Early Onset Colorectal Cancer: Epidemiology and Etiology

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Epidemiology and Prevention".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 20239

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Department of Medicine, Biochemistry, Oncology, Genetics & Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Interests: energy balance; obesity cancer
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Dear Colleagues,

Early Onset Colorectal Cancer (EO-CRC), occurring in individuals younger than 50 years of age, has been noted to be increasing in incidence in the U.S. and many countries around the world. The emergence of EO-CRC is particularly notable, since the overall incidence of CRC is decreasing, presumably due to widespread screening resulting in early detection and treatment of premalignant lesions. The apparent shift in occurrence of CRC to EO-CRC presents multiple challenges to our understanding and approach to CRC carcinogenesis. It is especially concerning, since EO-CRC is reported to have worse prognosis than CRC, and also because it is more likely to impact individuals in their prime productive years. Prognosis of EO-CRC may be associated with distinct anatomical distribution and/or molecular phenotypes. In addition, EO-CRC has been noted among unique populations where it may be related to genetics, exposures, and/or may be associated with disparities in care. Epidemiologic and molecular studies suggest contributions from family history, obesity, maternal obesity, antibiotic use and specific dietary components.

We are pleased to invite you to submit an article for this special issue of Cancers focused on better defining epidemiologic and etiologic factors as well as animal models that will contribute to better understanding and possible mechanisms and translational insights that may contribute to early detection, prevention, control and/or therapy of EO-CRC. In this special issue, original research articles and reviews are welcome. We look forward to receiving your contributions.

Prof. Dr. Nathan A. Berger
Guest Editor

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Keywords

  • Early Onset-Colorectal Cancer (EO-CRC)
  • EO-CRC – Molecular Genetics and Epigenetics
  • EO-CRC – Animal Models
  • EO-CRC – Epidemiology
  • EO-CRC – Anatomical Distribution
  • EO-CRC – Obesity
  • EO-CRC – Unique Populations
  • EO-CRC – Geographic Distribution
  • EO-CRC – Dietary Components

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Published Papers (9 papers)

