Colorectal Health

Colorectal health encompasses the well-being of the colon and rectum, with a particular focus on the prevention, detection, and management of colorectal cancer (CRC). CRC is a significant global health concern and a major cause of morbidity and mortality. While early detection often leads to a favorable prognosis, the outlook for advanced-stage CRC remains challenging, underscoring the critical need for effective prevention and early identification strategies. A family history of CRC is a notable risk factor, approximately doubling the risk for individuals with a first-degree relative affected by the disease. Studies indicate that nearly 15% of CRC patients have a familial history of the condition^[1].

Biological Basis

Inherited susceptibility is estimated to contribute to about 35% of all CRC cases ^[2]. However, well-known high-risk germline mutations in genes such as APC, DNA mismatch repair genes, MUTYH, SMAD4, BMPR1A, and LKB1 account for less than 6% of all cases ^[3]. This suggests that the substantial remaining heritable risk, around 30%, is likely due to the combined effects of multiple common genetic variants, each exerting a modest influence ^[3].

Genome-wide association studies (GWASs) have been instrumental in identifying numerous common germline single nucleotide polymorphisms (SNPs) significantly associated with CRC susceptibility ^[4]. These studies have pinpointed several susceptibility loci across the genome, including regions such as 8q24, 8q23.3 (encompassing EIF3H), 10p14, 11q23, 15q13, 18q21 (involving SMAD7), 19q13.1 (RHPN2), and 20p12.3 ^[4]. While individual risk alleles typically confer only small effects, carriers of multiple such alleles can face substantially elevated risks. Further research is essential to fully characterize the genetic variation at these loci and elucidate their functional consequences, which ultimately contribute to CRC development.

Clinical Relevance

Understanding the genetic underpinnings of colorectal health is crucial for improving clinical outcomes. The identification of genetic susceptibility loci facilitates the development of more precise risk assessment tools, potentially enabling earlier and more targeted screening interventions. Such advancements can lead to earlier disease detection and, consequently, better patient prognosis. Beyond incidence, common germline genetic variation may also influence survival outcomes after a CRC diagnosis. The cumulative impact of multiple risk alleles, even if individually small, highlights the public health relevance of these genetic discoveries, particularly as more susceptibility loci are identified.

Social Importance

Given that a considerable proportion of the population carries at-risk genotypes, genetic insights into colorectal health have broad social implications. By identifying individuals at higher genetic risk, public health initiatives can be tailored to promote personalized prevention strategies, such as lifestyle modifications or more intensive surveillance programs. This knowledge empowers individuals and healthcare providers to make informed decisions, potentially reducing the overall burden of CRC on society and improving population health outcomes.

Limitations

Research into colorectal health, particularly through genetic association studies, is subject to several limitations that influence the completeness and interpretation of findings. A balanced understanding requires acknowledging these constraints without diminishing the value of the discoveries made.

Methodological and Statistical Considerations

Current studies face inherent methodological constraints that can limit the scope of analysis. For example, sample size limitations have often precluded extensive stratified analyses by specific factors such as tumor site, or the evaluation of associations with responses to particular treatments ^[5] This means that nuanced genetic effects, which might vary significantly across different patient subgroups or influence therapeutic efficacy, may not be fully discerned. Furthermore, a fundamental limitation of the genome-wide association study (GWAS) approach is the necessity of applying a stringent P-value threshold for genome-wide significance, primarily to mitigate the risk of false-positive findings ^[5]A direct consequence of this stringency is a higher likelihood of false-negative findings, potentially causing important genetic associations with colorectal health and survival to be overlooked^[5]

