optimizing screening for older individuals?