What you carry at this position in your DNA and what research says about it.
Colorectal Cancer Risk: 8/10 evidence, 53 publications.
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Sample genotype (not yours): T/T
Higher Risk of Colorectal Cancer
Presence of the T/T genotype is associated with a higher risk of developing colorectal cancer and colon polyps. However, this genetic profile is linked to a typical response to standard chemotherapy treatments.
What this genotype means: Higher risk of colorectal cancer; Increased likelihood of colon polyps.
Sample genotype (not yours): C/C
Lowest Colorectal Cancer Risk but Reduced Chemotherapy Survival
Presence of two C alleles is associated with the lowest risk of colorectal cancer, but may lead to reduced survival if treated with certain chemotherapies. This trade-off represents a classic genetic double-edged sword.
What this genotype means: Significantly lower risk of colorectal cancer; Reduced survival on capecitabine or FOLFOX chemotherapy; Slightly higher mean corpuscular hemoglobin.
Sample genotype (not yours): T/C
Lower Risk of Colorectal Cancer
Presence of one protective C allele is linked to a moderately reduced risk of colorectal cancer. It is also associated with a typical response to standard chemotherapy treatments.
What this genotype means: Moderately lower risk of colorectal cancer; Typical chemotherapy response.
Gene function and biological role
Gene Function: The SMAD7 gene encodes a protein that acts as a key negative regulator of the transforming growth factor-beta (TGF-beta) signaling pathway [1]. This pathway is crucial for regulating cell growth, differentiation, and programmed cell death, particularly in the lining of the colon [1]. By blocking TGF-beta signaling, SMAD7 helps control the balance of cell division and prevents uncontrolled cellular proliferation [1]. Alterations in SMAD7 expression or function can disrupt this delicate balance, potentially contributing to the development of inflammatory bowel conditions and colorectal tumors [2]. Additionally, SMAD7 is known to interact with other major cellular pathways, including the Wnt and NF-kB pathways, which further influences tumor suppression and inflammation [1].
Variant Impact: The rs4939827 variant is an intronic change located within the SMAD7 gene on chromosome 18. Although it does not directly alter the amino acid sequence of the SMAD7 protein, this genetic variation is thought to influence how the gene is expressed or regulated [3]. Specifically, the T allele is associated with an increased risk of developing colorectal cancer and colon polyps [2]. Conversely, the C allele has been shown to have a protective effect, lowering the likelihood of colorectal tumor development [2]. This variant may also play a role in how patients respond to certain chemotherapy treatments, such as capecitabine or FOLFOX [4].
Key Insight: The protective C allele of this variant is actually the more common version globally, meaning more than half of the population naturally carries some level of genetic protection against colorectal cancer.
Location: SMAD7. Chromosome 18 · 18q21.1 · 48.9 Mb
Estimated prevalence by population
Global 19.3%; European 26.5%; African 9.9%; East Asian 9.0%; South Asian 8.7%; Americas 14.0%; Ashkenazi 31.7%; Finnish 22.0%; Middle Eastern 22.4%; Amish 29.9%.
Estimated TT genotype frequency.
Global 47.2%; European 50.0%; African 43.1%; East Asian 42.0%; South Asian 41.6%; Americas 46.8%; Ashkenazi 49.2%; Finnish 49.8%; Middle Eastern 49.9%; Amish 49.6%.
Estimated TC genotype frequency.
Global 33.5%; European 23.5%; African 47.0%; East Asian 49.1%; South Asian 49.7%; Americas 39.2%; Ashkenazi 19.1%; Finnish 28.2%; Middle Eastern 27.8%; Amish 20.5%.
Estimated CC genotype frequency.
Showing effects for T/T genotype
Cancer & Oncology
Colorectal Cancer
Colorectal Cancer. Evidence: 8/10. Source: PMID 17934461. Increased Risk.
Colon Polyps. Evidence: 8/10. Source: PMID 39024449. Increased Risk.
