Novel, Emerging Risk Factors for Colorectal Cancer Remain Understudied

See “Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location,” by Jin EH, Han K, Lee DH, et al, on page 637.For more than 3 decades, colorectal cancer (CRC) incidence rates have been increasing rapidly among adults <50 years of age (ie, early-onset CRC) in the United States and in other parts of the world.1Siegel R.L. Torre L.A. Soerjomataram I. et al.Global patterns and trends in colorectal cancer incidence in young adults.Gut. 2019; 68: 2179-2185Crossref PubMed Scopus (244) Google Scholar More recently, incidence rates have started to increase in adults ages 50–54 years old.2Zaki T.A. Singal A.G. May F.P. et al.Increasing incidence rates of colorectal cancer at ages 50-54 years.Gastroenterology. 2022; 162: 964-965.e3Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Despite broad recognition in the medical and public health communities about the increasing morbidity and mortality associated with early-onset CRC, the factors driving this increase are largely unknown. Many studies have investigated risk of early-onset CRC associated with traditional, well-known risk factors for CRC , including a Western diet,3Zheng X. Hur J. Nguyen L.H. et al.Comprehensive assessment of diet quality and risk of precursors of early-onset colorectal cancer.J Natl Cancer Inst. 2021; 113: 543-552Crossref PubMed Scopus (29) Google Scholar heavy alcohol use,4Rosato V. Bosetti C. Levi F. et al.Risk factors for young-onset colorectal cancer.Cancer Causes Control. 2013; 24: 335-341Crossref PubMed Scopus (86) Google Scholar tobacco use,5Kim J.Y. Jung Y.S. Park J.H. et al.Different risk factors for advanced colorectal neoplasm in young adults.World J Gastroenterol. 2016; 22: 3611-3620Crossref PubMed Scopus (36) Google Scholar sedentary behavior,6Nguyen L.H. Liu P.H. Zheng X. et al.Sedentary behaviors, TV viewing time, and risk of young-onset colorectal cancer.JNCI Cancer Spectr. 2018; 2: pky073Crossref PubMed Google Scholar obesity,7Kim N.H. Jung Y.S. Yang H.J. et al.Prevalence of and risk factors for colorectal neoplasia in asymptomatic young adults (20-39 years old).Clin Gastroenterol Hepatol. 2019; 17: 115-122Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,8Liu P.H. Wu K. Ng K. et al.Association of obesity with risk of early-onset colorectal cancer among women.JAMA Oncol. 2019; 5: 37-44Crossref PubMed Scopus (179) Google Scholar and diabetes.7Kim N.H. Jung Y.S. Yang H.J. et al.Prevalence of and risk factors for colorectal neoplasia in asymptomatic young adults (20-39 years old).Clin Gastroenterol Hepatol. 2019; 17: 115-122Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In this issue of Gastroenterology, Jin et al9Jin E.H. Han K. Lee D.H. et al.Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location.Gastroenterology. 2022; 163: 637-648Abstract Full Text Full Text PDF Scopus (1) Google Scholar continued this line of research by using the South Korean National Health Insurance Service database to conduct a cohort study of more than 5.7 million adults ages 20–49 years and more than 4.1 million adults aged ≥50 years investigating the association of obesity and metabolic syndrome with early-onset CRC. Importantly, the magnitude of the association for each of these established CRC risk factors was compared between age groups (aged 20–49 years vs ≥50 years). Also, among those in the 20–49 years age group, hazard ratio (HR) estimates were presented separately by anatomic site (proximal colon, distal colon, and rectum). Jin et al9Jin E.H. Han K. Lee D.H. et al.Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location.Gastroenterology. 2022; 163: 637-648Abstract Full Text Full Text PDF Scopus (1) Google Scholar reported that metabolic syndrome was similarly associated with an increased risk of early-onset CRC (HR, 1.20; 95% confidence interval, 1.14–1.27) and CRC in those diagnosed at ages ≥50 years (HR, 1.19; 95% confidence interval, 1.17–1.21). Higher body mass index and waist circumference were also associated with increased risk of early-onset CRC. In reporting HR estimates for early-onset CRC by anatomic site, the authors stress that “dose-response (ie, per number of metabolic syndrome components) associations were significant in distal colon and rectal cancers, though not for proximal colon cancers.” However, metabolic syndrome, overall, was significantly associated