Colorectal Carcinoma

Colorectal carcinoma (CRC), commonly known as colorectal cancer, is a significant global health concern, ranking as the third most common cancer and the fourth-leading cause of cancer-related death worldwide.^[1] The lifetime risk for developing CRC in Western European and North American populations is approximately 5%. ^[1]

The development of colorectal cancer is complex, influenced by both genetic and environmental factors. Inherited genetic factors are estimated to contribute to about one-third to 35% of disease variance.^[1] Historically, the known genetic contribution to CRC primarily involved rare, high-penetrance variants in genes such as DNA mismatch repair genes, APC, SMAD4, BMPR1A, and MUTYH. ^[2] However, recent genome-wide association studies (GWAS) have significantly expanded this understanding, revealing that common genetic variations also play a crucial role in CRC risk. These studies have identified susceptibility loci at regions like 8q24, 18q21 (SMAD7), 11q23 (rs3802842 ), 14q22.2 (rs4444235 , BMP4), 16q22.1 (rs9929218 , CDH1), 19q13.1 (rs10411210 , RHPN2), and 20p12.3 (rs961253 ). ^[3]

While individual common genetic alleles may exert only small effects, the presence of multiple risk alleles can lead to a substantially increased risk. For instance, carrying all six possible risk alleles has been shown to yield an odds ratio of 2.6 for CRC. ^[1] This understanding has significant clinical relevance, as it suggests that a high proportion of the population may carry at-risk genotypes, which could impact public health strategies as more susceptibility loci are identified. Further research is needed to fully characterize the genetic variation at these loci and determine their functional consequences that contribute to CRC development. ^[1]

The social importance of understanding colorectal carcinoma’s genetic basis lies in its potential to inform personalized risk assessments, improve screening strategies, and ultimately reduce the burden of this prevalent disease. Identifying individuals at higher genetic risk could enable more targeted preventive measures and earlier interventions, thereby improving patient outcomes.

Limitations of Current Colorectal Carcinoma Research

Understanding the genetic architecture of colorectal carcinoma (CRC) is complex, and current research efforts, while yielding significant discoveries, operate under several important limitations. These constraints influence the interpretation of findings and highlight areas for future investigation.

Methodological and Statistical Constraints

Current genome-wide association studies (GWAS) for colorectal carcinoma are inherently limited by their design and statistical power. Many studies have high power to detect common genetic variants with modest effects, such as those conferring risks of 1.2 or greater for alleles with frequencies above 0.2 in European populations. However, there is significantly reduced power to identify alleles with smaller effects or those with minor allele frequencies (MAFs) below 0.1. This limitation is compounded by the tagging single nucleotide polymorphisms (SNPs) used in array-based GWAS, which capture approximately 80% of common SNPs in European populations but only about 12% of SNPs with MAFs between 5–10%. Consequently, a large class of susceptibility alleles, particularly low-penetrance variants, likely remains undiscovered. Furthermore, these array-based strategies are not optimally configured to identify low-frequency variants with potentially stronger effects or to capture copy number variants, both of which could contribute to CRC risk. The stringent statistical thresholds required for significance in GWAS, along with financial constraints on follow-up studies, also limit the number of variants that can be robustly validated.

The estimation of genetic contributions to CRC risk can also be conservative. The effect of a causal variant is typically larger than the association detected through a proxy tag SNP, meaning the reported risk contribution of identified loci may underestimate their true impact. Additionally, individual loci might harbor multiple causal variants, including low-frequency variants with more substantial effects, which current study designs may not fully resolve. These factors suggest that while existing findings are informative, they likely represent only a fraction of the complex genetic landscape underlying colorectal carcinoma.

Generalizability Across Populations

A significant limitation of many colorectal carcinoma genetic studies, including large-scale GWAS meta-analyses, is their predominant focus on populations of European ancestry. For instance, some cohorts are exclusively composed of individuals of European descent from specific regions, such as the UK. While these studies provide valuable insights into the genetic risk factors within these populations, their findings may not be directly generalizable to other ethnic groups. Observed heterogeneity in genetic associations, such as differences noted for thers3802842 variant between Scottish and Japanese populations, underscores the importance of population-specific genetic architectures. The transferability of findings to non-European populations, especially those with considerably different prevalences of colorectal carcinoma, therefore remains a key challenge and a critical area for expanded research.

