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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Gut. Author manuscript; available in PMC 2012 March 1.
Published in final edited form as:
Published online 2010 October 29. doi:  10.1136/gut.2010.217182
PMCID: PMC3040598

Molecular Pathologic Epidemiology of Colorectal Neoplasia: An Emerging Transdisciplinary and Interdisciplinary Field


Colorectal cancer is a complex disease resulting from somatic genetic and epigenetic alterations, including locus-specific CpG island methylation and global DNA or LINE-1 hypomethylation. Global molecular characteristics such as microsatellite instability (MSI), CpG island methylator phenotype (CIMP), global DNA hypomethylation, and chromosomal instability cause alterations of gene function in a genome-wide scale. Activation of oncogenes including KRAS, BRAF and PIK3CA affects intracellular signaling pathways and has been associated with CIMP and MSI. Traditional epidemiology research has investigated various factors in relation to an overall risk of colon and/or rectal cancer. However, colorectal cancers comprise a heterogeneous group of diseases with different sets of genetic and epigenetic alterations. To better understand how a particular exposure influences the carcinogenic process, somatic molecular changes and tumor biomarkers have been studied in relation to the exposure of interest. Moreover, an investigation of interactive effects of tumor molecular changes and the exposures of interest on tumor behavior (prognosis or clinical outcome) can lead to a better understanding of tumor molecular changes, which may be prognostic or predictive tissue biomarkers. These new research efforts represent “Molecular Pathologic Epidemiology”, which is a multidisciplinary field of investigations of the interrelationship between exogenous and endogenous (e.g., genetic) factors, tumoral molecular signatures and tumor progression. Furthermore, integrating genome-wide association studies (GWAS) with molecular pathologic investigation is a promising area. Examining the relationship between susceptibility alleles identified by GWAS and specific molecular alterations can help elucidate the function of these alleles and provide insights into whether susceptibility alleles are truly causal. Although there are challenges, molecular pathologic epidemiology has unique strengths, and can provide insights into the pathogenic process and help optimize personalized prevention and therapy. In this review, we overview this relatively new field of research and discuss measures to overcome challenges and move this field forward.

Keywords: colorectal carcinoma, multistep carcinogenesis, etiologic, risk factor, survival, molecular change, prevention

Introduction to Molecular Pathologic Epidemiology

Molecular pathologic epidemiology, the concept of which has been consolidated by Ogino and Stampfer, [1] is a relatively new field of epidemiology based on molecular classification of cancer. In molecular pathologic epidemiology, a known or suspected etiologic factor is examined in relation to a specific somatic molecular change, in order to gain insights into the carcinogenic mechanism.[1] In recent years, there is a new direction of this field where we examine an interactive effect of tumoral molecular features and a lifestyle or other exposure factor on tumor behavior (prognosis or clinical outcome).[2] In this review, we focus on colorectal neoplasia, overview current status of molecular pathologic epidemiology, describe various challenges in this field, and propose future directions.

Molecular Classification of Colorectal Cancer

Colorectal cancer is a disease which is characterized by uncontrolled growth of colorectal epithelial cells. According to the multistep carcinogenesis theory, [3, 4] colorectal epithelial cells accumulate a number of molecular changes and eventually become fully malignant cells. Genetic and epigenetic events during the carcinogenesis process differ considerably from tumor to tumor. Thus, colorectal cancer is not a single disease. Rather, colorectal cancer encompasses a heterogeneous complex of diseases with different sets of genetic and epigenetic alterations. Essentially, each tumor arises and behaves in a unique fashion that is unlikely to be exactly recapitulated by any other tumor.[5]

We typically classify colorectal cancers into categories according to a well-defined molecular feature (e.g., microsatellite instability, MSI-high vs. microsatellite stability, MSS), because substantial evidence suggests that tumors with similar characteristics (e.g., MSI-high) have arisen by similar mechanisms and will behave in a similar fashion.[5] Thus, the major purposes of molecular classification are: 1) to predict natural history (i.e., prognosis); 2) to predict response or resistance to a certain treatment or intervention; and 3) to examine the relationship between a certain etiologic factor (i.e., lifestyle, environmental or genetic) and a molecular subtype, so that we can provide evidence for causality and optimize preventive strategies.