with early-onset CRC in the proximal colon, distal colon, and rectum, which suggests that metabolic syndrome is associated with early-onset CRC throughout the colon and rectum.This large study in a well-characterized cohort provides further evidence that many of the same risk factors associated with CRC, overall, are also associated with early-onset CRC. However, it falls short of shedding additional light on the factors that are driving the global increase in early-onset CRC, as well as continued increases among adults aged 50–54 in some regions of the world. Early-onset CRC does not have a stronger association with metabolic syndrome than later onset CRC and, although the prevalence of metabolic syndrome and obesity have increased globally over the same time period that early-onset CRC incidence has increased, recent evidence suggests that traditional risk factors explain only 10% of the increase in early-onset CRCs.10GBD 2019 Colorectal Cancer Collaborators. Global, regional, and national burden of colorectal cancer and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.Lancet Gastroenterol Hepatol. 2022; 7: 627-647Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar There are likely new, emerging risk factors for CRC that remain undiscovered.11Hofseth L.J. Hebert J.R. Chanda A. et al.Early-onset colorectal cancer: initial clues and current views.Nat Rev Gastroenterol Hepatol. 2020; 17: 352-364Crossref PubMed Scopus (119) Google Scholar,12Siegel R.L. Jakubowski C.D. Fedewa S.A. et al.Colorectal cancer in the young: epidemiology, prevention, management.Am Soc Clin Oncol Educ Book. 2020; 40: 1-14PubMed Google Scholar However, to date, there is a dearth of studies evaluating novel risk factors, and studies that extend beyond traditional CRC risk factors are critically needed to address the alarming rise in early-onset CRC and more recent increases in CRC after age 50 years.A key epidemiologic clue that should act to guide future investigations of risk factors is that early-onset CRC disproportionately impacts minoritized groups, including Black people.13Muller C. Ihionkhan E. Stoffel E.M. et al.Disparities in early-onset colorectal cancer.Cells. 2021; 10: 1018Crossref PubMed Scopus (9) Google Scholar Recent early-onset CRC “hotspot” analyses have also documented higher rates of early-onset CRC in areas with higher levels of poverty, lower college completion rates, and rural areas.14Rogers C.R. Moore J.X. Qeadan F. et al.Examining factors underlying geographic disparities in early-onset colorectal cancer survival among men in the United States.Am J Cancer Res. 2020; 10: 1592-1607PubMed Google Scholar Although disparities in the incidence of early-onset CRC may be driven by several factors, including a differing prevalence of traditional CRC risk factors by race, ethnicity, and sociodemographic factors, these differences do not entirely account for the excess risk of early-onset CRC among racial and ethnic minorities.13Muller C. Ihionkhan E. Stoffel E.M. et al.Disparities in early-onset colorectal cancer.Cells. 2021; 10: 1018Crossref PubMed Scopus (9) Google Scholar Thus, we need to turn toward other factors that may have increased in these populations over time.One hypothesis to explain the disproportionate impact of early-onset CRC in racial and ethnic minorities and those living in areas with poorer socioeconomic indicators points to the link between these factors and the increased cumulative burden of stress over the life course. Population-based surveys report increases in stress for children, adolescents, and young adults since the 1960s.15Twenge J.M. The age of anxiety? Birth cohort change in anxiety and neuroticism, 1952-1993.J Pers Soc Psychol. 2000; 79: 1007-1021Crossref PubMed Scopus (520) Google Scholar,16Divecha D. Our teens are more stressed than ever: why, and what can you do about it?.https://www.developmentalscience.com/blog/2019/5/7/our-teens-are-more-stressed-than-everGoogle Scholar This increase in stress is concomitant with a birth cohort effect demonstrating that the incidence of early-onset CRC began increasing among those born in the 1960s. There is also recent evidence that chronic stress is associated with CRC mortality,17Batty G.D. Russ T.C. Stamatakis E. et al.Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies.BMJ. 2017; 356: j108Crossref PubMed Scopus (178) Google Scholar and there is long-standing research showing a higher prevalence of chronic stress among some of the populations with the highest incidence of early-onset CRC, including Black populations and low-income populations.18Troxel W.M. Matthews K.A. Bromberger J.T. et al.Chronic stress burden, discrimination, and subclinical carotid artery disease in African American and Caucasian women.Health Psychol. 2003; 22: 300-309Crossref PubMed Scopus (228) Google Scholar,19Williams D.R. Yan Y. Jackson J.S. et al.Racial differences in physical and mental health: socio-economic status, stress and discrimination.J Health Psychol. 1997; 2: 335-351Crossref PubMed Scopus (2652) Google Scholar Furthermore, a growing literature suggests that chronic stress results in inflammation and increases in stress hormones that promote tumorigenesis.20Dai S. Mo Y. Wang Y. et al.Chronic stress promotes cancer development.Front Oncol. 2020; 10 (1492–1492)Crossref Scopus (59) Google Scholar Although one hypothesized link to mediate the increased risk of early-onset CRC among racial and ethnic minorities is an increasing cumulative burden of stress, other novel factors also need to be identified and investigated.Despite clear evidence from epidemiologic and histologic studies of early-onset CRC that novel risk factors are likely driving the increase in early-onset CRC, we have yet to identify any of these novel risk factors. To do so, researchers and funders must be willing to take risks by embarking on research that strays away from the usual suspects. By exploring potential novel risk factors for early-onset CRC, including increased burden of stress, changes in gut microbiota owing to antibiotic use, and increased air pollution and oxidative stress, we are poised to discover new pathways for CRC development that could inform additional avenues for CRC prevention and treatment across all age groups. See “Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location,” by Jin EH, Han K, Lee DH, et al, on page 637. See “Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location,” by Jin EH, Han K, Lee DH, et al, on page 637. See “Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location,” by Jin EH, Han K, Lee DH, et al, on page 637. For more than 3 decades, colorectal cancer (CRC) incidence rates have been increasing rapidly among adults <50 years of age (ie, early-onset CRC) in the United States and in other parts of the world.1Siegel R.L. Torre L.A. Soerjomataram I. et al.Global patterns and trends in colorectal cancer incidence in young adults.Gut. 2019; 68: 2179-2185Crossref PubMed Scopus (244) Google Scholar More recently, incidence rates have started to increase in adults ages 50–54 years old.2Zaki T.A. Singal A.G. May F.P. et al.Increasing incidence rates of colorectal cancer at ages 50-54 years.Gastroenterology. 2022; 162: 964-965.e3Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Despite broad recognition in the medical and public health communities about the increasing morbidity and mortality associated with early-onset CRC, the factors driving this increase are largely unknown. Many studies have investigated risk of early-onset CRC associated with traditional, well-known risk factors for CRC , including a Western diet,3Zheng X. Hur J. Nguyen L.H. et al.Comprehensive assessment of diet quality and risk of precursors of early-onset colorectal cancer.J Natl Cancer Inst. 2021; 113: 543-552Crossref PubMed Scopus (29) Google Scholar heavy alcohol use,4Rosato V. Bosetti C. Levi F. et al.Risk factors for young-onset colorectal cancer.Cancer Causes Control. 2013; 24: 335-341Crossref PubMed Scopus (86) Google Scholar tobacco use,5Kim J.Y. Jung Y.S. Park J.H. et al.Different risk factors for advanced colorectal neoplasm in young adults.World J Gastroenterol. 2016; 22: 3611-3620Crossref PubMed Scopus (36) Google Scholar sedentary behavior,6Nguyen L.H. Liu P.H. Zheng X. et al.Sedentary behaviors, TV viewing time, and risk of young-onset colorectal cancer.JNCI Cancer Spectr. 2018; 2: pky073Crossref PubMed Google Scholar obesity,7Kim N.H. Jung Y.S. Yang H.J. et al.Prevalence of and risk factors for colorectal neoplasia in asymptomatic young adults (20-39 years old).Clin Gastroenterol Hepatol. 2019; 17: 115-122Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar,8Liu P.H. Wu K. Ng K. et al.Association of obesity with risk of early-onset colorectal cancer among women.JAMA Oncol. 