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Editorial: sporadic early‐onset colorectal cancer—appreciating aetiologic complexity

Earlyonset colorectal cancer (EOCRC i.e., CRC diagnosed before age 50) has been increasing since the 1990s.1 Most EOCRCs are sporadic (i.e., without hereditary or familial association), presenting challenges for early detection and prevention.2,3 EOCRC often presents with advanced stage at diagnosis, distal colon or rectal location, and low prevalence of BRAF and RAS mutations. However, study populations may have contained nonsporadic cases, potentially limiting validity and/or generalisability.4,5 Vuik et al.6 recently characterised the clinicopathological features of sporadic EOCRC using the Netherlands Cancer Registry and Dutch national pathology registry, identifying patients diagnosed with colon or rectum adenocarcinoma between 1989 and 2016 and excluding those with microsatellite instability (MSI). The 6400 EOCRC individuals (49% male; mean age 43), were divided into three groups aged 2029 (group I), 3039 (group II) and 4049 (group III). Groups I and II, when compared to group III, had greater proportions of signetring cancers (5.4% and 3.7%, respectively, vs 1.4%; P < 0.01), lymphatic invasion (33.3% and 28% vs 20.3%; P = 0.09), and poor differentiation (28.5% and 20.3% vs 16.6%; P < 0.01). Group I had a greater proportion of individuals with positive lymph nodes than groups II and III (16.2% vs 9.3% and 7.9%, P < 0.01). There were no differences in overall survival, or KRAS, NRAS or BRAF mutations among the groups. When comparing two time periods, 19892004 and 20052018, the authors found a decline in the proportion of poorly differentiated cancers in the latter period in groups II (25.1% vs 17.4%, P = 0.05) and III (20.3% vs 15%, P < 0.01), but no change in group I. In the latter period, there was a greater proportion of rectal cancers in groups II (41.6% vs 33.8%, P = 0.01) and III (40.7% vs 34.3%, P < 0.01), and a greater proportion of CRCs diagnosed in women in group I (54.9% vs 34.5%, P = 0.01), but no genderbased differences in groups II and III. This innovative, largescale study confirms previous findings of EOCRC4,7 and moves the needle forward by finding that, for EOCRC without MSI, very young individuals (2029 years) had more advanced histologic features and no difference in poorly differentiated cancers across the two time periods than those aged 3049, with no survival difference between the two age groups. In addition, overall 5year diseasefree survival improved between 20052018 and 19892004. While questions remain, such as the true 30year incidence patterns for men and women, distribution of disease within the colon (proximal vs distal), and factors contributing to improved survival in the latter time period (both leadtime bias and stage migration8 are possible contributors), this study identifies clinicopathological heterogeneity in the absence of overt genetic heterogeneity within sporadic EOCRC for which there may be a complex interplay of (as yet unknown) genetic variants and environmental exposures. Studies incorporating early childhood and adulthood exposures, in combination with molecular and clinicopathological features, are required for understanding this interplay and for the development of prevention strategies and targeted therapies.