Genetic Coverage and Remaining Heritability

The comprehensive understanding of genetic contributions to colorectal health is also limited by the current capabilities of genetic profiling. Genotyping platforms typically capture only a subset of the entire genome, leaving many variations untyped^[5] While imputation methods are employed to infer these missing common variants, the accuracy of imputed SNPs can influence the statistical significance of findings, potentially leading to more conservative estimates ^[5]Moreover, existing GWAS strategies are not optimally designed to identify low-frequency variants, which may have stronger effects, nor are they well-suited to capture copy number variants, both of which are likely to contribute to colorectal cancer risk^[5] These technical limitations collectively suggest that a substantial number of low-penetrance genetic variants remain to be discovered, indicating a continued gap in fully explaining the heritability of colorectal conditions ^[5]

Population and Phenotypic Heterogeneity

Challenges in generalizing findings across diverse populations and addressing phenotypic variability also impact the interpretation of genetic studies. Although efforts are made to identify variants consistently associated with colorectal cancer risk across different ancestral groups, the underlying concern about population-specific genetic architectures persists^[5] This highlights the potential for genetic effects to vary or for different genetic markers to be relevant in distinct populations. Additionally, the inclusion of colorectal adenomas as a major precursor lesion, while enhancing statistical power, can introduce phenotypic heterogeneity into analyses ^[5]This is because some genetic variants may exert their effects later in the adenoma-cancer progression, meaning their associations might be obscured when adenomas and cancers are grouped together, thereby complicating the precise mapping of genetic influences throughout disease development^[5]

Variants

Genetic variations play a crucial role in influencing an individual’s susceptibility to various health conditions, including colorectal diseases. Single nucleotide polymorphisms (SNPs) within or near specific genes can alter gene function, protein activity, or regulatory processes, thereby impacting cellular pathways relevant to colorectal health. The following variants highlight diverse mechanisms, from RNA regulation and cellular signaling to cell adhesion and inflammation, that contribute to the complex genetic landscape of colorectal disease risk.

Variants associated with regulatory and immune-related pathways include rs12198456 , rs29234 , and rs2821158 . The rs12198456 variant, located near MIR3144 and RNU6-214P, may influence the expression of microRNAs and small nuclear RNAs, which are key regulators of gene expression, affecting cell proliferation and differentiation pathways critical in colorectal tissue. Similarly, rs29234 , linked to the SUMO2P1 pseudogene and the MOG gene, could impact SUMOylation, a post-translational modification vital for protein function and cellular stress responses, or modulate immune system activity relevant to colonic inflammation. The rs2821158 variant, associated with the AKAP8P1 and JKAMPP1 pseudogenes, might exert regulatory effects on their functional counterparts or other genes, potentially altering cell signaling cascades that contribute to the development or progression of colorectal conditions.

Other variants affect genes involved in cell adhesion, development, and structural integrity of tissues. For instance, rs11129766 in the CHL1 gene, which encodes a cell adhesion molecule, could modify cell-cell interactions and migration, influencing the stability of the colonic epithelium or facilitating tumor cell invasion and metastasis. The rs12136737 variant, located in C1orf21, a gene with emerging roles in fundamental cellular processes, might affect cell cycle control or stress responses, which are critical for maintaining healthy colorectal tissue. Additionally, rs11028546 , linked to LUZP2 and RPL36AP40, may impact cytoskeletal organization, affecting the structural integrity and motility of colon cells, while pseudogene influence could subtly alter ribosomal function and overall protein synthesis.

Further variants are implicated in disease pathways, inflammation, and extracellular matrix remodeling, all pertinent to colorectal health. Thers2323183 variant, associated with HS3ST3B1 and RPS18P12, could alter the biosynthesis of heparan sulfate proteoglycans, essential components of the extracellular matrix that mediate cell signaling and adhesion, potentially affecting tissue homeostasis and tumor growth in the colon. The rs34856929 variant, near JAKMIP2 and SPINK1, is particularly relevant as SPINK1is a known protease inhibitor with roles in inflammation and cancer; this variant might influence inflammatory responses in the gut, a significant factor in colorectal cancer risk. Moreover,rs9836145 , associated with MDFIC2 and SAMMSON, could impact transcriptional regulation, mitochondrial function, and cell survival pathways that are often disrupted in colorectal malignancies. Finally, rs9451766 in the EYSgene, while primarily known for retinal function, may contribute to the extracellular matrix integrity or cell-matrix signaling in various tissues, potentially influencing the tumor microenvironment and overall colorectal health.