2019; 5: 37-44Crossref PubMed Scopus (179) Google Scholar and diabetes.7Kim N.H. Jung Y.S. Yang H.J. et al.Prevalence of and risk factors for colorectal neoplasia in asymptomatic young adults (20-39 years old).Clin Gastroenterol Hepatol. 2019; 17: 115-122Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar In this issue of Gastroenterology, Jin et al9Jin E.H. Han K. Lee D.H. et al.Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location.Gastroenterology. 2022; 163: 637-648Abstract Full Text Full Text PDF Scopus (1) Google Scholar continued this line of research by using the South Korean National Health Insurance Service database to conduct a cohort study of more than 5.7 million adults ages 20–49 years and more than 4.1 million adults aged ≥50 years investigating the association of obesity and metabolic syndrome with early-onset CRC. Importantly, the magnitude of the association for each of these established CRC risk factors was compared between age groups (aged 20–49 years vs ≥50 years). Also, among those in the 20–49 years age group, hazard ratio (HR) estimates were presented separately by anatomic site (proximal colon, distal colon, and rectum). Jin et al9Jin E.H. Han K. Lee D.H. et al.Association between metabolic syndrome and the risk of colorectal cancer diagnosed before 50 years according to tumor location.Gastroenterology. 2022; 163: 637-648Abstract Full Text Full Text PDF Scopus (1) Google Scholar reported that metabolic syndrome was similarly associated with an increased risk of early-onset CRC (HR, 1.20; 95% confidence interval, 1.14–1.27) and CRC in those diagnosed at ages ≥50 years (HR, 1.19; 95% confidence interval, 1.17–1.21). Higher body mass index and waist circumference were also associated with increased risk of early-onset CRC. In reporting HR estimates for early-onset CRC by anatomic site, the authors stress that “dose-response (ie, per number of metabolic syndrome components) associations were significant in distal colon and rectal cancers, though not for proximal colon cancers.” However, metabolic syndrome, overall, was significantly associated with early-onset CRC in the proximal colon, distal colon, and rectum, which suggests that metabolic syndrome is associated with early-onset CRC throughout the colon and rectum. This large study in a well-characterized cohort provides further evidence that many of the same risk factors associated with CRC, overall, are also associated with early-onset CRC. However, it falls short of shedding additional light on the factors that are driving the global increase in early-onset CRC, as well as continued increases among adults aged 50–54 in some regions of the world. Early-onset CRC does not have a stronger association with metabolic syndrome than later onset CRC and, although the prevalence of metabolic syndrome and obesity have increased globally over the same time period that early-onset CRC incidence has increased, recent evidence suggests that traditional risk factors explain only 10% of the increase in early-onset CRCs.10GBD 2019 Colorectal Cancer Collaborators. Global, regional, and national burden of colorectal cancer and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019.Lancet Gastroenterol Hepatol. 2022; 7: 627-647Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar There are likely new, emerging risk factors for CRC that remain undiscovered.11Hofseth L.J. Hebert J.R. Chanda A. et al.Early-onset colorectal cancer: initial clues and current views.Nat Rev Gastroenterol Hepatol. 2020; 17: 352-364Crossref PubMed Scopus (119) Google Scholar,12Siegel R.L. Jakubowski C.D. Fedewa S.A. et al.Colorectal cancer in the young: epidemiology, prevention, management.Am Soc Clin Oncol Educ Book. 2020; 40: 1-14PubMed Google Scholar However, to date, there is a dearth of studies evaluating novel risk factors, and studies that extend beyond traditional CRC risk factors are critically needed to address the alarming rise in early-onset CRC and more recent increases in CRC after age 50 years. A key epidemiologic clue that should act to guide future investigations of risk factors is that early-onset CRC disproportionately impacts minoritized groups, including Black people.13Muller C. Ihionkhan E. Stoffel E.M. et al.Disparities in early-onset colorectal cancer.Cells. 