The estimated annual incidence of colorectal cancer (CRC) worldwide is 1.3 million, making it the third most common cancer in males and the second most common cancer in females.1 There is wide geographic, racial, and ethnic variation in incidence and patterns, with 55% of cases occurring in high-resource nations. Higher proportions of colon cancers than rectal cancers (RC) and increased onset after age 50 are characteristics of CRC in high-income countries.2 A recent analysis of the Surveillance, Epidemiology, and End Results data for 393,241 patients with CRC between 1975 and 2010 showed an overall decreasing trend in the incidence and mortality rates of CRC in the United States.3 However, the incidence in younger adults showed an increasing trend with a striking rectal preponderance. A previous analysis revealed that the incidence of RC increased 3.8% per year between 1984-2005 among people aged 40 and younger.4 Data from the United States suggests that approximately 11% of colon cancers and 18% of RCs occur in individuals younger than age 50.4 These cancers are more likely to be poorly differentiated, have mucinous and signet ring features, and present at advanced stages. Familial syndromes account for approximately 20% of these cases. Possible reasons for this disturbing trend are speculated to be lack of screening in young adults and lifestyle factors, such as obesity, physical inactivity, and a diet rich in processed foods and red meat with a low intake of fruits and vegetables.3
Low-resource countries such as India have reported CRC incidence rates of 4.2 and 3.2 per 100,000 in males and females, respectively.5 This is relatively low when compared with data from high-resource nations, where the incidence ranges from 25-44 per 100,000.1 The highest estimated rates have been reported from Australia and New Zealand with age-adjusted rates of 44.8 and 32.2 per 100,000 in males and females, respectively. The traditional Indian diet, consisting predominantly of plant-based, fiber-rich foods and antioxidant-rich spices, has been postulated to be protective.6 Available data, however, indicate a steady rise in incidence, presumably a result of increasing urbanization and changing lifestyles and dietary patterns.7 However, these factors still do not sufficiently explain the striking differences that have been noted in the clinicopathologic profile of CRCs occurring in India when compared with their Western counterparts, with chief among these differences being a significantly lower median age of incidence and a rectal preponderance.8,9
|The estimated annual incidence of colorectal cancer (CRC) worldwide is
1.3 million, making it the third most common cancer in males and the second most common cancer in females.
|There is an increase in CRC incidence in low-income countries and a significantly higher proportion of early-onset cancers.|
|There is a rising incidence of CRC in young adults from diverse geographic and ethnic backgrounds, which could be linked to environmental pollution or lifestyle factors, such as obesity, physical inactivity, and a diet rich in processed foods.|
An analysis of the “Cancer Incidence in Five Continents” database shows an increase in CRC incidence in resource-constrained countries, including India, with a significantly higher proportion of early-onset cancers.10 Data from various oncology centers in India suggest that the ratio of early- to late-onset cancers ranges from 0.52-0.64, which is strikingly higher than the international average of 0.07.11 A substantial proportion of early-onset cancers are of rectal origin with poorly differentiated histology and advanced stage at diagnosis. Most of these cases have been reported as sporadic in onset, with no known familial predisposition. Data from other highly populated resource-constrained countries in Asia, such as Israel,12 Nepal,13 Saudi Arabia,14 Iran,15 Pakistan,16,17 Taiwan,18 Jordan,19 Egypt,20 Singapore,21 and Bangladesh,22 reveal similar patterns of incidence. Data from African countries are sparse, although a report from Nigeria23 showed findings similar to those from resource-constrained Asian nations.
Young-Onset CRC in Resource-Constrained Countries: A Distinct Genetic Entity?
In the Western world, there have been major advances in knowledge of molecular mechanisms involved in CRC carcinogenesis, particularly regarding cytogenetic and epigenetic events. It is now recognized that there are at least three major pathways that lead to colorectal carcinogenesis: the chromosomal instability pathway (CIN), the microsatellite instability pathway (MSI), and the cytosine-phosphate-guanine island meth-ylator phenotype pathway (CIMP).24 CIN accounts for approximately 70%-85% of all sporadic CRCs in the Western population. These cancers are often distal in location and are associated with poorer outcomes, regardless of stage.25 MSI results from point mutations in defect mismatch repair genes and is associated with approximately 15%-20% of sporadic CRCs. These tumors are usually proximally located with mucinous histology, poor differentiation, and a dense lymphocytic infiltration. CIMP, the third most commonly involved event, is characterized by widespread methylation of cytosine-phosphate-guanine islands of suppressor promoters. Sporadic MSI tumors are usually CIMP-positive and are predominantly located in the proximal colon (up to 40%). Activating mutations in BRAF occur almost exclusively in MSI- and CIMP-positive CRC. Mutations in KRAS are more commonly seen CIMP-low tumors.