Pharmacogenomics
Chemotherapy Response
Chemotherapy Response. Evidence: 5/10. Source: PMID 32732498. Typical Response.
Cardiovascular & Metabolic
Blood Cell & Iron Traits
Red Blood Cell Traits. Evidence: 7/10. Source: PMID 32888493. Typical Levels.
Showing effects for C/C genotype
Colorectal Cancer. Evidence: 8/10. Source: PMID 17934461. ~27% Lower Risk.
Colon Polyps. Evidence: 8/10. Source: PMID 39024449. Typical Risk.
Chemotherapy Response. Evidence: 5/10. Source: PMID 32732498. Reduced Survival.
Red Blood Cell Traits. Evidence: 7/10. Source: PMID 32888493. Slightly Higher MCH.
Showing effects for T/C genotype
Colorectal Cancer. Evidence: 8/10. Source: PMID 17934461. ~14% Lower Risk.
What this genotype means for the people who carry it
Sample genotype: TT (Homozygous)
A double dose of the T allele is associated with a higher risk of developing colorectal cancer compared to carrying the protective C allele [1]. Large-scale genome-wide association studies have consistently identified the T allele as a risk factor for colorectal tumors [2]. This genetic variation is also associated with a higher likelihood of developing colon polyps, which can sometimes be precursors to cancer [3]. On the positive side, individuals with the T/T genotype do not carry the C/C genotype associated with reduced survival during certain chemotherapy regimens [4]. Consequently, standard treatments like FOLFOX or capecitabine may perform as expected if treatment is ever needed [4]. Ultimately, lifestyle factors play a major role alongside genetics in determining overall colon health.
Higher risk of colorectal cancer; Increased likelihood of colon polyps.
Sample genotype: CC (Homozygous)
Two copies of the C allele offer the strongest genetic protection against developing colorectal cancer, with studies showing a 27% reduction in risk [1]. Such a protective effect is highly replicated across multiple large-scale genetic studies [2]. However, if colorectal cancer does develop, this genotype is associated with a significantly reduced survival rate when treated with standard adjuvant chemotherapies like capecitabine, tegafur, or FOLFOX [3]. Evidence suggests that the C/C genotype may alter how tumor cells respond to these specific drugs [3]. Additionally, the C/C genotype is associated with slightly higher mean corpuscular hemoglobin (MCH) levels, though this is generally a benign blood measurement [4]. The combination of a strong preventive benefit and a potential treatment challenge highlights the complexity of genetic variants. Knowing both the risks and benefits allows for more informed decision-making regarding colon health.
Significantly lower risk of colorectal cancer; Reduced survival on capecitabine or FOLFOX chemotherapy; Slightly higher mean corpuscular hemoglobin.
Sample genotype: TC (Heterozygous)
A single copy of the protective C allele provides a moderate protective effect against the development of colorectal cancer [1]. Research indicates that individuals with one copy of the C allele have about a 14% lower risk of colorectal tumors compared to those with the T/T genotype [2]. This protective effect is thought to be mediated through the regulation of the SMAD7 gene, which controls cell growth in the colon lining [3]. Additionally, this genotype is associated with a typical response to common colorectal cancer chemotherapy drugs like capecitabine and FOLFOX [4]. Unlike those with the C/C genotype, individuals with T/C do not show a significantly reduced survival rate on these treatments [4]. Maintaining routine screenings is still recommended to monitor colon health. Standard preventive guidelines should be followed to ensure early detection of any issues. Combining genetic insights with healthy lifestyle choices offers the best approach to long-term wellness.
Moderately lower risk of colorectal cancer; Typical chemotherapy response.
Variants with shared genetic architecture
rs2337106 · SMAD7 Gene · Chr 18 · Kidney Function
rs12953717 · SMAD7 Gene · Chr 18 · Colorectal Cancer Risk
rs4464148 · SMAD7 Gene · Chr 18 · Colorectal Cancer Risk
A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk.
The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression.
Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
The Polygenic and Monogenic Basis of Blood Traits and Diseases.
Content updated August 2026.
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