Key Variants

RS ID	Gene	Related Traits
rs12198456	MIR3144 - RNU6-214P	colorectal health
rs29234	SUMO2P1 - MOG	BCAN/MOG protein level ratio in blood MOG/PTPRN2 protein level ratio in blood MOG/RTBDN protein level ratio in blood MOG/SEZ6L protein level ratio in blood KLK6/MOG protein level ratio in blood
rs2323183	HS3ST3B1 - RPS18P12	colorectal health
rs34856929	JAKMIP2 - SPINK1	colorectal health
rs12136737	C1orf21	colorectal health
rs11129766	CHL1	colorectal health
rs11028546	LUZP2 - RPL36AP40	colorectal health
rs2821158	AKAP8P1 - JKAMPP1	colorectal health
rs9836145	MDFIC2, SAMMSON	colorectal health
rs9451766	EYS	colorectal health

Classification, Definition, and Terminology

Colorectal health broadly refers to the overall well-being and functional status of the colon and rectum. Its assessment often centers on the presence or absence of colorectal cancer (CRC) and conditions that may predispose individuals to it. Research in this area frequently focuses on the epidemiology, prevention, screening, and risk factors associated with colorectal cancer.

Definition of Colorectal Cancer

Colorectal cancer is a malignancy affecting the colon or rectum. It is a significant focus of studies related to colorectal health^[6]. Colorectal cancer cases are often characterized by specific factors, including:

• Age at diagnosis ^[7].
• Stage at diagnosis:This classification describes the extent of the cancer’s spread^[7]:
  • I/localized:Cancer is confined to the original site^[7].
  • II–III/regional:Cancer has spread to nearby tissues or lymph nodes^[7].
  • IV/distant:Cancer has metastasized to distant organs^[7].
• Tumor site: The specific location within the colon or rectum where the tumor originates ^[7].

Related Terms and Classifications

• Genetic Epidemiology of Colon Cancer:This field investigates the role of genetic factors and their interaction with environmental factors in the development of colon cancer^[8]. Resources like the Cancer Family Registry (CCFR) serve as international platforms for such studies^[8].
• Colorectal Cancer Prevention Strategies:These are interventions or lifestyle modifications aimed at reducing the risk of developing colorectal cancer. Examples studied include:
  • Energy Balance:Research has explored the relationship between energy balance, including physical activity, and colon cancer risk^[9].
  • Dietary and Supplemental Factors: Studies have investigated the role of beta-carotene, vitamins E and C, multivitamins ^[10], and specific dietary components like red meat consumption ^[7].
  • Pharmacological Agents:The regular use of aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), or both has been examined for its potential impact on colorectal cancer-related factors^[7].
• Cancer Screening Trials:These are organized programs designed to detect cancer early in asymptomatic individuals. Examples include the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial^[6] and the Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study ^[7].
• Risk Factors:Various factors are considered in assessing colorectal cancer risk, including^[7]:
  • Smoking status (never, former, or current smoker)
  • Body Mass Index (BMI)
  • Alcohol consumption
  • Red meat consumption
• Study Populations and Registries:Research on colorectal health often involves large cohort studies and registries, such as^[7]:
  • Colon Cancer Family Registry (CCFR)
  • Darmkrebs: Chancen der Verhütung durch Screening study (DACHS)
  • Diet, Activity and Lifestyle Study (DALS)
  • Health Professionals Follow-up Study (HPFS)
  • Nurses’ Health Study (NHS)
  • Ontario Familial Colorectal Cancer Registry (OFCCR)
  • Physicians’ Health Study
  • Postmenopausal Hormone study-Colon Cancer Family Registry (PMH-CCFR)
  • Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)
  • VITamins And Lifestyle (VITAL) Study
  • Women’s Health Initiative (WHI)
• Covariates:In statistical models, covariates are variables adjusted for to isolate the effect of a primary factor. Common covariates in colorectal cancer research include age and principal components (PCs)^[7].

Signs and Symptoms

Colorectal health encompasses the well-being of the colon and rectum, with a primary focus on conditions such as colorectal cancer (CRC) and its precursors. Understanding how these conditions present and are measured is crucial for prevention and management.

Typical Presentations

Colorectal cancer and related conditions were identified in studies based on specific diagnostic criteria rather than patient-reported symptoms. These presentations included:

• Confirmed colorectal cancer (CRC)^[7].
• Colorectal neoplasia, which refers to abnormal cell growth ^[7].
• Colorectal adenomas, which are benign growths that can potentially become cancerous ^[7].

For specific study participants, cases of colorectal neoplasia were defined by certain characteristics:

• A diagnosis of colorectal cancer at 75 years of age or younger^[7].
• Any colorectal adenoma diagnosed at 45 years of age or younger^[7].
• Three or more colorectal adenomas diagnosed at 75 years of age or younger ^[7].
• A large adenoma (greater than 1 cm in diameter) or an aggressive adenoma (villous and/or severely dysplastic) diagnosed at 75 years of age or younger ^[7].

Measurement Approaches

The assessment of colorectal health conditions in research studies involves several approaches to characterize the disease and its genetic underpinnings:

• Age at Diagnosis:The age at which colorectal cancer or related conditions were diagnosed was recorded for study participants^[7].
• Stage at Diagnosis:The extent of the cancer’s spread at the time of diagnosis was categorized into stages: I/localized, II–III/regional, or IV/distant^[7].
• Tumor Site: The specific location of the tumor within the colon or rectum was identified ^[7].
• Genetic Analysis: Genetic variations were measured using various genotyping platforms, including Illumina assays such as 300/240S, 610K, 550K, and 550Kduo ^[7].
• Epigenetic Profiling:Research also involved examining epigenetic profiles, such as histone modifications in colorectal cancer cell lines, using tools like ChromHMM^[7].
• Bioinformatic Annotation: Genetic variants were analyzed for their potential to affect transcription factor binding or enhancer elements using computational tools like the CADD (combined annotation dependent depletion) web-server ^[7].

Variability

The presentation and characteristics of colorectal cancer can vary across individuals and populations:

• Age, Stage, and Tumor Site:There is variability in the age at which individuals are diagnosed, the stage of the cancer at diagnosis, and the specific site of the tumor^[7].
• Sex-Specific Associations: Certain genetic variants may show different prevalences between sexes. For instance, one specific genetic variant (rs12080929 ) was observed to be slightly more common in males compared to females ^[7].
• Tumor Site-Specific Associations: Some genetic variants may be more prevalent depending on the tumor’s location. Another genetic variant (rs11987193 ) was found to be more common in rectal cancers ^[7].
• Population Differences:The overall prevalence of colorectal cancer can differ considerably among various populations, with some non-European populations exhibiting a lower prevalence^[7].
• Study Populations:Research studies often include diverse populations, such as participants from the Health Professionals Follow-up Study, Nurses’ Health Study, Physicians’ Health Study, Prostate, Lung, Colon and Ovarian Cancer Screening Trial, VITamins and Lifestyle Study, and Women’s Health Initiative, indicating that observations are made across varied demographic and health cohorts^[7].