For any marker for molecular classification, we need to consider two key points. The first question is whether a given molecular feature reflects genome-wide changes. For example, MSI, chromosomal instability (CIN), the CpG island methylator phenotype (CIMP), and global DNA hypomethylation reflect genome-wide or epigenome-wide aberrations. Because these molecular features often confound the relationship between a locus-specific change and an exposure or outcome of interest, it is important to consider potential confounding by these genome-wide features whenever one examines locus-specific changes. The second question is whether a given molecular change has by itself driven cancer initiation or progression, or is simply linked to other important molecular events. For example, loss of heterozygosity (LOH) events may not by itself cause tumor progression; rather, underlying genomic instability (i.e., CIN) or functional loss of important genes within the lost chromosomal segment may cause tumor progression. Nevertheless, even if a given molecular change is consequential rather than causal, the change not only can be a good surrogate marker of a certain cancer pathway, but also may ultimately become a driver in later steps of tumor progression.

Emergence and Evolution of Molecular Pathologic Epidemiology

Traditional epidemiology research has investigated lifestyle, environmental or genetic factors that might increase or decrease risk of developing colorectal cancer.[6, 7] The weight of the evidence, in conjunction with results from in vitro and animal models or human experimental trials, can lead to particular factors being widely considered to be etiologically linked to cancer. Etiologic factors which have been implicated in colorectal carcinogenesis include red and processed meat, excess alcohol intake, deficiency of B and D vitamins, obesity, physical inactivity, diabetes mellitus, smoking, family history of colorectal cancer, inflammatory bowel diseases, among others.[8] More recently, the field of molecular epidemiology has evolved since 1990s, encompassing genome-wide association studies (GWAS) since 2000s.[9, 10] Molecular epidemiology refers to a specialized field of epidemiology where investigators examine genetic and molecular variation in a population and its interaction with dietary, lifestyle or environmental factors, to find clues to plausible causative links between etiologic factors and diseases. However, the mechanisms with which plausible etiologic factors influence the carcinogenic process remain largely speculative.

In traditional molecular pathology, investigators examine molecular characteristics in tumor cells to better understand carcinogenic processes and tumor cell behavior. In the last two decades, our knowledge on somatic molecular alterations in the carcinogenic process has substantially improved.[5, 1116] As illustrated in Figure 1, these two approaches, epidemiology and molecular pathology, have converged to improve our understanding of how certain exposures influence carcinogenesis by examining molecular pathologic marks of tumor initiation or progression, in relation to the exposures of interest.[1] This represents a relatively new field of scientific investigation, which has been coined “Molecular Pathologic Epidemiology”.[1] If a specific lifestyle or dietary factor can prevent the occurrence of a specific somatic molecular change, it would add considerable scientific basis to such a preventive strategy. Specificity of the association for a certain molecular change provides further evidence for a causal relationship. For an individual who has a susceptibility to a specific somatic molecular change, we may be able to develop a personalized preventive strategy, which targets specific molecules or pathways.

Figure 1
Illustration of traditional epidemiology (A), traditional molecular pathology (B), and molecular pathologic epidemiology (C). Note that molecular pathology plays a central role in molecular pathologic epidemiology. Molecular pathologic epidemiology addresses ...

Table 1 is a comprehensive list of molecular pathologic epidemiology studies on colorectal neoplasia.[1745][4688][89101][102151] One challenge is that, despite a number of studies on some topics (e.g., one-carbon metabolism gene polymorphisms and epigenetic changes), generalisable confirmed findings are uncommon. We discuss possible reasons and various challenges in a later section. Nonetheless, there have been observations confirmed by notable independent studies: a case-control study by the Slattery et al.’s group[114] and a prospective cohort study by Iowa Women’s Health Study (IWHS)[78] have independently shown that cigarette smoking is associated with CIMP-positive tumor, and with BRAF-mutated tumor. As another example, the association between obesity and microsatellite stable (MSS) tumor has been demonstrated by three independent case-control studies, including the Slattery et al.’s group, [123] North Carolina Colon Cancer Study (NCCCS), [116] and Colon Cancer Family Registry (CCFR).[35] With regard to germline genetic variants and molecular changes, MLH1 rs1800734 promoter SNP has been associated with MSI-high tumors in three independent case-case and case-control studies, [38, 108, 115] and MGMT rs16906252 promoter SNP has been associated with MGMT promoter methylation and loss of expression in colorectal cancer[94] and normal colorectal mucosa and peripheral blood cells in individuals without cancer.[152, 153] These consistent data across different studies increase validity of each other’s findings and support etiologic roles of cigarette smoking, obesity and germline variants in specific pathways of colorectal carcinogenesis. Ultimately, our understanding of these specific neoplasia pathways will clarify areas for disease intervention.

