Colorectal cancer (CRC) is the third most common cancer worldwide. Although the overall incidence of CRC has been decreasing over the past 40 y, early-onset colorectal cancer (EOCRC), which is defined as a CRC diagnosis in patients aged >50 y has increased. In this Perspective, we highlight and summarize the association between diet quality and excess adiposity, and EOCRC. We also explore chronic psychosocial stress (CPS), a less investigated modifiable risk factor, and EOCRC. We were able to show that a poor-quality diet, characterized by a high intake of sugary beverages and a Western diet pattern (high intake of red and processed meats, refined grains, and foods with added sugars) can promote risk factors associated with EOCRC development, such as an imbalance in the composition and function of the gut microbiome, presence of chronic inflammation, and insulin resistance. Excess adiposity, particularly obesity onset in early adulthood, is a likely contributor of EOCRC. Although the research is sparse examining CPS and CRC/EOCRC, we describe likely pathways linking CPS to tumorigenesis. Although additional research is needed to understand what factors are driving the uptick in EOCRC, managing body weight, improving diet quality, and mitigating psychosocial stress, may play an important role in reducing an individual\'s risk of EOCRC.

Early-onset colorectal cancer (CRC), which refers to CRC diagnosed in individuals below the age of 50 years, is a growing health concern that presents unique challenges in diagnosis, treatment, and long-term outcomes. Although approximately 70% of early-onset CRC cases are sporadic, with no apparent family history, approximately 25% have a familial component, and up to 20% may be associated with germline mutations, indicating a higher prevalence compared with the general population. Despite the progress in identifying the environmental, molecular, and genetic risk factors of early-onset CRC, the underlying causes for the global increase in its incidence remain unclear. This comprehensive review aims to provide a thorough analysis of early-onset CRC by examining the trends associated with its incidence, clinical and pathological characteristics, risk factors, molecular and genetic profiles, prognosis and screening strategies. By deepening our understanding of early-onset CRC, significant advances related to improving the outcomes and alleviating the burden of this disease on individuals, families, and healthcare systems can be achieved.

OBJECTIVE: Early-onset colorectal cancer (EoCRC) constitutes 2%-10% of all colorectal cancers and is becoming more common globally. Diabetes mellitus (DM) has increased substantially in younger adults; however, its involvement in EoCRC remains unclear. We conducted a systematic review and meta-analysis of observational studies to (1) explore the prevalence of DM in individuals with EoCRC and (2) investigate the association between DM and EoCRC.
METHODS: A systematic literature search was conducted to identify studies published before May 2022 that evaluated the association between DM and EoCRC risk in four databases, including Medline (PubMed), Embase, Web of Science, and the Cochrane Central Register of Controlled Trials. Results from the studies were summarized in meta-analyses using random effects models.
RESULTS: Nineteen eligible studies were included. A total of 33,359 EoCRC cases and 14,259,289 controls in 12 studies were included in the meta-analysis. The pooled odds ratio [OR] of 1.43 (95% confidence interval [CI]: 1.08-1.8) indicated significant positive association between DM and increased risk of EoCRC. Subgroup analysis demonstrated that diabetes severity was significantly associated with unmanaged DM (OR = 1.28, 95% CI: 1.02-1.6), but not with managed DM (OR = 1.04, 95% CI: 0.84-1.28).
CONCLUSIONS: Our results suggest that DM is a risk factor for EoCRC, and the higher prevalence of DM among younger adults may contribute to the increasing incidence of EoCRC. Interventions to reduce this bidirectional risk should be further investigated for the development of effective prevention and treatment strategies. PROSPERO registration: CRD42022306347.

The aim of this meta-analysis is to determine the impact of bariatric surgery on the risk of early-onset colorectal neoplasia. This systematic review was conducted according to PRISMA recommendations. It was registered in the PROSPERO international database. A comprehensive search was conducted in electronic databases (MEDLINE, EMBASE, and Web of Science) for completed studies until May 2022. The Search was made using a mixture of indexed terms and title, abstract and keywords. The search included terms: obese, surgical weight loss intervention, colorectal cancer, and colorectal adenomas. Studies that included bariatric intervention patient\'s vs non-surgical obese patients younger than 50 years were considered. Inclusion criteria were patients with BMI more than 35 kg/m2 who underwent a colonoscopy. Studies with follow-up colonoscopy performed in less than 4 years after bariatric surgery and those that evaluated patients with a mean age difference of 5 or more years between groups were excluded. Outcomes analyzed in obese patients with surgical treatment vs control patients included colorectal cancer incidence. From 2008 to 2021, a total of 1536 records were identified. Five retrospective studies that included 48,916 patients were analyzed. Follow-up period ranged from 5 to 22.2 years. 20,663 (42.24%) patients underwent bariatric surgery and 28,253 (57.76%) were part of the control patients. Roux-en-Y gastric bypass was performed in 14,400 (69.7%) individuals. The intervention and control group were similar in age range, proportion of female participants and initial body mass index (35-48.3 vs 35-49.3, respectively). 126/20663 (0.61%) patients in the bariatric surgery group and 175/28253 (0.62%) individuals in the control group presented CRC. In this meta-analysis, we were unable to demonstrate a significant impact of the Bariatric Surgery on EOCRC risk. Prospective trials with longer follow-up periods should be done to prove the colorectal cancer risk reduction.

Despite the general decrease in overall incidence of colorectal cancer since the early 1990s, the incidence of colorectal cancer in patients less than 50 years old has nearly doubled. A systematic review was performed using the PubMed database (2011-2020) and Cochrane Database of Systematic Reviews (2011-2021) to identify studies (published in English) evaluating epidemiologic, clinical, hereditary, and molecular features; as well as evaluation, management, and prognosis of young-onset colorectal cancer patients. Our search yielded a total of 3401 articles, after applying our inclusion criteria. We fully reviewed 94 full-length studies. This systematic review demonstrates the increasing incidence of young-onset colorectal cancer and highlights the importance of being hypervigilant for the differential diagnosis colorectal cancer when evaluating a young adult who presents with gastrointestinal symptoms.

Genome-wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM, MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter methylation analysis in 473 familial/early-onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutional PTPRJ epimutations were identified. Assessment of allele frequencies in controls compared with familial/early-onset patients with CRC showed association with increased nonpolyposis CRC risk of disruptive variants in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.-110G>C, and FOCAD large deletions.

The incidence of colorectal cancer (CRC) in persons under the age of 50 years (EOCRC) is increasing even as the incidence of CRC in persons over age 50 is decreasing. This has led to recommendations to lower the age of CRC screening to age 45. It is not clear whether EOCRC is identical to CRCs in older patients or whether there are distinctive features between the two groups.
We reviewed the literature on the clinical and genetic aspects of EOCRC.
We found that there is an increased likelihood of a strong genetic basis for EOCRC, but that at least 80% of cases do not come from the known high-penetrance cancer syndromes. Early-onset CRCs tend to occur in the distal colon or rectum, are more likely to be detected due to cancer-related symptoms, appear to be increasing in whites more than non-whites on a population-wide analysis, and are more likely to present in an advanced stage of disease. There are some unique genetic features of EOCRC, including an increased proportion of tumors with LINE-1 hypomethylation, and combined chromosomal and microsatellite stability.
EOCRC deserves additional attention because of the high number of life years at risk with EOCRC, and the implications for earlier CRC screening. Additional focus is needed on determining whether some cases of EOCRC have a unique mechanistic basis.

The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age-specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high-risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well-documented in the United States. This rise in incidence in the young has not been reported from other countries that share long-term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health-care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood-screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps.