Review ArticleEarly onset sporadic colorectal cancer: Worrisome trends and oncogenic features
Introduction
Despite a recent overall decrease in colorectal cancer incidence and mortality, there has been a significant increase in colorectal cancer diagnoses in young adults [[1], [2], [3]].
Early onset colorectal cancer (eoCRC) is defined as a colorectal cancer (CRC) diagnosed before the age of 50, widely considered the optimal age for initiating CRC screening for individuals at average risk. While a subset of eoCRC patients harbor highly penetrant germline mutations, most cases do not appear to be associated with hereditary cancer syndromes (80%) [[4], [5], [6], [7], [8]]. The incidence of eoCRC has increased rapidly, and it is forecasted to increase by up to 142.2% [9]. Obesity, diabetes mellitus, diet and sedentary life-style have been proposed as potential risk factors, but do not fully explain the increase in eoCRCs. Based on reports of eoCRCs exhibiting more aggressive behavior, some have suggested that these tumors be considered a unique molecular subgroup [[4], [10], [11]].
Section snippets
Epidemiology
CRC incidence rises with age, doubling by each 5-year group starting from 20y: after 60y, the increase is much less dramatic [[3], [12]]. Up to 10% of all CRCs are younger than 50y [[4], [13], [14], [15], [16], [17], [18]] and about three quarters of these are diagnosed at age 40–49y [[4], [15], [19], [20], [21], [22], [23]]. The median age of diagnosis for eoCRC is 42–44y [[4], [13], [14], [15], [16], [17], [21], [24]].
The proportion CRC cases diagnosed under age 50y is nearly double among
Risk factors
Oncogenesis is a multifactorial process [3]. Several exogenous and endogenous conditions have been associated with predisposition to CRC [41], including sedentary life-style, obesity, diet and diabetes mellitus [[42], [43]]. However, no unique risk factor seems to be exclusive to the younger population [3], and investigation is needed to determine what may be driving the challenging epidemiology of CRC.
Pathogenesis and molecular alterations
Cancer is a genetic disease dependent on the sequential accumulation of somatic mutations [103]. For CRC, the most important genes and pathways implicated in cancer development include Adenomatous Polyposis Coli (APC), Mitogen-Activated Protein (MAP)-Kinase, Transforming Growth Factor β (TGFβ), and Tumoral Protein 53 (TP53) (Fig. 2) [[103], [104]].
APC is a tumor suppressor and fundamental regulator of WNT pathway, notably of the WNT canonical major player, βCatenin. Because of APC mutations,
Pathology and tumor location
60–80% of eoCRC are distal to the splenic flexure [[4], [5], [12], [13], [19], [21], [34], [78], [82], [166], [167], [168], [169], [170], [171]], and while the rise in eoCRC pertains predominantly to distal cancers (annual percentage change of 3.5% in men; 2.9% in women [22] for 35–39y [172]), this is not always the case [[173], [174], [175]] (Fig. 3). After comprehensive clinical examination, including focused digital rectal examination, young patients with alarming symptoms [176] must undergo
Prognosis
The issue of prognosis in eoCRC has been the subject of debate for some time: a number of studies have suggested that these cases are associated with poorer prognosis [[13], [81], [166], [167], [168], [183], [184], [185]], but recent studies suggest more variability in outcomes [[79], [171], [186], [187]].
Although prognosis is overall worse for eoCRC compared to loCRC [[13], [78], [81], [188], [189]], stage-matched survival is superior [[189], [190], [191]] or non-inferior [19], even among
Chemiosensitivity
A major challenge to CRC therapy is chemoresistance, and genetic analysis may redirect therapeutic options. In one instance, APC mutations reduce the sensitivity to 5FU [214], and Lynch syndrome cases derive minimal benefit from adjuvant 5FU, but oxaliplatin-based regimens may be more beneficial [201]. Mitogenic Reg genes potentially allow evasion of apoptotic death during 5FU therapy [[201], [215], [216]]. Finally, BMPR1A overexpression resists apoptotic cell death in MSI-h tumors, and BMPR1A
Prevention and indications for surveillance
The greatest prevention method is keeping a high suspect on young patients reporting alarming symptoms for CRC [[3], [13], [14], [19], [79], [235], [236], [237]]. As most eoCRCs arise in individuals considered to be at “average risk”, most patients are symptomatic at presentation (83–90%) [14], many for 6–12 months (1 week-72 months [19]) before seeking medical advice [[13], [19], [78], [79], [238]]. Nearly 50% of patients experience physician related delays in diagnosis [235] (26% for 3 months
Concluding remarks
CRCs in young patients present a significant challenge in terms of treatment and prevention. Although current oncologic treatment protocols treat eoCRC and loCRC similarly, emerging data suggest tumors from young individuals have distinguishing clinical, pathological, biological and molecular features, suggesting that eoCRC is a fundamentally different subtype of CRC. It is likely that future oncological treatment algorithms will need to adopt a more personalized approach tailored to the
Key messages
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Incidence of eoCRC is increasing, with current trends forecasting up to 142% increase in young rectal cancer diagnoses by 2030 compared to today’s incidence.
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No single risk factor (inherited predisposition, diet, health behaviors) explains such epidemiological trends.
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Most eoCRCs occur distal to the splenic flexure and often present at advanced stage, with histopathological features suggestive of more aggressive disease. Even so, individuals with eoCRC exhibit better stage-matched median and
Conflict of interest
None declared.
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Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines
2023, Clinical Gastroenterology and HepatologyGlobal, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019
2022, The Lancet Gastroenterology and HepatologyCitation Excerpt :In line with previous studies,32–36 we observed large increases in new cases and age-specific rates in individuals aged 20–49 years between 1990 and 2019, especially in high SDI countries. In the USA, a previous study37 also noted substantial increases in colorectal cancer incidence rates in individuals aged 20–49 years from 1975 to 2010 and the incidence rate of colon cancers is expected to increase by an estimated 90%, and the incidence rate of rectal cancers is expected to increase by 140%, by 2030.37,38 In most high-income countries, screening is recommended from the age of 50 years onwards; however, the recent trends in growing colorectal cancer incidence in younger adults (<50 years) have led to calls for a reconsideration of screening recommendations to include individuals aged 40–49 years.
Colorectal Cancer in Younger Adults
2022, Hematology/Oncology Clinics of North AmericaCitation Excerpt :Some nonmodifiable risk factors, including older age, male sex, and non-White race, are associated with EOCRC.6,54,66,67 Because 80% of patients diagnosed with EOCRC have MSS tumors, implicating the adenoma-carcinoma sequence as in later-onset CRC, earlier exposures likely lead to an earlier sequence of carcinogenesis.68,69 As detailed below, several modifiable lifestyle factors increase risk of EOCRC, including dietary patterns, obesity and metabolic syndrome, sedentary behavior, and alcohol and tobacco use.
Strategies for the treatment of colorectal cancer caused by gut microbiota
2022, Life SciencesCitation Excerpt :Postulates by Fearon and Vogelstein point out that this is due to genetic mutations and chromosomal instability, which lead to epithelial dysplasia and hyperplasia of cells that make up the colon [20]. Thus, CRC is initiated when the stem cells present in the crypt of the intestinal microvilli develop mutations that prevent the activation of cellular apoptosis mechanisms, stimulates angiogenesis and invasion of secondary tissues characterizing metastasis, mainly involved with the suppressor genes of tumor, β-catenin, P53, and oncogenes such as myelocytomatosis [5,21]. According to data released in the last world cancer report, authored by the International Agency for Research on Cancer, in 2020 the rate of diagnosis of CRC was estimated at 1.8 million new cases, which is classified as the third most common type of cancer and the fourth leading cause of death, with approximately 881.000 deaths per year.
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The authors contributed equally to this study.