2021; 10: 1018Crossref PubMed Scopus (9) Google Scholar Recent early-onset CRC “hotspot” analyses have also documented higher rates of early-onset CRC in areas with higher levels of poverty, lower college completion rates, and rural areas.14Rogers C.R. Moore J.X. Qeadan F. et al.Examining factors underlying geographic disparities in early-onset colorectal cancer survival among men in the United States.Am J Cancer Res. 2020; 10: 1592-1607PubMed Google Scholar Although disparities in the incidence of early-onset CRC may be driven by several factors, including a differing prevalence of traditional CRC risk factors by race, ethnicity, and sociodemographic factors, these differences do not entirely account for the excess risk of early-onset CRC among racial and ethnic minorities.13Muller C. Ihionkhan E. Stoffel E.M. et al.Disparities in early-onset colorectal cancer.Cells. 2021; 10: 1018Crossref PubMed Scopus (9) Google Scholar Thus, we need to turn toward other factors that may have increased in these populations over time. One hypothesis to explain the disproportionate impact of early-onset CRC in racial and ethnic minorities and those living in areas with poorer socioeconomic indicators points to the link between these factors and the increased cumulative burden of stress over the life course. Population-based surveys report increases in stress for children, adolescents, and young adults since the 1960s.15Twenge J.M. The age of anxiety? Birth cohort change in anxiety and neuroticism, 1952-1993.J Pers Soc Psychol. 2000; 79: 1007-1021Crossref PubMed Scopus (520) Google Scholar,16Divecha D. Our teens are more stressed than ever: why, and what can you do about it?.https://www.developmentalscience.com/blog/2019/5/7/our-teens-are-more-stressed-than-everGoogle Scholar This increase in stress is concomitant with a birth cohort effect demonstrating that the incidence of early-onset CRC began increasing among those born in the 1960s. There is also recent evidence that chronic stress is associated with CRC mortality,17Batty G.D. Russ T.C. Stamatakis E. et al.Psychological distress in relation to site specific cancer mortality: pooling of unpublished data from 16 prospective cohort studies.BMJ. 2017; 356: j108Crossref PubMed Scopus (178) Google Scholar and there is long-standing research showing a higher prevalence of chronic stress among some of the populations with the highest incidence of early-onset CRC, including Black populations and low-income populations.18Troxel W.M. Matthews K.A. Bromberger J.T. et al.Chronic stress burden, discrimination, and subclinical carotid artery disease in African American and Caucasian women.Health Psychol. 2003; 22: 300-309Crossref PubMed Scopus (228) Google Scholar,19Williams D.R. Yan Y. Jackson J.S. et al.Racial differences in physical and mental health: socio-economic status, stress and discrimination.J Health Psychol. 1997; 2: 335-351Crossref PubMed Scopus (2652) Google Scholar Furthermore, a growing literature suggests that chronic stress results in inflammation and increases in stress hormones that promote tumorigenesis.20Dai S. Mo Y. Wang Y. et al.Chronic stress promotes cancer development.Front Oncol. 2020; 10 (1492–1492)Crossref Scopus (59) Google Scholar Although one hypothesized link to mediate the increased risk of early-onset CRC among racial and ethnic minorities is an increasing cumulative burden of stress, other novel factors also need to be identified and investigated. Despite clear evidence from epidemiologic and histologic studies of early-onset CRC that novel risk factors are likely driving the increase in early-onset CRC, we have yet to identify any of these novel risk factors. To do so, researchers and funders must be willing to take risks by embarking on research that strays away from the usual suspects. By exploring potential novel risk factors for early-onset CRC, including increased burden of stress, changes in gut microbiota owing to antibiotic use, and increased air pollution and oxidative stress, we are poised to discover new pathways for CRC development that could inform additional avenues for CRC prevention and treatment across all age groups. Association Between Metabolic Syndrome and the Risk of Colorectal Cancer Diagnosed Before Age 50 Years According to Tumor LocationGastroenterologyVol. 163Issue 3PreviewAn evaluation of 5.7 million young Koreans (aged 20–49 years) revealed that metabolic syndrome and obesity were associated with an increased risk of earlier-onset colorectal cancer in the left colon. Full-Text PDF