A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers

Andrea Cercek, MD; Walid K. Chatila, MS; Rona Yaeger, MD; Henry Walch, MS; Gustavo Dos Santos Fernandes, MD; Asha Krishnan, BS; Lerie Palmaira, MPH; Anna Maio, BS; Yelena Kemel, MS; Preethi Srinivasan, PhD; Chaitanya Bandlamudi, PhD; Erin Salo-Mullen, MS; Prince R. Tejada, BA; Kimeisha Belanfanti, BS; Jesse Galle, BA; Vijai Joseph, PhD; Neil Segal, MD; Anna Varghese, MD; Diane Reidy-Lagunes, MD; Jinru Shia, MD; Efsevia Vakiani, MD; Sebastian Mondaca, MD; Robin Mendelsohn, MD; Melissa A. Lumish, MD; Felix Steinruecke, BS; Nancy Kemeny, MD; Louise Connell, MD; Karuna Ganesh, MD, PhD; Arnold Markowitz, MD; Garrett Nash, MD; Jose Guillem, MD; J. Joshua Smith, MD, PhD; Phillip B. Paty, MD; Liying Zhang, MD; Diana Mandelker, MD; Ozge Birsoy, PhD; Mark Robson, MD; Kenneth Offit, MD; Barry Taylor, PhD; Michael Berger, PhD; David Solit, MD; Martin Weiser, MD; Leonard B. Saltz, MD; Julio Garcia Aguilar, MD; Nikolaus Schultz, PhD; Luis A. Diaz Jr, MD; Zsofia K. Stadler, MD


J Natl Cancer Inst. 2021;113(12):1683-1692. 

In This Article

Abstract and Introduction


Background: The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC).

Methods: Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014–2019), divided into age 35 years and younger and 36–49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided.

Results: In total, 759 patients with EO-CRC (35 years, n = 151; 36–49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36–49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36–49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36–49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01).

Conclusions: EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.


In the United States, colorectal cancer (CRC) incidence and mortality have declined following the implementation of CRC screening based on standardized guidelines adopted in the late 1990s.[1–4] However, in adults aged younger than 50 years, for whom routine CRC screening is not recommended, the incidence of CRC has been increasing steadily by 1%-2% annually since the 1990s.[2] The greatest increase appears to be in patients aged 20–29 years; incidence in this group has increased by 3.8% annually since 1987, especially for distal colon and rectal cancers.[4–6] It is estimated that, by 2030, 10.9% of all colon cancers and 22.9% of all rectal cancers will be diagnosed in patients younger than 50 years, compared with 4.8% and 9.5%, respectively, in 2010.[7]

The etiology of this increase in CRC among younger patients (early-onset CRC [EO-CRC]) is unknown, and it is unclear whether EO-CRC has a unique biology, compared with average-onset CRC (AO-CRC; aged 50 years and older). EO-CRC may be associated with more aggressive disease biology, resulting in more advanced stages at diagnosis.[8–11] However, because patients aged 50 years and younger do not routinely undergo CRC screening, advanced stage at diagnosis may result from selection bias, wherein EO-CRCs are diagnosed only upon development of symptoms.[12] Previous results on EO-CRC tumor genomics have been mixed and partially confounded by the inclusion of patients with EO-CRC with well-established genetic and/or medical predispositions for CRC.[7,9,13] A recent genomic report suggested there are few molecular differences between EO-CRC and AO-CRC, besides an enrichment for high-frequency microsatellite instability (MSI) in EO-CRC, consistent with the expected higher prevalence of Lynch syndrome (LS).[14] The majority of cases of EO-CRC are seemingly sporadic, occurring in patients without an identifiable genetic predisposition.[15] Established AO-CRC risk factors, such as obesity, diet high in red meat and low in fiber, excess alcohol consumption, physical inactivity, and smoking, do not adequately explain the increase in EO-CRC.[16] Dietary and lifestyle factors have been associated with an increase in predominantly right-sided CRCs;[17] however, the greatest increase in young patients has been in left-sided CRCs.[3–5]

Whether EO-CRC represents a disease distinct from AO-CRC is an important clinical question with critical implications for the oncological management of these young adults. To elucidate the clinical profile and molecular underpinnings of EO-CRC, we compared the clinical, somatic, and germline characteristics of EO-CRC and AO-CRC. As the prevalence of CRC is most drastically increasing among young individuals (age 35 years and younger), possibly representing a different subgroup of EO-CRC,[18–21] we further divided EO-CRC patients by age at diagnosis (35 years and younger and 36–49 years).