Unexplained Heritability and Undiscovered Genetic Factors

Despite significant progress in identifying genetic variants associated with colorectal carcinoma, a substantial portion of the inherited susceptibility remains unexplained. High-risk germline mutations in well-known genes like APC, mismatch repair (MMR) genes, MUTYH, SMAD4, BMPR1A, and STK11/LKB1 account for a small percentage of all cases, even though inherited susceptibility is responsible for a larger proportion of total CRC cases. The common, low-risk variants identified through GWAS studies, while numerous, individually explain only a very small fraction of this inherited risk. This gap between the estimated inherited risk and the risk explained by known genetic factors points to “missing heritability.” It is highly probable that a substantial number of low-penetrance variants, as well as low-frequency or rare variants with stronger effects, have yet to be discovered. Further efforts are needed to expand the scale of GWA meta-analyses in terms of sample size and SNP coverage to comprehensively identify these additional variants and bridge the existing knowledge gaps in CRC genetics.

Variants

Genetic variations play a crucial role in an individual’s susceptibility to colorectal carcinoma by influencing gene function and cellular pathways. The following variants, located across various chromosomes, have been implicated in the development and progression of this disease.

One significant locus for colorectal carcinoma risk is found on chromosome 18q21, involving theSMAD7 gene. The variant rs6507874 is situated within or near SMAD7, a gene critical for regulating the transforming growth factor-beta (TGF-β) signaling pathway. TGF-β signaling is a complex process that controls cell growth, differentiation, and programmed cell death, and its dysregulation is a hallmark of cancer.SMAD7 acts as an inhibitory SMAD, meaning it negatively regulates TGF-β signaling. Variants like rs6507874 may alter SMAD7expression or function, leading to unchecked cell proliferation and reduced immune surveillance, thereby increasing colorectal cancer risk^[4]. Studies have consistently replicated associations between this region and colorectal cancer, highlighting its importance in disease etiology^[1].

The 8q24 chromosomal region is a well-established hotbed for cancer susceptibility, including colorectal carcinoma. Several variants in this region, such asrs6983267 and rs10505477 , are associated with genes like CASC8, CCAT2, POU5F1B, and PCAT1. CASC8(Cancer Susceptibility 8) andCCAT2(Colon Cancer Associated Transcript 2) are long non-coding RNAs (lncRNAs) that regulate gene expression, often promoting cell proliferation and survival in cancer.POU5F1B (POU Class 5 Homeobox 1B) is a pseudogene related to the stem cell factor POU5F1, and PCAT1(Prostate Cancer Associated Transcript 1) is another lncRNA. Variants in this region, includingrs10505477 which has been subject to fine mapping, may alter the expression or stability of these regulatory RNAs and pseudogenes, thereby modulating critical oncogenic pathways and contributing to the development of colorectal cancer^[1].

Other variants linked to colorectal carcinoma includers58658771 near SCG5 and GREM1-AS1, rs139427218 in SLC33A1, and rs7130173 in POU2AF2. SCG5 (Secretogranin V) is involved in neuroendocrine functions, while GREM1-AS1 is an antisense lncRNA that can influence the expression of GREM1, a gene encoding a bone morphogenetic protein (BMP) antagonist; dysregulation of BMP signaling is implicated in colorectal cancer.SLC33A1(Solute Carrier Family 33 Member 1) encodes an acetyl-CoA transporter, important for lipid metabolism and autophagy, processes often altered in cancer cells.POU2AF2(POU Class 2 Homeobox Associating Factor 2), also known as OBF1 or BOB.1, is a coactivator of POU transcription factors, playing a key role in B-cell development and immune responses. Variations in these genes could impact cellular metabolism, immune surveillance, or growth factor signaling, thus influencing colorectal cancer risk.

Finally, several long non-coding RNAs and structural genes also harbor relevant variants. rs72746180 in LINC00604, rs12135286 in LINC01705, and *rs16892766 near LINC00536 and EIF3H represent lncRNAs that can regulate gene expression at various levels, from transcription to translation. EIF3H (Eukaryotic Translation Initiation Factor 3 Subunit H) is a component of the EIF3 complex, which is essential for initiating protein synthesis; altered translation can contribute to oncogenesis. The variant rs1741640 is found in LAMA5 (Laminin Subunit Alpha 5), a gene encoding a component of laminin, a major protein in the basement membrane. Laminins are crucial for cell adhesion, migration, and tissue architecture. Variants in LAMA5could affect the integrity of the extracellular matrix, influencing tumor cell invasion and metastasis, thereby impacting colorectal carcinoma progression.

Key Variants

RS ID	Gene	Related Traits
rs6507874	SMAD7	colon carcinoma colorectal cancer colorectal carcinoma
rs58658771	SCG5 - GREM1-AS1	colorectal cancer, colorectal adenoma Red cell distribution width colorectal cancer mean corpuscular hemoglobin mean corpuscular hemoglobin concentration
rs6983267	CASC8, CCAT2, POU5F1B, PCAT1	prostate carcinoma colorectal cancer colorectal cancer, colorectal adenoma cancer polyp of colon
rs10505477	POU5F1B, CASC8, PCAT1	prostate carcinoma colorectal cancer prostate specific antigen amount cancer colorectal carcinoma
rs139427218	SLC33A1	colorectal carcinoma
rs7130173	POU2AF2	colorectal cancer polyp of colon polyp of large intestine colorectal carcinoma
rs72746180	LINC00604	colorectal carcinoma
rs12135286	LINC01705	colorectal carcinoma
rs16892766	LINC00536 - EIF3H	colorectal cancer colorectal cancer, colorectal adenoma AGRP/NPY protein level ratio in blood rectum cancer benign colon neoplasm
rs1741640	LAMA5	colorectal cancer, colorectal adenoma colorectal cancer colorectal carcinoma

Colorectal Carcinoma

Definition

Colorectal carcinoma (CRC) is a malignant tumor originating in the colon or rectum. In the context of the studies, CRC was specifically defined according to codes 153–154 of the ninth revision of the International Classification of Diseases (ICD-9)^[3]. All individuals identified as having CRC in these studies had pathologically proven adenocarcinoma ^[3].

Classification and Related Terminology

Colorectal carcinoma is classified and characterized by several factors, including:

• Site: The anatomical location of the tumor, which can be in either the colon or the rectum ^[3].
• Pathology:Diagnosis requires pathologically proven adenocarcinoma, confirming the specific cellular type of the cancer^[3].
• MSI Status (Microsatellite Instability Status): This molecular characteristic is used to classify tumors based on the integrity of their DNA mismatch repair system ^[3].
• Family History Status: Individuals are categorized based on whether they have at least one first-degree relative diagnosed with CRC ^[3].
• Age at Diagnosis: Classification can involve stratifying individuals into groups based on their age at the time of CRC diagnosis, often using the median age as a cutoff ^[3].
• Gender: Patient gender is also a variable used in the analysis and classification of CRC cases ^[3].
• Colorectal Neoplasia: A general term for abnormal growths in the colon or rectum, encompassing both benign (adenomas) and malignant (carcinomas) lesions ^[3].
• Colorectal Adenoma: A non-cancerous growth or polyp in the colon or rectum that can be a precursor to CRC. Specific criteria for identifying significant adenomas in study participants included:
  • Any colorectal adenoma diagnosed at age 45 or younger^[3].
  • Three or more colorectal adenomas diagnosed at age 75 or younger ^[3].
  • A large (greater than 1 cm in diameter) or aggressive (villous and/or severely dysplastic) adenoma diagnosed at age 75 or younger ^[3].
• Specific Hereditary Syndromes: Certain genetic conditions significantly increase the risk of developing CRC. These include:
  • Dominant polyposis syndromes: Inherited conditions characterized by the development of numerous polyps in the digestive tract.
  • Hereditary nonpolyposis colorectal carcinoma (HNPCC), also known as Lynch syndrome:A common inherited cause of colorectal cancer and other cancers.
  • Bi-allelic MUTYH mutation carriers:Individuals with mutations in both copies of the MUTYH gene, which predispose them to an increased risk of colorectal polyps and cancer.
  • Individuals with these known syndromes were typically excluded from some study cohorts to focus on other genetic risk factors ^[3].

Signs and Symptoms

Colorectal carcinoma (CRC) is characterized by pathologically proven adenocarcinoma.^[5]. For research purposes, cases are often defined by clinical characteristics such as colorectal neoplasia, CRC diagnosed at age 75 or younger, any colorectal adenoma at age 45 or younger, three or more colorectal adenomas at age 75 or younger, or a large (>1 cm diameter) or aggressive (villous and/or severely dysplastic) adenoma at age 75 or younger.^[5].

Measurement ApproachesThe definitive diagnosis of colorectal carcinoma relies on pathological confirmation of adenocarcinoma.^[5]. Microsatellite instability (MSI) in colorectal carcinomas is determined from formalin-fixed paraffin-embedded tumor sections. Tumor DNA is extracted from microdissected regions containing at least 60% tumor. Genotyping is performed for the mononucleotide microsatellite loci BAT25 and BAT26. Samples showing novel alleles at either BAT25 or BAT26, or both, are classified as MSI. ^[5]. Genotyping accuracy for single nucleotide polymorphisms (SNPs) is ensured through quality control measures, including the use of duplicate DNA samples and direct sequencing of subsets of samples, yielding high concordance rates, typically over 99.9%.^[5].

VariabilityThe presentation of colorectal carcinoma can vary based on several factors. In various studies, the mean age at diagnosis for participants with CRC ranges from approximately 59.3 to 60.9 years.^[5]. Gender distribution in study cohorts indicates a tendency for a higher number of females than males among cases. ^[5].

Genotype-phenotype correlations reveal specific variations in presentation. For instance, the association between the rs4444235 variant in the BMP4 gene and CRC is significantly stronger in cases with microsatellite stable (MSS) tumors compared to those with microsatellite instability (MSI). ^[5]. Additionally, the susceptibility allele for the rs9929218 variant is observed to be more common in females than in males. ^[5]. Other clinicopathological data, such as the site of the tumor or family history, are also considered in understanding the overall genetic susceptibility to CRC. ^[5].

Causes of Colorectal Carcinoma

Colorectal carcinoma (CRC) is a significant global health concern, ranking as the third most common cancer and the fourth leading cause of cancer death worldwide. The lifetime risk in Western European and North American populations is approximately 5%. The development of CRC is influenced by both genetic and environmental factors, with inherited genetic factors accounting for about one-third of the disease variance^[6].

Genetic Factors

Genetic factors play a substantial role in the etiology of colorectal carcinoma. These can be broadly categorized into rare, highly penetrant variants and more common genetic variations.

Rare, High-Penetrance VariantsHistorically, the identified genetic contributions to CRC included rare variants in specific genes associated with a high risk of developing the disease. Notable among these are DNA mismatch repair genes^[2] and MUTYH ^[7]. Mutations in these genes significantly increase an individual’s susceptibility to CRC.

Common Genetic VariationRecent genome-wide association studies (GWAS) have expanded the understanding of CRC genetics by identifying common genetic variations, often single nucleotide polymorphisms (SNPs), that contribute to disease risk. These studies have identified susceptibility loci, such as those on chromosome 8q24^[3]. While individual risk alleles at these loci may exert only small effects, carriers of multiple risk alleles experience substantially larger risks ^[3]. It is thought that regulatory sequence variants or position effects, rather than causative coding sequence variants, likely underlie many of these associations ^[3].

Furthermore, genetic effects can vary by population and tumor site. For example, a locus at 11q23 has shown significantly different allelic effects between Japanese and Scottish populations. Site-specific differences have also been observed, with certain loci having a greater impact on rectal cancer risk compared to colonic cancer, which can explain some population-level differences in risk^[3].

Environmental Factors

Environmental factors also contribute to the risk of developing colorectal carcinoma^[6]. Their role in conjunction with genetic predispositions is recognized as crucial for disease etiology.

Biological Background

Colorectal cancer (CRC) is a significant global health concern, ranking as the third most common cancer and the fourth-leading cause of cancer death worldwide. The lifetime risk of developing CRC in Western European and North American populations is approximately 5%^[6]. The development of CRC is influenced by both genetic and environmental factors, with about one-third of disease variability attributed to inherited genetic factors^[6].

Genetic Contributions to Colorectal Cancer

Genetic predisposition to CRC can arise from both rare, high-penetrance variants and common genetic variations.

Rare, High-Penetrance Variants

Historically, the defined genetic contribution to CRC has included rare, high-penetrance variants in several key genes:

• DNA Mismatch Repair (MMR) Genes: Mutations in these genes are known to increase susceptibility to CRC ^[8].
• APC (Adenomatous Polyposis Coli)
• SMAD4
• BMPR1A (Bone Morphogenetic Protein Receptor Type 1A)
• MUTYH (MutY Homolog):Defects in this gene are associated with colorectal cancer^[7].
• Base-Excision Repair Genes: Germline defects in genes involved in base-excision repair can also lead to susceptibility to CRC ^[9].

Common Genetic Variation

Recent research has identified common genetic variations that also contribute to CRC risk:

• Chromosome 8q24: Susceptibility loci for CRC have been identified in this region ^[3]. These associations are likely due to regulatory sequence variants or position effects rather than causative coding sequence variants in genes such as POU5F1P1, HsG57825, and DQ515897 ^[1].
• Chromosome 18q21 (SMAD7): Common genetic variation in this region also contributes to CRC risk ^[1].

Molecular and Cellular Pathways

The development and progression of colorectal cancer involve dysregulation of several critical molecular and cellular pathways.

• Wnt–β-catenin Signaling Pathway: Aberrant activation of this pathway is considered an initiating event in the development of CRC ^[1].
• CDH1 (E-cadherin): The gene encoding cadherin 1, also known as E-cadherin, plays an established role in CRC. Somatic inactivation of CDH1, through mechanisms such as mutation or promoter methylation, occurs frequently in CRC ^[1]. This inactivation leads to increased activity of the β-catenin–TCF transcription factor, which is a downstream effect of Wnt–β-catenin pathway dysregulation. Furthermore, CDH1 is involved in promoting invasiveness in several cancers, including CRC, by downregulating adherens junction formation ^[1]. Germline mutations in CDH1 are also noted.

The identification of these genetic loci and understanding their mechanisms can provide insights for developing chemoprevention and chemotherapy interventions for CRC ^[1].

Clinical Relevance

Colorectal carcinoma (CRC) is a significant global health concern, ranking as the third most common cancer and the fourth leading cause of cancer death worldwide. In Western European and North American populations, the lifetime risk of developing CRC is approximately 5%^[5]. Both genetic and environmental factors contribute to the disease, with about one-third of the disease variability attributed to inherited genetic factors^[5].

Historically, the understanding of genetic contributions to CRC focused on rare variants with high penetrance in specific genes, such as DNA mismatch repair genes, APC, SMAD4, BMPR1A, and MUTYH ^[5]. However, recent research highlights the role of common genetic variations in regions like 8q24 and 18q21 (SMAD7) in influencing CRC risk ^[5].

Studies have identified ten single nucleotide polymorphisms (SNPs) that contribute to the familial risk of CRC. While each individual allele may exert only a small effect, the presence of multiple risk alleles can significantly increase an individual’s susceptibility. For instance, carrying all six possible risk alleles identified in one study was associated with an odds ratio of 2.6 (95% CI = 1.75-3.89) for CRC^[5]. These findings advance the understanding of how common genetic variation influences CRC development ^[5].

These identified SNPs hold potential public health relevance, particularly as further susceptibility loci are discovered ^[5]. Understanding these genetic markers can contribute to improved risk assessment, especially for individuals carrying multiple risk alleles.

Genotype-phenotype correlations further refine the clinical picture:

• The association between rs4444235 (BMP4) and CRC risk is notably stronger in cases with microsatellite stable (MSS) tumors compared to those with microsatellite instability (MSI) ^[5]. This suggests that the genetic pathways influenced by rs4444235 may differ based on the tumor’s MSI status.
• An association has also been observed between rs9929218 and gender, with the susceptibility allele being more prevalent in females than males ^[5].

Specific alleles can also influence risk individually:

• The minor allele of rs961253 is associated with an increased risk of CRC in a dose-dependent manner, with higher risk in homozygous carriers (ORhet = 1.14, 95% CI 1.08–1.20 and ORhom = 1.29, 95% CI 1.20–1.38) ^[5].
• Similarly, the minor allele of rs4444235 is linked to an increased risk (ORhet = 1.13, 95% CI 1.07–1.20 and ORhom = 1.23, 95% CI 1.15–1.32) ^[5].
• Conversely, the minor allele of rs10411210 is associated with a decreased risk of CRC in a dose-dependent manner (ORhet = 0.87, 95% CI 0.83–0.92 and ORhom = 0.72, 95% CI 0.59–0.89) ^[5].

Further research is necessary to fully characterize the genetic variation at these loci and to determine the specific functional consequences that lead to CRC ^[5]. This ongoing work is crucial for translating genetic insights into clinical applications for prevention, diagnosis, and personalized management of colorectal carcinoma.

Frequently Asked Questions About Colorectal Carcinoma

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

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1. My dad had CRC; does that mean I’ll get it too?

Not necessarily, but your risk is higher. Inherited genetic factors contribute to about one-third of colorectal cancer cases. If your father had CRC, you might have inherited some of the high-risk variants, like those in DNA mismatch repair genes or APC, or a combination of common risk alleles that increase your susceptibility. However, environmental factors also play a significant role, so it’s not a certainty.

2. Can eating healthy really overcome my family history of CRC?

Yes, to a significant extent. While inherited genetic factors, including rare high-risk variants and common susceptibility alleles, contribute to about 35% of CRC risk, environmental and lifestyle factors are also crucial. Adopting a healthy diet and other preventive measures can help mitigate some of your genetic predisposition, even if CRC runs in your family.

3. I’m not European; does my background change my CRC risk?

Yes, your ancestry can matter. Most genetic studies, particularly large-scale genome-wide association studies, have focused predominantly on populations of European descent. This means that genetic risk factors identified might not be directly generalizable to other ethnic groups, and your specific ancestral background could have different genetic predispositions or prevalence rates for colorectal carcinoma.

4. Should I get a genetic test to check my CRC risk?

It depends on your family history and overall risk profile. Genetic testing can identify specific high-penetrance variants in genes like APC, MUTYH, or DNA mismatch repair genes that significantly increase risk. For others, it might reveal the presence of multiple common risk alleles, which individually have small effects but can collectively raise your risk, potentially informing personalized screening strategies.

5. Why do some people get CRC with no family history?

Colorectal cancer development is complex, and many cases arise without a clear family history. While inherited factors contribute significantly, environmental factors and spontaneous genetic mutations also play a role. Additionally, common genetic variations, each with small individual effects, can combine to increase risk even if no single “high-risk” gene is present in your family.

6. Do tiny gene differences really raise my CRC risk?

Yes, absolutely. Recent research has shown that common genetic variations, often called susceptibility loci, each with a very small individual effect, can collectively increase your risk for colorectal cancer. For instance, carrying multiple such risk alleles can lead to a substantially increased odds ratio, making these “tiny differences” clinically significant.

7. If I have some “bad” genes, am I doomed to get CRC?

No, not at all. While having certain genetic variations, whether rare high-risk mutations or a collection of common risk alleles, increases your susceptibility, it does not guarantee you will develop colorectal cancer. Lifestyle choices and environmental factors also play a crucial role, and identifying these genetic factors can actually help you take proactive steps for prevention and early screening.

8. My sibling got CRC, but I’m healthy. Why the difference?

Even within families, genetic inheritance and environmental exposures can vary. You might have inherited different combinations of common risk alleles or even different rare high-penetrance variants compared to your sibling. Additionally, individual lifestyle choices, diet, and other environmental factors over a lifetime can significantly influence who develops the disease, despite shared genetics.

9. Can early screening help even if CRC runs in my family?

Yes, definitely. Understanding your genetic risk, especially if CRC runs in your family, is crucial because it can inform more targeted and earlier screening strategies. Identifying individuals at higher genetic risk allows for personalized preventive measures and earlier interventions, which are key to improving outcomes and reducing the burden of the disease.

10. Do my genes determine everything about my CRC risk?

No, that’s a misconception for colorectal cancer. While inherited genetic factors are estimated to contribute to about one-third to 35% of the disease’s variance, environmental factors play an equally significant role. Your lifestyle choices, diet, and other external factors interact with your genetic makeup to influence your overall risk.

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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

[1] Tenesa, A. et al. “Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24.”Nature Genetics, vol. 39, 2007, pp. 989–994.

[2] Aaltonen L, et al. “Explaining the Familial Colorectal Cancer Risk Associated with Mismatch Repair (MMR)-Deficient and MMR-Stable Tumors.”Clin. Cancer Res, vol. 13, 2007, pp. 356–361.

[3] Tomlinson I, et al. “A Genome-wide Association Scan of Tag SNPs Identifies a Susceptibility Variant for Colorectal Cancer at 8q24.21.”Nat. Genet, vol. 39, 2007, pp. 984–988.

[4] Broderick P, et al. “A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk.”Nat. Genet, vol. 39, 2007, pp. 1315–1317.

[5] Houlston, Richard S., et al. “Architecture of genetic susceptibility to colorectal cancer.”Nature Genetics, 2010.

[6] Lichtenstein P, et al. “Environmental and Heritable Factors in the Causation of Cancer—Analyses of Cohorts of Twins from Sweden, Denmark, and Finland.”N. Engl. J. Med, vol. 343, 2000, pp. 78–85.

[7] Tenesa, A., et al. “Association of MUTYH and colorectal cancer.”Br. J. Cancer, vol. 95, 2006, pp. 239–242.

[8] Barnetson, R. A., et al. “Identification and survival of carriers of multations in DNA mismatch-repair genes in colon cancer.”N. Engl. J. Med, vol. 354, 2006, pp. 2751–2763.

[9] Farrington, S. M., et al. “Germline susceptibility to colorectal cancer due to base-excision repair gene defects.”Am. J. Hum. Genet, vol. 77, 2005, pp. 112–119.