In contrast, very little is known about the genetic and epigenetic alterations in CRC from resource-constrained countries. Emerging data seem to suggest that these cancers have distinct characteristics that are substantially different from their Western counterparts. An analysis of one of the first studies on genetic, epigenetic, and clinical profiles of RC from India revealed that 52% of patients were younger than age 45, with a higher percentage of low-rectal, advanced-stage, and aggressive tumors (poorly differentiated/mucinous).26 MSI and BRAF mutations were uncommon and seen in 5.0% and 2.5% of samples, respectively, but high frequencies of overall KRAS mutations (67.5%) were seen. Thirty-eight percent of patients had CIMP-high, KRAS-mutated tumors. The younger patients exhibited higher codon 15 and 18 KRAS mutations as compared to the older patients, who showed mutations more commonly in codon 12 or 13, similar to their Western counterparts. This study also revealed a novel KRAS G15S mutation with concomitant RASSF1 methylation in early-onset cases, findings that have not been previously reported. The investigators noted that the early-onset subgroup showed the most unfavorable disease characteristics, including advanced stage, poorly differentiated tumors, and the poorest survival outcomes. A few previous studies from early-onset Indian and Bangladeshi patients with CRC also reported similar findings.27,28
Molecular studies comparing early- and late-onset CRC have been rare. One such study from India27 compared early- (age ≤ 50 years) versus late-onset (age ≥ 60 years) CRC with respect to common genetic aberrations including Wnt, KRAS, p53, and MSI. They found that only 54.6% of cases exhibited substantial b-catenin nuclear localization in contrast to 80%-100% reported in the Western literature.9 More significantly, the b-catenin nuclear positivity was substantially lower in early- versus late-onset tumors (46% vs. 64%). Although not statistically significant, the proportion of MSI-positive samples was higher in early-onset (40%) when compared to late-onset (30%) tumors. In MSI-negative samples, Wnt activation was significantly lower in early- (42.8%) compared with late-onset (78.0%) samples. More importantly, the proportion of Wnt-negative, MSI-negative samples was higher in early- (34%) compared to late-onset (16%) CRC samples, which strongly suggests that early-onset CRC is driven by non-canonical pathways in Indian patients.
Possible HPV Connection
Certain oncogenic subtypes of HPV have been conclusively implicated in cancers of the cervix, head and neck, and anal canal. Many investigators have attempted to find an association between HPV and CRC, with discrepant results. Recently, two meta-analyses with data from 16 and 37 studies showed a 10-fold29 and 6-fold30 higher risk of CRC with HPV positivity, respectively. More specifically, HPV prevalence varied by geographical region, with the highest prevalence in South America, followed by Asia and the Middle East, suggesting a possible correlation linking high-risk sexual behavior, lifestyle, and HPV infection with CRC rates in resource-constrained countries. Laskar et al.26 detected HPV DNA in 31.2% of patients with RC in their study, of which 76% had HPV subtype 18, 8% had subtype 16, 8% had both subtypes 16 and 18, and 8% had subtypes other than 18 and 16.
Environmental Pollution and CRC: A Growing Body of Evidence
Young-onset CRCs exhibit more aggressive pathologic characteristics and advanced stage at presentation. Most of these cases occur sporadically, with no known genetic or familial risk factors. Considering that dietary patterns in countries such as India are largely thought to be protective, the large proportion of patients presenting who are younger than age 45 has baffled clinicians.