Table 1
Molecular pathologic epidemiology studies on possible etiologic factors and molecular changes in colorectal neoplasia

Recently, GWAS have identified a number of candidate susceptibility loci for colorectal cancer.[9, 10] Currently, a significant limitation in interpreting GWAS results is our limited understanding of the functional relevance of risk alleles identified by GWAS. As a promising future direction, a molecular pathologic epidemiology approach can be used to validate findings of GWAS in certain ways. First, if a candidate cancer susceptibility variant is hypothesized to regulate expression of a nearby gene, the relationship between the variant and gene expression in tumor tissue can be examined.[59] Second, if a candidate variant is hypothesized to cause a genetic or epigenetic alteration in a critical pathway, the relationship between the variant and tumoral molecular alterations in the particular pathway can be examined.[134] Specificity of the relationship between the variant and the tumor molecular alterations will provide additional evidence to support a causal effect of the putative cancer susceptibility allele.

Additional examples of studies and findings on three specific areas (energy balance, inflammation, and one-carbon metabolism) will be discussed in later sections because these have been particularly active areas of investigations.

Study Design in Molecular Pathologic Epidemiology

Figure 2 illustrates three basic approaches to investigate the relationship between an exposure (e.g., smoking) and a tumor molecular change (e.g., KRAS mutation). A fourth approach, an interventional cohort study (not illustrated in Figure 2) is a gold standard; however, to date no interventional molecular pathologic epidemiology data have been published.

Figure 2
Comparison of a case-case study design (A), a case-control study design (B) and a prospective cohort study design (C). Smoking status is used as an example of an exposure variable, and KRAS mutation status in colorectal cancer as an outcome variable. ...

The first approach is a “case-case” approach (Figure 2A), where tumors are classified into subtypes according to a molecular feature, and then distributions of an exposure variable of interest among different subtypes are compared. For example, if it is hypothesized that smoking causes KRAS mutation, one may expect to observe that KRAS-mutated cancer patients contain a higher fraction of smokers than KRAS-wild-type cancer patients. A limitation of this approach is that it is not possible to obtain information on distribution of an exposure variable among the background population that has given rise to the cancer cases. Thus, the direction of any association cannot be determined; if there is a positive association between smoking and KRAS-mutated tumors (i.e., a negative association between smoking and KRAS-wild-type tumors), it is uncertain whether smoking protects against KRAS-wild-type tumors, or smoking causes KRAS-mutated tumors.

The second approach is a case-control study (Figure 2B), where non-cancer control subjects should ideally be randomly sampled from the background population that has given rise to the cancer cases. In traditional cancer epidemiology, distributions of an exposure of interest between cases and controls are compared. In molecular pathologic epidemiology, one can compare distributions of a given exposure between cancer cases with a specific molecular alteration (e.g., KRAS mutation), cancer cases without the alteration, and controls. If the exposure has caused the particular alteration, it is expected to see a higher fraction of exposed individuals among cancer cases with the alteration but not among cancer cases without the alteration, compared to controls. Nevertheless, case-control approaches in molecular pathologic epidemiology face the same inherent limitations of traditional case-control studies. Such caveats include recall bias, differential selection bias between cases and controls, among others. One advantage of a case-control design over a prospective cohort design is its relative ease to recruit a large number of colorectal cancer cases. Important examples of case-control studies include Colon Cancer Family Registry (CCFR), [26, 34, 35, 39, 56, 66, 76, 77, 79, 80, 106, 107, 154] a population-based case-control study of colorectal cancer by Slattery et al., [4145, 113115, 123139, 155, 156] and the Molecular Epidemiology of Colorectal Cancer Study (MECCS) in northern Israel.[59, 110, 111, 157159]

The third approach is a prospective cohort study (Figure 2C), which is less prone to potential bias related to case-case and case-control designs. A nested case-control design, a case-case design within a prospective cohort study, and a case-cohort design[160] are derivatives of prospective cohort studies. In molecular pathologic epidemiology, investigators examine the incidence rates of cancer with a specific alteration (e.g., KRAS mutation) in exposed vs. unexposed individuals, as well as the incidence rates of cancer without the specific alteration in exposed vs. unexposed individuals. If the exposure causes the particular alteration, one would expect to see a higher incidence rate of cancer with the alteration in exposed individuals than in unexposed individuals, and similar incidence rates of cancer without the alteration between the exposed and unexposed groups. In molecular pathologic epidemiology of colorectal cancer, to date, seven prospective cohort studies have published substantial data: European Prospective Investigation into Cancer and Nutrition (EPIC), [89, 103, 161164] the Health Professionals Follow-up Study (HPFS), [2, 1825, 36, 61, 65, 72, 91101, 118, 119, 121] the Iowa Women’s Health Study (IWHS), [78, 165, 166] the Melbourne Collaborative Cohort Study (MCCS), [53, 167169] the Netherlands Cohort Study (NLCS), [2833, 4648, 64, 8284, 141, 144, 146, 147] the Northern Sweden Health and Disease Study (NSHDS), [142, 170, 171] and the Nurses’ Health Study (NHS).[2, 1825, 36, 61, 65, 72, 91101, 117119, 121, 172] Prospective cohort studies require substantial amounts of participants, follow-up time and funding support, and substantial efforts of researchers and other personnel. Therefore, judicious utilization of the existing resource of prospective cohort studies is a cost effective approach.