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Research

16 pages, 2443 KiB  
Article
Immune Microenvironment in Sporadic Early-Onset versus Average-Onset Colorectal Cancer
by Fanny Andric, Ala Al-Fairouzi, Yvonne Wettergren, Louis Szeponik, Elinor Bexe-Lindskog, James C. Cusack, Jr., Gerald Tumusiime, Marianne Quiding-Järbrink and David Ljungman
Cancers 2023, 15(5), 1457; https://doi.org/10.3390/cancers15051457 - 24 Feb 2023
Cited by 1 | Viewed by 2091
Abstract
The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating [...] Read more.
The incidence of left-sided colon and rectal cancer in young people are increasing worldwide, but its causes are poorly understood. It is not clear if the tumor microenvironment is dependent on age of onset, and little is known about the composition of tumor-infiltrating T cells in early-onset colorectal cancer (EOCRC). To address this, we investigated T-cell subsets and performed gene expression immune profiling in sporadic EOCRC tumors and matched average-onset colorectal cancer (AOCRC) tumors. Left-sided colon and rectal tumors from 40 cases were analyzed; 20 EOCRC (<45 years) patients were matched 1:1 to AOCRC (70–75 years) patients by gender, tumor location, and stage. Cases with germline pathogenic variants, inflammatory bowel disease or neoadjuvant-treated tumors were excluded. For T cells in tumors and stroma, a multiplex immunofluorescence assay combined with digital image analysis and machine learning algorithms was used. Immunological mediators in the tumor microenvironment were assessed by NanoString gene expression profiling of mRNA. Immunofluorescence revealed no significant difference between EOCRC and AOCRC with regard to infiltration of total T cells, conventional CD4+ and CD8+ T cells, regulatory T cells, or γδ T cells. Most T cells were located in the stroma in both EOCRC and AOCRC. Immune profiling by gene expression revealed higher expression in AOCRC of the immunoregulatory cytokine IL-10, the inhibitory NK cell receptors KIR3DL3 and KLRB1 (CD161), and IFN-a7 (IFNA7). In contrast, the interferon-induced gene IFIT2 was more highly expressed in EOCRC. However, in a global analysis of 770 tumor immunity genes, no significant differences could be detected. T-cell infiltration and expression of inflammatory mediators are similar in EOCRC and AOCRC. This may indicate that the immune response to cancer in left colon and rectum is not related to age of onset and that EOCRC is likely not driven by immune response deficiency. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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13 pages, 2393 KiB  
Article
Geographic Variation and Risk Factor Association of Early Versus Late Onset Colorectal Cancer
by Weichuan Dong, Uriel Kim, Johnie Rose, Richard S. Hoehn, Matthew Kucmanic, Kirsten Eom, Shu Li, Nathan A. Berger and Siran M. Koroukian
Cancers 2023, 15(4), 1006; https://doi.org/10.3390/cancers15041006 - 04 Feb 2023
Cited by 3 | Viewed by 2829
Abstract
The proportion of patients diagnosed with colorectal cancer (CRC) at age < 50 (early-onset CRC, or EOCRC) has steadily increased over the past three decades relative to the proportion of patients diagnosed at age ≥ 50 (late-onset CRC, or LOCRC), despite the reduction [...] Read more.
The proportion of patients diagnosed with colorectal cancer (CRC) at age < 50 (early-onset CRC, or EOCRC) has steadily increased over the past three decades relative to the proportion of patients diagnosed at age ≥ 50 (late-onset CRC, or LOCRC), despite the reduction in CRC incidence overall. An important gap in the literature is whether EOCRC shares the same community-level risk factors as LOCRC. Thus, we sought to (1) identify disparities in the incidence rates of EOCRC and LOCRC using geospatial analysis and (2) compare the importance of community-level risk factors (racial/ethnic, health status, behavioral, clinical care, physical environmental, and socioeconomic status risk factors) in the prediction of EOCRC and LOCRC incidence rates using a random forest machine learning approach. The incidence data came from the Surveillance, Epidemiology, and End Results program (years 2000–2019). The geospatial analysis revealed large geographic variations in EOCRC and LOCRC incidence rates. For example, some regions had relatively low LOCRC and high EOCRC rates (e.g., Georgia and eastern Texas) while others had relatively high LOCRC and low EOCRC rates (e.g., Iowa and New Jersey). The random forest analysis revealed that the importance of community-level risk factors most predictive of EOCRC versus LOCRC incidence rates differed meaningfully. For example, diabetes prevalence was the most important risk factor in predicting EOCRC incidence rate, but it was a less important risk factor of LOCRC incidence rate; physical inactivity was the most important risk factor in predicting LOCRC incidence rate, but it was the fourth most important predictor for EOCRC incidence rate. Thus, our community-level analysis demonstrates the geographic variation in EOCRC burden and the distinctive set of risk factors most predictive of EOCRC. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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13 pages, 821 KiB  
Article
Early Onset Colorectal Cancer in Arabs, Are We Dealing with a Distinct Disease?
by Adhari Al Zaabi, Asmaa Al Shehhi, Shaymaa Sayed, Humaid Al Adawi, Faris Al Faris, Omaima Al Alyani, Maitha Al Asmi, Abdulrahman Al-Mirza, Sathiya Panchatcharam and Maha Al-Shaibi
Cancers 2023, 15(3), 889; https://doi.org/10.3390/cancers15030889 - 31 Jan 2023
Cited by 6 | Viewed by 1686
Abstract
Early-onset colorectal cancer (EOCRC) incidence is increasing worldwide. Efforts are directed to understand the biological and clinical signatures of EOCRC compared to late-onset colorectal cancer (LOCRC). EOCRC is thought to present differently across different ethnic groups and geographical regions. This study was an [...] Read more.
Early-onset colorectal cancer (EOCRC) incidence is increasing worldwide. Efforts are directed to understand the biological and clinical signatures of EOCRC compared to late-onset colorectal cancer (LOCRC). EOCRC is thought to present differently across different ethnic groups and geographical regions. This study was an attempt to contribute with data from the Arab world toward the understanding of the clinicopathological parameters of EOCRC compared to LOCRC. Data from 254 CRC patients diagnosed at Sultan Qaboos University Hospital from the period 2015–2020 were studied. About 32.6% of all diagnosed CRC patients are below 50 years old, with no differences in gender distribution between EOCRC and LOCRC (p-value 0.417). Rectal involvement and tumor laterality were comparable among the two groups. Adenocarcinoma accounts for 83.3% and 94.2% of EOCRC and LOCRC, respectively. More mucinous and signet ring adenocarcinoma (8.3% each) were reported in EOCRC than LOCRC (2.9% and 2.2%, respectively). MLH1 and PMS2 loss are more common among LOCRC, but MSH6 loss is more frequent in EOCRC. The overall survival of EOCRC and LOCRC was comparable (median survival 64.88 and 67.24 months, respectively). This study showed comparable clinicopathological parameters between EOCRC and LOCRC from Arabs, which adds to the bigger picture of understand the disease. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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12 pages, 542 KiB  
Article
Autoimmune and Metabolic Diseases and the Risk of Early-Onset Colorectal Cancer, a Nationwide Nested Case–Control Study
by Erik Lundqvist, Ida Hed Myrberg, Sol Erika Boman, Deborah Saraste, Caroline E. Weibull, Kalle Landerholm, Staffan Haapaniemi, Anna Martling, Pär Myrelid and Caroline Nordenvall
Cancers 2023, 15(3), 688; https://doi.org/10.3390/cancers15030688 - 22 Jan 2023
Cited by 3 | Viewed by 1839
Abstract
Incidence of early-onset (<50 years) colorectal cancer (EOCRC) is increasing in developed countries. The aim was to investigate autoimmune and metabolic conditions as risk factors for EOCRC. In a nationwide nested case–control study, we included all EOCRC cases in Sweden diagnosed during 2007–2016, [...] Read more.
Incidence of early-onset (<50 years) colorectal cancer (EOCRC) is increasing in developed countries. The aim was to investigate autoimmune and metabolic conditions as risk factors for EOCRC. In a nationwide nested case–control study, we included all EOCRC cases in Sweden diagnosed during 2007–2016, together with controls, matched for birth year, sex, and county. Information on exposure of autoimmune or metabolic disease was collected from the National Patient Register and Prescribed Drugs Registry. Hazard ratios (HR) as measures of the association between EOCRC and the exposures were estimated using conditional logistic regression. In total, 2626 EOCRC patients and 15,756 controls were included. A history of metabolic disease nearly doubled the incidence hazard of EOCRC (HR 1.82, 95% CI 1.66–1.99). A sixfold increased incidence hazard of EOCRC (HR 5.98, 95% CI 4.78–7.48) was seen in those with inflammatory bowel disease (IBD), but the risk increment decreased in presence of concomitant metabolic disease (HR 3.65, 95% CI 2.57–5.19). Non-IBD autoimmune disease was not statistically significantly associated with EOCRC. IBD and metabolic disease are risk factors for EOCRC and should be considered in screening guidelines. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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13 pages, 1077 KiB  
Article
Different Oncologic Outcomes in Early-Onset and Late-Onset Sporadic Colorectal Cancer: A Regression Analysis on 2073 Patients
by Caterina Foppa, Annalisa Maroli, Sara Lauricella, Antonio Luberto, Carlotta La Raja, Francesca Bunino, Michele Carvello, Matteo Sacchi, Francesca De Lucia, Giuseppe Clerico, Marco Montorsi and Antonino Spinelli
Cancers 2022, 14(24), 6239; https://doi.org/10.3390/cancers14246239 - 18 Dec 2022
Cited by 2 | Viewed by 1701
Abstract
The incidence of colorectal cancer (CRC) is increasing in the population aged ≤ 49 (early-onset CRC-EOCRC). Recent studies highlighted the biological and clinical differences between EOCRC and late-onset CRC (LOCRC-age ≥ 50), while comparative results about long-term survival are still debated. This study [...] Read more.
The incidence of colorectal cancer (CRC) is increasing in the population aged ≤ 49 (early-onset CRC-EOCRC). Recent studies highlighted the biological and clinical differences between EOCRC and late-onset CRC (LOCRC-age ≥ 50), while comparative results about long-term survival are still debated. This study aimed to investigate whether age of onset may impact on oncologic outcomes in a surgical population of sporadic CRC patients. Patients operated on for sporadic CRC from January 2010 to January 2022 were allocated to the EOCRC and LOCRC groups. The primary endpoint was the recurrence/progression-free survival (R/PFS). A total of 423 EOCRC and 1650 LOCRC was included. EOCRC had a worse R/PFS (p < 0.0001) and cancer specific survival (p < 0.0001) compared with LOCRC. At Cox regression analysis, age of onset, tumoral stage, signet ring cells, extramural/lymphovascular/perineural veins invasion, and neoadjuvant therapy were independent risk factors for R/P. The analysis by tumoral stage showed an increased incidence of recurrence in stage I EOCRC (p = 0.014), and early age of onset was an independent predictor for recurrence (p = 0.035). Early age of onset was an independent predictor for worse prognosis, this effect was stronger in stage I patients suggesting a potentially—and still unknown—more aggressive tumoral phenotype in EOCRC. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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10 pages, 741 KiB  
Article
Time Trend and Association of Early-Onset Colorectal Cancer with Diverticular Disease in the United States: 2010–2021
by Lindsey Wang, Rong Xu, David C. Kaelber and Nathan A. Berger
Cancers 2022, 14(19), 4948; https://doi.org/10.3390/cancers14194948 - 09 Oct 2022
Cited by 9 | Viewed by 2178
Abstract
Purpose: To examine time trends of incidence rates of EOCRC from 2010 to 2021 among patients with and without diverticular disease and to examine whether diverticular disease is associated with increased risk of EOCRC. Methods: This is a retrospective cohort study of 46,179,351 [...] Read more.
Purpose: To examine time trends of incidence rates of EOCRC from 2010 to 2021 among patients with and without diverticular disease and to examine whether diverticular disease is associated with increased risk of EOCRC. Methods: This is a retrospective cohort study of 46,179,351 young adults aged 20–49, including 298,117 with diverticular disease. We examined yearly incidence rate of first diagnosis of EOCRC from 2010 through 2021 among patients with and without diverticular disease. The 5-year risk of EOCRC among patients with pre-existing diverticular disease was compared to propensity-matched patients without diverticular disease and EOCRC and odds ratio (OR) and 95% confidence interval (CI) were calculated. Results: The yearly incidence rate of new diagnosis of EOCRC (measured as new cases per 100,000 people per year) in young adults with pre-existing diverticular disease increased from 100 in 2010 to 402 in 2021, 4–6 times higher than in those without diverticular disease (24 in 2010 to 77 in 2021) (p < 0.001). Patients with diverticular disease were at higher risk for EOCRC than those without (OR: 1.76, 95% CI: 1.40–2.32). Conclusion: The incidence of EOCRC continuously increased from 2010 through 2021 in patients with and without diverticular disease and was 4–6 times higher among patients with diverticular disease. Patients with pre-existing diverticular disease were at a significantly increased risk for EOCRC. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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11 pages, 751 KiB  
Article
Patterns of Healthcare Utilization Leading to Diagnosis of Young-Onset Colorectal Cancer (yCRC): Population-Based Case-Control Study
by Ameer Farooq, Carl J. Brown, Eric C. Sayre, Manoj J. Raval, Jonathan M. Loree, Ria Garg and Mary A. De Vera
Cancers 2022, 14(17), 4263; https://doi.org/10.3390/cancers14174263 - 31 Aug 2022
Cited by 1 | Viewed by 1377
Abstract
Background: The increasing risk of young-onset colorectal cancer (yCRC) in adults < 50 years has called for better understanding of patients’ pathways to diagnosis. This study evaluated patterns of healthcare utilization before diagnosis of yCRC. Methods: Using linked administrative health databases in British [...] Read more.