Causes of Colorectal Health

Colorectal health, particularly concerning the risk of colorectal cancer, is influenced by a complex interplay of genetic and environmental factors. Research indicates that both inherited predispositions and lifestyle choices contribute to an individual’s risk.^[1][11]

Genetic Factors

Genetic predisposition plays a significant role in colorectal cancer risk.^[12]Studies on cohorts of twins have highlighted the heritable component in cancer causation.^[1][11]

Genome-wide association studies (GWAS) have identified several genetic susceptibility loci for colorectal cancer. For instance, common alleles of theSMAD7 gene have been shown to influence risk. ^[13]Other identified loci include a common variant in the 6q26–q27 region, associated with distal colon cancer in some populations,^[14] and variations near CDKN1A, POLD3, and SHROOM2. ^[15]Further meta-analyses of GWAS data have identified additional susceptibility loci for colorectal cancer and tumors.^[4][3]

Genetic variations in specific pathways are also relevant. For example, polymorphisms in genes related to the calcium-sensing receptor ^[16]and the vitamin D gene pathway have been linked to colorectal cancer risk.

Environmental Factors

Environmental factors, especially dietary habits, are important contributors to colorectal health. The metabolism of certain nutrients, such as B-vitamins found in fruits and vegetables, can influence risk.^[17] Additionally, the consumption of red meat, particularly its doneness and the resulting carcinogenic by-products from cooking or processing, is a recognized environmental factor. ^[17]

Gene-Environment Interactions

Recent research has focused on how common genetic variants, known as single nucleotide polymorphisms (SNPs), can modify the relationship between dietary factors and the risk of colorectal cancer.^[18] These genotype-environment interactions are being investigated to understand how an individual’s genetic makeup influences their response to environmental exposures. ^[19]

Studies have explored candidate SNPs in genes involved in nutrient metabolism, such as B-vitamins, or the processing of carcinogens from cooked meat. ^[17] Genome-wide studies are also underway to comprehensively analyze gene-diet interactions. ^[19]

Biological Background

The initiation and progression of colorectal cancer (CRC) are significantly linked to the abnormal regulation of intestinal epithelial homeostasis, which refers to the normal balance and function of cells lining the intestine. Research into the genetics and biology of CRC aims to uncover the molecular mechanisms driving its development^[20].

Genetic Predisposition

Genetic factors play a crucial role in an individual’s susceptibility to colorectal cancer^[12]. Studies continuously update the understanding of the genetics involved in CRC ^[21]. The molecular genetics of colorectal cancer involves a complex interplay of various genes and pathways^[20].

Key Signaling Pathways

Several signaling pathways are central to colorectal cancer development. The Wnt and Bone Morphogenetic Protein (BMP) pathways are prominent examples, where variations in genes within these pathways can influence CRC risk^[22]. Specific genetic locations (loci) within the BMP pathway, including GREM1, BMP4, and BMP2, have been identified as contributors to the inherited risk of colorectal cancer^[23].

Other Influential Genes and Pathways

Beyond the Wnt and BMP pathways, common genetic variations near genes such as CDKN1A, POLD3, and SHROOM2 also affect the risk of developing colorectal cancer^[15].

Other molecular components are also implicated in colorectal cancer risk. Genetic variations in the calcium-sensing receptor gene have been linked to the risk of colon cancer^[16]. Similarly, common genetic variations (polymorphisms) within the Vitamin D gene pathway are associated with the risk of colorectal cancer^[2]. The p38 Mitogen-Activated Protein Kinase (MAPK) signaling pathway represents another cellular mechanism with established functions in cellular processes ^[24].

Aberrant regulation of intestinal epithelial homeostasis plays an important role in the initiation and progression of colorectal cancer (CRC). Studies aim to uncover the molecular mechanisms of CRC tumorigenesis.

Molecular and Physiological Mechanisms

• Genetic Predisposition: Genetic factors contribute significantly to the risk of colorectal cancer^[12]. Research has identified and fine-mapped specific susceptibility loci in the genome, such as those at 8q23.3, 16q22.1, and 19q13.11 ^[25]. These loci are believed to contain functional variations and potential candidate target genes that influence cancer development^[25].
• TGF-beta Superfamily Signaling: Alterations within the components of the Transforming Growth Factor-beta (TGF-beta) superfamily signaling pathways have been observed in human cancers ^[26]. Smad proteins, which are key intracellular messengers in TGF-beta signaling, are expressed in human colorectal cancer cells^[27]. A specific mechanism involves Smad7, which can induce tumorigenicity by blocking the growth-inhibiting and apoptosis-inducing effects of TGF-beta ^[28].
• p38 MAPK Signaling: The p38 Mitogen-Activated Protein Kinase (MAPK) signaling pathway is another cellular mechanism with important functions ^[24].