Interactive Effect of Exposure and Tumoral Feature on Tumor Aggressiveness: New Direction of Molecular Pathologic Epidemiology

As a new direction of molecular pathologic epidemiology, our group has started examining how lifestyle or genetic factors interact with tumor molecular features to influence tumor cell behavior (prognosis or clinical outcome). Table 2 lists studies on interactive prognostic effects of lifestyle or genetic factors and tumoral features in colorectal cancer.[2, 1821, 57, 72, 92, 93, 95101, 173178] In traditional molecular pathology, investigators examine tumoral molecular characteristics to better predict prognosis and response to specific treatments.[11] In addition to tumoral molecular features, lifestyle, environmental or genetic factors likely influence tumor cell behavior through the tumor microenvironment. Lifestyle factors (e.g., physical activity or smoking) or genetic factors (e.g., SNPs or family history) have been shown to influence clinical outcome of colorectal cancer patients.[168, 179185] To better understand how a certain lifestyle, environmental or genetic factor influences tumor cell behavior, it is of interest to examine interactive prognostic effects of the lifestyle, environmental or genetic factor and tumoral molecular features. If a particular exposure is associated with worse outcome only among patients with a specific tumoral molecular change, but not among those without the molecular change, this provides evidence that the exposure factor might influence tumor aggressiveness through that molecular change or pathway. We will discuss specific examples in the following sections.

Table 2
Molecular pathologic epidemiology studies to examine interactive prognostic effects of lifestyle or other etiologic factors and tumoral somatic changes in colorectal cancer.

Interactive Prognostic Effects of Obesity, Physical Activity and Tumoral Changes

Studies have shown that obesity is associated with worse survival of colon cancer patients.[168, 186189] However, how obesity affects clinical outcome of cancer patients remains largely unknown. In 2008, our group started a new direction of molecular pathologic epidemiology, to examine an interactive prognostic effect of obesity (prediagnosis body mass index, BMI) and FASN (fatty acid synthase) expression in colon cancer.[2] We found that the adverse prognostic effect of obesity was present in patients with FASN-positive colon cancers, but not in patients with FASN-negative colon cancers.[2] These data suggest that excessive energy present in obese patients may contribute to growth and proliferation of tumor cells with FASN activation.[2] This study has opened new opportunities for investigating how lifestyle factors affect tumor cell behavior through cellular molecules. In traditional epidemiology, investigators examine the relationship between an exposure factor (e.g., obesity) and survival of cancer patients regardless of tumor molecular subtype; thus, mechanistic hypotheses remain speculative. For example, it is hypothesized that obesity increases tumor aggressiveness potentially through a certain cellular molecule such as FASN. Without analysis of FASN in tumor, the hypothesis still remains speculative. In molecular pathologic epidemiology, we can specifically test the hypothesis by examining the relations between obesity and patient survival in tumor FASN-positive cases and between obesity and patient survival in tumor FASN-negative cases.[2] If the hypothesis is true, we expect to observe the significant obesity/survival relationship in FASN-positive cases, but not in FASN-negative cases.[2]

Our subsequent investigations have found that a number of other tumor molecular changes interact with prediagnosis BMI to modify tumor aggressiveness.[96, 98, 99] Those tumor changes include STMN1 expression, [96] CDKN1A (p21) expression, [99] and CDKN1B (p27) cellular localization, [98] all of which have been linked to energy balance and related signal transduction pathways.[190193] In addition, our analysis on interactive prognostic effects of physical activity and tumor markers have revealed that postdiagnosis physical activity is beneficial only in patients with CDKN1B-nuclear-positive colon cancers, but not in patients with CDKN1B-altered or lost colon cancers.[174] These results collectively provide evidence for tumor-host interactions (energy balance status and tumor molecular alterations) that influence tumor cell behavior.

Inflammation and Carcinogenesis

Epidemiological studies have shown that regular use of aspirin or non-steroidal anti-inflammatory drug (NSAID) is associated with decreased risks of colorectal cancer and adenomas.[194203] Randomized trials have confirmed that regular use of aspirin[204206] or other inhibitors of PTGS2 (prostaglandin endoperoxide synthase 2, cyclooxygenase-2, COX-2)[207209] decreases risk of developing colorectal adenomas. Experimental evidence suggests an important role of PTGS2 in colorectal carcinogenesis.[210212] Thus, it is hypothesized that PTGS2 (COX-2) inhibitors may prevent colorectal tumor through inhibition of PTGS2. Molecular pathologic epidemiology research has provided further insights on mechanisms of cancer preventive effect of PTGS2 inhibition. Utilizing the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we found that regular aspirin use decreases risk of cancers with PTGS2 (COX-2) overexpression, but not that of cancers without PTGS2 overexpression.[36] This specific inverse association between aspirin use and incidence of PTGS2-positive cancer provides further evidence for the carcinogenic role of PTGS2 (COX-2), and for the role of PTGS2 (COX-2) inhibitors in cancer prevention.

We have also shown that PTGS2 (COX-2) overexpression is associated with aggressive tumor behavior, [176] and that regular aspirin use after colorectal cancer diagnosis significantly decreases mortality in patients with PTGS2-positive cancers, but not in patients with PTGS2-negative cancers.[173] This specificity of the relation between aspirin use and low mortality in PTGS2-expressing cases provides additional evidence for the role of PTGS2 inhibition in prevention of cancer progression.

One-Carbon Metabolism, Germline Variants, and Somatic Epigenetic Changes

Colorectal cancer is a complex disease resulting from both genetic and epigenetic alterations, including abnormal DNA methylation patterns.[213, 214] DNA hypomethylation at LINE-1 repetitive elements has been associated with poor prognosis in colon cancer.[177] LINE-1 hypomethylation may provide alternative promoter activation, [215] and contribute to non-coding RNA expression that regulates expression of many genes.[216, 217] Retrotransposons activated by DNA hypomethylation may transpose themselves throughout the genome, leading to gene disruptions[218] and chromosomal instability (CIN).[219, 220] In addition, there exists a specific tumor phenotype – the CpG island methylator phenotype (CIMP), characterized by propensity for widespread CpG island hypermethylation.[221] High degree of CIMP (CIMP-high) is a distinct phenotype, [5, 15, 222225] and the most common cause of microsatellite instability (MSI) in colorectal cancer through epigenetic inactivation of a mismatch repair gene MLH1.[226230] Independent of MSI, CIMP-high is associated with older age, female gender, proximal tumor location, [228, 231, 232] high tumor grade, signet ring cells, [233] BRAF mutation, [228, 231, 232] wild-type TP53, [228, 234] inactive PTGS2 (COX-2), [234] inactive CTNNB1 (β-catenin), [235] loss of CDKN1B (p27), [236] high-level LINE-1 methylation, [231, 237] stable chromosomes, [238, 239] and expression of DNMT3B, [175] CDKN1A (p21), [240] and SIRT1.[92] Thus, CIMP status is a potential confounder for many locus-specific tumor variables.[5] Moreover, the relationship between KRAS mutation and another type of CIMP {“CIMP-low”, [5, 231, 241245] “CIMP2”, [246] and “intermediate-methylation epigenotype”[247]} has been demonstrated. Importantly, different CIMP subtypes appear to show different locus-specific methylation patterns.[231, 244, 246248] Accumulating evidence suggests that CIMP-high colorectal cancers arise through the “serrated pathway”, [249259] which has substantial implications in studies on colorectal polyps and adenomas, because of potential differences in detection rates, removal rates and natural histories between conventional and serrated precursor lesions. The elucidation of mechanisms of epigenetic aberrations will improve our understanding of the carcinogenic process.

One-carbon metabolism is considered to play major roles in DNA synthesis and methylation reactions.[260] In most epidemiological studies, low folate intake has been associated with higher risks of colorectal cancer[261266] and adenoma.[266269] However, results from randomized clinical trials of folic acid supplementation among individuals with a prior history of colorectal adenomas have been disappointing. A meta-analysis of these randomized trials[270] has demonstrated that folic acid supplementation does not decrease adenoma recurrence risk after short-term follow-up. In fact, one randomized trial[271, 272] suggested a potential tumor-promoting effect of folic acid supplementation. Thus, there has been much controversy on dietary folate, folic acid fortification/supplementation and risks of colorectal neoplasia.[270, 272274] Examining molecular changes in tumor cells in relation to folate intake may provide additional insights on the possible link between one-carbon metabolism and carcinogenesis.

Folate deficiency is associated with an increase in de novo DNA methyltransferase activity.[275, 276] Altered levels of folate metabolites and intermediates are associated with aberrant DNA methylation patterns.[70, 277] The MTHFR rs1801131 polymorphism (codon 429) has been associated with colon cancer with the CpG island methylator phenotype (CIMP) in case-control and case-case studies, [41, 61] although another case-cohort study has not confirmed this finding.[48] Notably, the latter case-cohort study has shown that the MTR rs1805087 polymorphism is inversely associated with CIMP in men.[48] Collectively, genetic variations in one-carbon metabolism pathways may play roles in epigenetic events during carcinogenesis.

With regard to global DNA methylation level, experimental data support a link between folate level and cellular DNA methylation level.[278280] In our prospective cohort studies, subjects reporting low folate intake experienced an increased risk of colon cancer with global DNA (LINE-1) hypomethylation, but folate intake had no influence on a risk of LINE-1 hypermethylated cancer.[119] In a randomized, double-blinded, placebo-controlled trial, folic acid supplementation was inversely associated with global DNA hypomethylation in normal colon mucosa.[281] However, in the Aspirin/Folate Polyp Prevention Trial, there was no significant influence on LINE-1 methylation in normal colon mucosa by folic acid supplementation.[282]

Besides influence of one-carbon nutrients, local DNA sequence context may influence assembly of a methylation reaction machinery and locus-specific DNA methylation. Studies have shown that cis-acting elements cause allele-specific methylation in the mammalian genome.[283286] Thus, germline variations in putative cis-acting elements may influence epigenetic status; such examples include MLH1 rs1800734 promoter SNP, [38, 108, 115] and MGMT rs16906252 promoter SNP.[94, 152, 153]

Challenges in Molecular Pathologic Epidemiology

Although molecular pathologic epidemiology is a very promising field, a number of challenges exist. Molecular pathologic epidemiology research has the same set of inherent limitations as traditional epidemiology research and pathology research, including those related to bias (e.g., selection bias, recall bias, measurement errors, and misclassification), confounding, generalisability and causal inference. In addition, there are other issues specific to molecular pathologic epidemiology. Many of the issues have previously been discussed.[287289] In this section, we systematically discuss various issues specific to molecular pathologic epidemiology and propose measures to overcome those issues.

1. Selection bias

Since we can analyze only a finite number of cases, controls, or cohort participants, selection bias is a universal issue. The use of cancer cases in one or a few hospitals may be a source of selection bias since patients have selected the one or few hospitals based on referral or their own preference. To decrease bias due to differential hospital selection by patients, a large population-based investigation or multicenter investigation is desirable. To minimize selection bias, it is necessary to make the best effort to retrieve enough tissue materials from as many hospitals and pathology laboratories as possible.

In molecular pathologic epidemiology, a tumor tissue retrieval rate is almost inevitably less than 100%.[156, 290] Patient and disease characteristics may influence the tissue retrieval rate. Specimen availability may be related to tumor size and patient outcome;[291] this may be especially true in colorectal adenomas. A large epidemiological study has shown that tumor tissue retrieval rates in early-stage intramucosal cancer and advanced stage IV cancer are lower compared to stage I-III cancers.[156] Nonetheless, both case-control and prospective cohort studies have shown that demographic features and dietary and other exposure factors are similar between cases with tumor tissue analyzed and those without available tumor tissue.[36, 156]

Another source of selection bias is treatment before surgical resection of tumor. While this has not been a major issue in colon cancer, treatment prior to surgical resection of rectal cancer is now common. First, selection of patients for treatment is likely nonrandom and influenced by many factors. Second, treatment before surgery can eliminate most or all tumor cells in resection specimens in some patients, while treatment is ineffective in other patients. Thus, availability of ample tumor cells is determined by treatment effect which is likely influenced by tumor molecular characteristics. Third, treatment itself can introduce molecular changes which may not naturally occur. Thus, if treatment is administered before surgical resection, it is recommended to collect tumor specimens that were taken prior to such treatment.

2. Sample size

In studies on tumor prognostic markers, a frequent problem is using inappropriate sample sizes that are too small to conduct robust statistical analysis and draw meaningful conclusions.[292] Small sample sizes lead to a number of problems including a large variation of an effect estimate with wide confidence limits, random and nonrandom selection bias, and publication bias. Publication bias refers to a phenomenon that studies with null findings have a higher likelihood of being unwritten and unpublished compared to studies with “significant” findings. In the published literature, small underpowered studies with “significant” findings have been over-represented, relative to small underpowered studies with null findings. In a meta-analysis of TP53 alterations and head and neck cancer outcome, [293] not only publication bias, but also selective presentations of data in many small studies appear to be a serious problem that can lead to biased and misleading conclusions.

In molecular pathologic epidemiology, sample size is a substantial issue. Even when a parent study is large-scale, any given molecular pathologic epidemiology study requires multiple exclusions based on availability of tumor tissue materials and valid assay results. In molecular pathologic epidemiology, by definition, a subset analysis for different outcomes (a molecular change present vs. absent) is performed. A sample size for a smaller subset may not be large enough to provide adequate statistical power. Population-based studies have shown that molecular subtyping is often skewed: BRAF mutation (10–15% mutated vs. 85–90% wild-type), [53, 228, 294, 295] PIK3CA mutation (15–20% mutated vs. 80–85% wild-type), [296, 297] NRAS mutation (2% mutated vs. 98% wild-type), [65] MSI (15% high vs. 85% low/MSS), [35, 64, 126, 231] KRAS mutation (35–40% mutated vs. 60–65% wild-type), [30, 242, 298] or CIMP (10–20% high vs. 80–90% low/negative;[170, 243, 294, 299] or 15–30% positive vs. 70–85% negative[53, 64, 228]). Therefore, for any future cancer epidemiology research, one should design a study as large as possible, because tumor molecular subtyping is increasingly common in cancer epidemiology.

3. Measurement error and misclassification

In addition to measurement error and misclassification in exposure variables and covariates, nontrivial measurement error and misclassification may be present in an outcome variable, i.e., tumor molecular subtyping. This particular combination (i.e., measurement errors and misclassification in both exposure and outcome assessments) is a unique challenge in molecular pathologic epidemiology.

Tumor molecular and immunohistochemical assays should be validated and monitored for its precision and accuracy. In immunohistochemical analysis, it is possible to observe a correlative error between two completely unrelated proteins because of the presence of poor quality tissue specimens, which fail to react with any specific antibody leading to false negative results.[5] Thus, in such poor quality cases, negativity of one protein tends to coincide with negativity of another protein even with the absence of any true association. Since those cases with poor quality materials are inevitably present in large-scale epidemiology studies, one should be cautious when interpreting an apparent positive correlation between two proteins by immunohistochemistry assays.[5] The presence of internal control in tumor tissue may solve this problem to some extent.

To decrease run-to-run variability in immunohistochemical assays, the use of tissue microarray (TMA) is recommended.[289] All cases in the same TMA slide can be processed and treated in a similar manner during immunostaining. We recommend inclusion in TMA of normal tissue adjacent to tumor tissue from the same individual whenever normal tissue is available. Normal colon mucosa may serve as an internal control. Tissue cores can be separately taken from tumor edge and center and labeled as such. Because TMA is cost efficient for a large-scale study, any epidemiology study or clinical trial should consider TMA for immunohistochemical evaluations of expression of multiple proteins.

4. Multiple hypothesis testing

Multiple hypothesis testing is a common issue in epidemiology, and is even more problematic in molecular pathologic epidemiology. By definition, molecular pathologic epidemiology involves subset analyses on tumor subtypes, which exacerbate the potential for false positive findings due to multiple hypothesis testing.[1] If one crosses a wide range of lifestyle and other exposure variables with a variety of molecular changes, the likelihood for a nominally significant chance finding is high.[1] In this post-genomic era, we can potentially generate a countless number of hypotheses as we have already experienced in GWAS.[300302] False positive findings can potentially confuse the literature, scientific field, and clinical practice.[303] If a higher significance level is required, then we require to have a large sample size.

An important question is whether the molecular pathologic epidemiology approach should be hypothesis-driven or exploratory as GWAS. If the former is the case, how can we prioritize various hypotheses to allocate our limited resource? If the latter is the case, how can we make formal rules of statistical significance and validation of findings? The border between hypothesis-driven research and exploratory research may not be distinct in molecular pathologic epidemiology. For example, a proposed link between smoking and MSI-high, CIMP-high or BRAF-mutated colon cancers may be regarded as either exploratory or hypothesis-based. Where do we draw a line between hypothesis testing vs. exploration? At the very least, initial few studies examining the relationship between a certain exposure and a specific molecular change should be regarded as exploratory and hypothesis-generating. Any generated hypothesis needs to be validated by independent datasets.

We acknowledge that any novel hypothesis could at first result from a fortuitous discovery by multiple hypothesis testing. If we successfully implement proper measures, the pace of our new discovery can be much faster than before. To generate and test new hypotheses, validate new findings, solidify new knowledge, and implement new public health recommendations and measures, we should develop an optimal and standardized way of streamlining the sequence of discoveries and validation in molecular pathologic epidemiology.

