Table 2.

Statements Pertaining to the Diagnosis (D), Risk Factors (R), and Genetics (G) of Early-Onset Colorectal Cancer

Question and statement	Level of evidence, grade of recommendation, agreement level, and clarity
Diagnosis of early onset colorectal cancer (D)
D.1: What is the age cutoff to define eoCRC?    EoCRC is defined as CRC diagnosed younger than age 50.	LE 2A; GR B Agreement: 91.7% (A+ 50.0%|A 41.7%|A− 8.3%)
D.2: Which symptoms and clinical signs prompt evaluation for eoCRC?    Symptoms and signs that should prompt evaluation for eoCRC include (but are not limited to) any of the following: hematochezia, unexplained iron deficiency anemia, or unexplained weight loss.	LE 2B; GR B Agreement: 90.7% (A+ 53.5%| A 37.2%|A− 7.0%|D− 2.3%)
D.3: Which test(s) should be used to evaluate eoCRC signs and symptoms?    A diagnostic colonoscopy is recommended for evaluation of alarming symptoms and signs of eoCRC.	LE 2B; GR B Agreement: 85.4% (A+ 56.1%|A 29.3%|A− 7.3%|D− 4.9% |D 2.4%)
D.4: When should colonoscopy be performed for alarming symptoms?    A colonoscopy should be expedited, ideally within 30 days after referral to a healthcare professional.	LE 2B; GR C Agreement: 86.5% (A+ 35.1%|A 51.4%|A− 10.8%|D+ 2.7%)
Risk factors of early-onset colorectal cancer (R)
R.1: Does family history of CRC influence eoCRC detection?    A family cancer history can inform risk assessment for syndromic and non-syndromic CRC. Therefore, a thorough family history should be routinely collected for all individuals. In addition, in non-syndromic cases, CRC family history can facilitate the identification of high-risk individuals who may benefit from starting screening at an earlier age.	LE 1A; GR A Agreement: 89.2% (A+ 27.0%|A 62.2%|A− 8.1%|D 2.7%)
R.2: What other risk factors increase the risk of eoCRC?    Some studies have identified male sex, race and ethnicity, obesity, diabetes, alcohol consumption, and hyperlipidemia as potential risk factors for eoCRC. However, at this time the evidence is insufficient to recommend earlier CRC screening based on these factors.	LE 1B; GR A Agreement: 92.5% (A+ 27.5%|A 65.0%|A− 7.5%)
Genetics of early-onset colorectal cancer (G)
G.1: Which eoCRC patients should receive germline genetic testing and when?    A. All eoCRC patients should be offered multi-gene panel germline genetic testing and genetic counseling for those with a positive germline finding.    B. Genetic testing should be performed before treatment to maximize clinical utility, when feasible, but should not substantially delay treatment.	LE 1B; GR A Agreement: 100% (A+ 66.7%|A 33.3%) LE 2A; GR B Agreement: 91.9% (A+ 32.4%|A 59.5%|A− 8.1%)
G.2: What genes should be included in germline multi-gene panel tests for eoCRC patients?    Germline genetic testing for CRC patients diagnosed younger than age 50 should include at a minimum:	LE 1B; GR B Agreement: 97.1% (A+ 38.2%|A 58.8%|A− 2.9%)
• APC, BMPR1A, EPCAM, MLH1, MSH2, MSH6, MUTYH, POLD1, POLE, PMS2, PTEN, SMAD4, STK11, and TP53.
Where available and not cost-prohibitive testing should also include:
• The following genes that are reasonably prevalent in CRC and change clinical management: BRCA1, BRCA2, ATM, CHEK2, PALB2, and possibly, but less prevalent, BRIP1, BARD1, CDKN2A, CDH1, RAD51C, and RAD51D.
• The following genes that have been associated with CRC or polyposis: AXIN2, GREM1, MLH3, MSH3, MBD4, NTHL1, RNF43, and RPS20.
G.3: Are polygenic risk scores useful for identifying patients at risk for eoCRC?    Although emerging data suggest polygenic risk scores (PRS) may provide information that could improve CRC risk stratification, their performance has not been formally validated, and they are not yet ready for clinical use.	LE 2B; GR B Agreement: 100% (A+ 44.8%|A 55.2%)