Growing urbanization has brought a substantial rise in pollution levels in Southeast Asian and Eastern Mediterranean countries. Air pollution indices in these countries are among the highest in the world.31 The International Agency for Research on Cancer has classified outdoor air pollution as a carcinogen,32 conclusively linking it to lung and bladder cancers. A few studies have strongly suggested a possible link of CRC with chlorinated water and chemical and pesticide pollution of food.33
Although many studies have suggested an etiologic role for tobacco, alcohol, and HPV, little attention has been paid to factors such as occupational exposures, environmental and industrial pollution, and risk factors that have evolved in parallel to the incidence of these tumors. Publications on the topic are few and, in many cases, rather inconclusive. Pesticide remains and nitrate pollutants can easily contaminate surface water, and various studies have demonstrated a positive correlation to CRC. An epidemiologic study from China demonstrated that populations drinking surface and well water have higher RC and colon cancer risk than those using municipal groundwater.34 The consumption of pesticides in India has increased several hundred–fold, from 154 metric tons in 1954 to 41,822 metric tons in 2009-2010.35 Pesticides enter surface and groundwater primarily as runoff from crops and are most prevalent in agricultural areas. In most low-income countries, including India, it is estimated that approximately 10% of the contaminated water generated from various sources is treated; the rest is discharged as such into water bodies. Such water, which ultimately ends up being used in households, is often highly contaminated with chemicals and pesticides and can potentially cause various adverse health effects, including cancer.36,37
The Agricultural Health Study from the United States has demonstrated an elevated risk of CRC with exposure to pesticides.38 A cohort of 2,449 pesticide users in Iceland showed a 3-fold increased incidence of RC.39 Similar findings have been reported among farmers in Italy.40 In an epidemiologic correlation study, investigators from Egypt reported a high incidence of young-onset CRC, with over a third of patients younger than age 40 with a rectal preponderance, and noted a substantially elevated risk in people with pesticide exposures (odds ratio [OR] = 2.6) and in agricultural workers who ate food items from the field for half the time or more (OR = 4.6).41
Dumping sites for industrial wastes are largely unregulated in most low-income countries and can potentially result in soil and water pollution, with consequent health hazards. One study found that concentrations of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and coplanar polychlorinated biphenyls in soils from dumping sites in the Philippines, Cambodia, India, and Vietnam often exceeded environmental guideline values.42 In an analysis from Spain, CRC-related mortality rates were substantially higher in populations residing closer to industrial areas, particularly mines and refineries, among others.43 A recent review suggests that occupational exposures increase the risk of CRC by 11%-15% among laborers working in leather, basic metals, plastic, and rubber-manufacturing industries, including workers in the sector of repair and installation of machinery who are exposed to asbestos.44 Recently, a large rise in the incidence and mortality from gastrointestinal and other cancers was reported in the media from villages in the vicinity of the industrial belt near the National Capital Region of India.45 Local groups alleged that there is widespread unregulated dumping of industrial wastes and chemicals into the groundwater. A few studies from the Indian state of Punjab, one of the major agricultural areas with the highest consumption of pesticides in the country, show substantially increased cancer incidence and mortality rates.46 These rates correlated positively with a high level of pesticides in the water, soil, and blood samples of exposed persons. However, there are currently no large-scale epidemiologic studies conducted in India to clearly determine the association between pollution and cancer.
A Call to Action
There is a rising incidence of CRC in young adults from diverse geographic and ethnic backgrounds. Etiologic factors for the alarming increase in the proportion of young-onset CRC in low-income countries are inconclusive. Available evidence suggests that these tumors show distinct clinical patterns and genetic changes that are different from the classical CRC occurring in older adults in the Western population. Neither dietary and lifestyle nor genetic factors are sufficient to explain this phenomenon. The growing magnitude and aggressive behavior of these tumors warrant a comprehensive exploration of potential risk factors, including water and air pollution, initiation of preventive strategies, and screening programs.
The negative effects of pollution on health are undeniable, and there is mounting evidence to implicate its role in cancer causation. Proactive legislative measures and policy changes to reduce environmental pollution are the need of the hour and require a strong commitment from government and other stakeholders. Global oncology societies and multinational organizations can play a vital role in increasing awareness, aggregating and analyzing data, and initiating, coordinating, and supporting efforts towards control and preventive strategies.
About the Author: Dr. Malik is a radiation oncologist at Nizam’s Institute of Medical Sciences, in Hyderabad, India. Dr. Malik has been an ASCO member for 10 years and has served on the Membership and International Affairs Committees and has also participated in the Leadership Development Program.