5. Generalisability

All issues mentioned above affect generalisability of study findings. Many findings by molecular pathologic epidemiology studies (as shown in Tables 1 and and2)2) are yet to be validated in other independent datasets. It is challenging since there is a wide variety in study designs and populations, and differences in tumor molecular assays add further diversity between different studies. On the other hand, because of the presence of such enormous heterogeneity between different studies, consistent findings across different studies can be regarded as generalisable findings.

6. Direct causation of molecular changes vs. selective advantage

Although molecular pathologic epidemiology illuminates carcinogenic mechanisms, it still needs experimental data to confirm a causal relationship. There still remains a question whether an exposure of interest can either directly or indirectly cause a specific molecular change, or create a specific environment which can provide selective advantage for clonal expansion of a cell with a specific molecular change. Tumor molecular alterations may not only represent the interactions of carcinogens with DNA repair mechanisms or epigenetic machinery, but also reflect the tissue-specific selection of those alterations that provide pre-malignant and malignant cells with a clonal growth advantage.

7. How we can examine the process of tumor progression in observational molecular pathologic epidemiology

Since some molecular changes have been known to occur early (e.g., APC loss, KRAS mutation), etiologic factors which appear to cause those early events can be considered to contribute to tumor initiation/progression early in the carcinogenic process. Another way is to analyze colorectal polyp/adenoma and colorectal cancer within the same population, and investigate how an exposure of interest is related to somatic molecular events in cancer and precursor lesions.

8. Multidisciplinary research environment and cross-training and education

Molecular pathologic epidemiology is transdisciplinary and interdisciplinary by nature (see Stokols et al.[304] for the definitions of transdisciplinarity and interdisciplinarity). It requires expertise of diverse fields including, at least, epidemiology, biostatistics, pathology, and oncology. Therefore, collaborative environment is essential, and cross training and education are extremely useful to advance this interdisciplinary area of science. Especially, training in epidemiology and biostatistics during pathology training is very beneficial.[305] Increasing needs and trend for team science rather than solo science have been well documented.[304, 306, 307]

Future Direction and Concluding Remarks

“Molecular Pathologic Epidemiology” is a relatively new, evolving field of epidemiology which is designed to elucidate how various exposures affect initiation, transformation and progression of neoplasia.[1] A new direction of molecular pathologic epidemiology is to investigate interactive effects of dietary or lifestyle exposures and tumoral molecular features on tumor behavior (prognosis or clinical outcome), so that one can attribute the effects of dietary or lifestyle variables to a specific molecular subtype of cancer.[2] A number of hurdles must be overcome because of unique and new challenges which we have not faced in traditional epidemiology research. To overcome those issues, it is necessary to coordinate research effort around the world and to possibly formulate a system where one can discover and validate new findings. As a result, molecular pathologic epidemiology research will continue to provide profound insights on carcinogenic process and help us optimize prevention and treatment strategies.


We thank all investigators who have contributed to this emerging multidisciplinary field of science.

Funding: This work was supported by U.S. National Institute of Health [P01 CA87969 (to S.E. Hankinson), P01 CA55075 (to W.C. Willett), P50 CA127003 (to C.S.F.), R01 CA137178 (to A.T.C.), K07 CA122826 (to S.O.), R01 CA151993 (to S.O.)]. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. Funding agencies did not have any role in the decision to submit the manuscript for publication or the writing of the manuscript.


body mass index
Colon Cancer Family Registry
confidence interval
CpG island methylator phenotype
chromosomal instability
European Prospective Investigation into Cancer and Nutrition
genome-wide association study
Health Professionals Follow-up Study
hazard ratio
Kaiser Permanente Medical Care Program of Northern California, the state of Utah and the Twin City Metropolitan area of Minnesota (the M Slattery group’s case-control study)
loss of heterozygosity
Melbourne Collaborative Cohort Study
microsatellite instability
Molecular Epidemiology of Colorectal Cancer Study (northern Israel)
microsatellite instability-high
microsatellite instability-low
microsatellite stability
North Carolina Colon Cancer Study
Nurses’ Health Study
The Netherlands Cohort Study
non-steroidal anti-inflammatory drug
Northern Sweden Health and Disease Study
odds ratio
prostaglandin endoperoxide synthase 2 (cyclooxygenase-2, COX-2)
randomized, placebo-controlled trial
Surveillance Epidemiology, and End Results
single nucleotide polymorphism
Wheat Bran Fiber Trial


Competing interest: None to declare.

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