Background: The increasing risk of young-onset colorectal cancer (yCRC) in adults < 50 years has called for better understanding of patients’ pathways to diagnosis. This study evaluated patterns of healthcare utilization before diagnosis of yCRC. Methods: Using linked administrative health databases in British Columbia, Canada, we identified yCRC cases and cancer-free controls matched (1:10) on age, sex, and healthcare utilization. The index date was the date of diagnosis for yCRC cases and matched date for controls. Outpatient visits, emergency department visits, and hospitalizations over a 5-year prediagnosis period (e.g., year-1 to year-5) were compared using descriptive statistics and Poisson regression models. Results: The study included 2567 yCRC cases (49.6% females, 43.0 ± 5.8 years) and 25,455 controls (48.6% females, 43.0 ± 5.8 years). We observed an increasing number of outpatient visits from prediagnosis year-5 (median = 3) to year-1 (median = 8) for yCRC cases. Among controls, outpatient visits were stable and did not have a pattern of increase. Poisson regression models indicated higher adjusted count ratios for outpatient visits for yCRC cases compared to controls in the year before diagnosis (1.11; 95% CI, 1.07 to 1.15). In the year before diagnosis, 35.1% of yCRC cases had potentially related visits to CRC (e.g., nausea, vomiting) and 16.9% had potentially red flag visits (e.g., gastrointestinal hemorrhage or iron deficiency anemia). Conclusions: Using population-based data, we found that individuals with yCRC did not have higher healthcare utilization than individuals without in the prediagnosis period except for the year before diagnosis. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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17 pages, 1696 KiB  
Article
Insights into Early Onset Colorectal Cancer through Analysis of Normal Colon Organoids of Familial Adenomatous Polyposis Patients
by Matthew A. Devall, Stephen Eaton, Mourad W. Ali, Steven M. Powell, Li Li and Graham Casey
Cancers 2022, 14(17), 4138; https://doi.org/10.3390/cancers14174138 - 26 Aug 2022
Cited by 2 | Viewed by 1859
Abstract
Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify [...] Read more.
Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify individuals at-risk for CRC. To better define transcriptomic events that precede the development of CRC, we performed RNA-sequencing analysis in colon organoids derived from seven healthy and six familial adenomatous polyposis (FAP) patients. This led to the identification of 2635 significant differentially expressed genes (FDR < 0.05). Through secondary analysis of publicly available datasets, we found that these genes were enriched for significant genes also present in FAP CRC and non-hereditary CRC datasets, including a subset that were unique to EOCRC. By exposing FAP colon organoids to a three-day ethanol treatment, we found that two EOCRC-relevant genes were also targets of CRC related lifestyle factors. Our data provides unique insight into the potential, early mechanisms of CRC development in colon epithelial cells, which may provide biomarkers for patient monitoring. We also show how modifiable lifestyle factors may further alter genes relevant to EOCRC, adding weight to the hypothesis that such factors represent an important contributor to increased EOCRC incidence. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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17 pages, 2853 KiB  
Article
The Burden of Early-Onset Colorectal Cancer and Its Risk Factors from 1990 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019
by Wan-Jie Gu, Jun-Peng Pei, Jun Lyu, Naohiko Akimoto, Koichiro Haruki, Shuji Ogino and Chun-Dong Zhang
Cancers 2022, 14(14), 3502; https://doi.org/10.3390/cancers14143502 - 19 Jul 2022
Cited by 15 | Viewed by 3216
Abstract
Background: The incidence of early-onset colorectal cancer (CRC) diagnosed before age 50 has been increasing over the past decades. Hence, we examined the global, regional, and national burden of early-onset CRC and its risk factors from 1990 to 2019. Methods: Using data from [...] Read more.
Background: The incidence of early-onset colorectal cancer (CRC) diagnosed before age 50 has been increasing over the past decades. Hence, we examined the global, regional, and national burden of early-onset CRC and its risk factors from 1990 to 2019. Methods: Using data from the Global Burden of Disease (GBD) Study 2019, we reported the incidence, deaths, and disability-adjusted life-years (DALYs) attributable to the risk factors of early-onset CRC. All estimates were reported with 95% uncertainty intervals (UIs). Results: The global numbers of early-onset CRC for incidence, deaths, and DALYs in 2019 were 225,736 (95% UI, 207,658 to 246,756), 86,545 (80,162 to 93,431), and 4,259,922 (3,942,849 to 4,590,979), respectively. Despite large variations at the regional and national levels, the global incidence rate, death rate, and DALY rate increased from 1990 to 2019. Diets low in milk, diets low in calcium, and alcohol use were the leading risk factors in 2019. From 1990 to 2019, a high body mass index and high fasting plasma glucose ranked remarkably higher among males and females, while smoking and diets low in fiber ranked lower among both sexes, with a more profound change among females. Conclusions: Despite large variations in regional and national levels, the global incidence rate, death rate, and DALY rate increased during the past three decades. These findings may provide policymakers with an accurate quantification of the burden of early-onset CRC and targeted identification of those most at risk to mitigate the burden of early-onset CRC. Full article
(This article belongs to the Special Issue Early Onset Colorectal Cancer: Epidemiology and Etiology)
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