Clinical Relevance

Identifying robust prognostic markers for colorectal cancer (CRC) is critical for improving patient management and outcomes. While advances in early detection and treatment have led to declines in CRC mortality, the 5-year survival rate remains below 65%^[7]. Currently, the strongest predictor of CRC prognosis is the stage at diagnosis; however, significant variability in survival exists among individuals diagnosed at the same stage ^[7]. This heterogeneity underscores the need for more refined prognostic tools.

Genetic variations, such as single nucleotide polymorphisms (SNPs), represent a promising area for developing new prognostic markers. Genomewide SNP survival association studies are particularly useful as they examine a vast number of genetic markers across the genome, offering a comprehensive approach to identify variations that influence disease outcome^[7]. Such studies aim to integrate these new markers into prediction models to better distinguish cancer patients with different risks of disease progression and survival^[7].

The findings from genome-wide association studies highlight the potential significance of genetic variation in CRC prognosis. For instance, specific genetic variations, such as those in 1/ELOVL5, have been associated with survival outcomes in individuals with distant-metastatic CRC ^[7]. Further investigation into the functional significance of these variations could provide valuable insights into CRC pathogenesis. Ultimately, validating these genetic findings in diverse populations could facilitate the development of targeted colorectal cancer prevention strategies and more personalized treatment approaches, addressing the current gaps in understanding the role of germline genetic factors in CRC prognosis^[7].

Frequently Asked Questions About Colorectal Health

These questions address the most important and specific aspects of colorectal health based on current genetic research.

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1. My parents had colon cancer. Does that mean I’ll definitely get it too?

Not necessarily, but your risk is significantly higher. Having a first-degree relative with colorectal cancer can approximately double your risk. While inherited susceptibility contributes to about 35% of all cases, it doesn’t mean you’re destined to develop it, as many other factors are involved.

2. My family has no colon cancer. Am I totally safe from it?

Unfortunately, no. While a family history is a notable risk factor, nearly 85% of colorectal cancer patients donot have a clear familial history. A substantial portion of risk comes from common genetic variants that might not create an obvious family pattern, as well as lifestyle factors.

3. I eat super healthy. Can my genes still put me at risk for colon cancer?

Yes, absolutely. Inherited susceptibility contributes to about 35% of all colorectal cancer cases, often due to the combined effects of multiple common genetic variants, each having a small influence. While a healthy lifestyle is crucial for prevention, your underlying genetic makeup can still elevate your risk regardless of your habits.

4. Should I get a DNA test to check my colon cancer risk?

Genetic testing can be a valuable tool for more precise risk assessment. It can identify high-risk mutations in genes like APC or DNA mismatch repair genes, or even identify common genetic variants (SNPs) associated with increased susceptibility. This information can help you and your doctor tailor more targeted screening and prevention strategies.

5. If my family has a lot of colon cancer, can healthy living still protect me?

Yes, definitely. Even with a strong family history, lifestyle modifications are a key part of personalized prevention strategies. While your genetic background contributes to your risk, adopting healthy habits can still help mitigate that risk and improve your overall colorectal health.

6. Why do some people get colon issues early, even with no family history?

This can often be due to the cumulative impact of multiple common genetic variants, even if their individual effects are small. These variants, identified through studies like GWAS, contribute to a significant portion of inherited risk without necessarily presenting as a clear “family history” pattern.

7. Can a DNA test tell me exactly how to prevent colon cancer?

A DNA test can provide valuable insights into your genetic susceptibility, helping to guide more precise prevention strategies. However, current genetic profiling doesn’t capture all genetic variations, and many low-penetrance variants remain to be discovered. So, while it offers better guidance, it won’t give you an exact, foolproof prevention roadmap.

8. Are there still hidden genetic risks for colon cancer we don’t know about?

Yes, absolutely. Current research suggests that a substantial number of low-penetrance genetic variants, which contribute to colorectal cancer risk, are yet to be discovered. Existing genetic studies also have limitations in identifying low-frequency or copy number variants, indicating a continued gap in fully explaining the genetic heritability.

9. Does my ethnic background affect my risk for colon cancer?

Yes, it can. Research acknowledges that genetic effects can vary across different ancestral groups due to population-specific genetic architectures. This means certain genetic markers or risk factors might be more relevant or have different impacts in distinct populations, influencing overall risk.

10. Can my genes affect how bad my colon cancer might be?

Yes, they can. Beyond influencing your risk of developing colorectal cancer, common germline genetic variations may also play a role in how the disease progresses. This means your genetic makeup can potentially influence survival outcomes after a colorectal cancer diagnosis.

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This FAQ was automatically generated based on current genetic research and may be updated as new information becomes available.

Disclaimer: This information is for educational purposes only and should not be used as a substitute for professional medical advice. Always consult with a healthcare provider for personalized medical guidance.

References

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[10] Christen, W. G., et al. “Design of Physicians’ Health Study II–a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials.”Annals of epidemiology, vol. 10, 2000, pp. 125–134.

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[13] Broderick P, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007; 39:1315–1317.

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[16] Dong LM, Ulrich CM, Hsu L, Duggan DJ, Benitez DS, White E, et al. Genetic variation in calcium-sensing receptor and risk for colon cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2008; 17:2755–65.

[17] Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey AB, et al. Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 17: 3098–3107. 2008.

[18] Hutter CM, Chang-Claude J, Slattery ML, Pflugeisen BM, Lin Y, et al. Characterization of gene-environment interactions for colorectal cancer susceptibility loci. Cancer research 72: 2036–2044. 2012.

[19] Figueiredo JC, Lewinger JP, Song C, Campbell PT, Conti DV, et al. Genotype-environment interactions in microsatellite stable/microsatellite instability-low colorectal cancer: results from a genome-wide association study. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20: 758–766. 2011.

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[21] Kemp, Z, et al. “An update on the genetics of colorectal cancer.”Human Molecular Genetics, vol. 13, no. Spec No 2, 2004, pp. R177–R185.

[22] Fernandez-Rozadilla, C, et al. “Single nucleotide polymorphisms in the Wnt and BMP pathways and colorectal cancer risk in a Spanish cohort.”PLoS One, vol. 5, no. 9, 2010.

[23] Dunlop, MG, et al. “Pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.”PLoS Genetics, vol. 7, no. e1002105, 2011.

[24] Cuadrado, A, and AR Nebreda. “Mechanisms and functions of p38 MAPK signalling.” Biochem J, vol. 429, 2010, pp. 403–417.

[25] Jenkins, MA, et al. “Fine-mapping of colorectal cancer susceptibility loci at 8q23.3, 16q22.1 and 19q13.11: refinement of association signals and use of in silico analysis to suggest functional variation and unexpected candidate target genes.”Hum Mol Genet, 2011.

[26] Levy, L, and CS Hill. “Alterations in components of the TGF-beta superfamily signaling pathways in human cancer.”Cytokine Growth Factor Rev, vol. 17, 2006, pp. 41–58.

[27] Korchynskyi, O, et al. “Expression of Smad proteins in human colorectal cancer.”Int J Cancer, vol. 82, 1999, pp. 197–202.

[28] Halder, SK, et al. “Smad7 induces tumorigenicity by blocking TGF-beta-induced growth inhibition and apoptosis.” Exp Cell Res, vol. 307, 2005, pp. 231–46.