Did you know up to 80% of colorectal cancers are linked to APC gene mutations?
Mutations in the APC gene can disrupt key cell processes, increasing the risk of developing colorectal cancer. These mutations are often associated with polyposis syndromes, such as Familial Adenomatous Polyposis (FAP), which causes multiple polyps to develop in the colon and rectum. Early detection of these mutations can be vital for managing cancer risk.
So, how can you find out if you’re at risk? APC gene testing can provide answers.
In this blog, we’ll explain how the test works, what your results may mean, and how Biostate AI’s affordable RNA sequencing services are helping researchers improve cancer risk detection and prevention strategies.
What is APC Gene Testing?
APC gene testing detects Adenomatous Polyposis Coli (APC) gene mutations. The gene produces the APC tumor suppressor protein, a key regulator that helps manage cell growth and division. This protein is essential for maintaining healthy cell function and preventing uncontrolled cell proliferation.
Here are some key functions of the APC Protein.
WNT Signaling Pathway Regulation
The APC protein regulates the WNT signaling pathway, which controls cell growth and division. It does this by promoting the breakdown of beta-catenin, a protein that activates genes involved in cell growth. When the APC protein functions properly, beta-catenin levels remain controlled.
The APC protein maintains cell structure by positioning itself at the cell’s periphery and protrusions (extensions from the cell membrane). This helps cells maintain their shape, align properly within tissues, and move in the right direction. By supporting these processes, APC reduces the risk of abnormal cell movement that could lead to tumor spread.
Chromosome Stability
APC helps regulate the mitotic spindle (protein structure that separates chromosomes during cell division.), properly dividing chromosomes during cell replication. This function is essential for maintaining chromosome stability and reducing the risk of errors that can lead to cancer.
How APC Gene Mutations Affect These Functions?
Mutations in the APC gene are a major driver of colorectal cancer, with APC alterations found in most cases. These mutations disrupt essential cell processes, making it easier for abnormal cells to grow, spread, and become cancerous.
Understanding how these mutations affect cell function is key to improving early detection and treatment strategies.
Impaired Cell Adhesion and Migration
Mutations in the APC gene can weaken cell structure and reduce their ability to communicate with neighboring cells. As a result, affected cells may lose their proper positioning, detach from surrounding tissues, and move abnormally. This increases the risk of tumor cells spreading to other body parts.
Chromosome Instability
APC mutations can weaken cell structure, making it harder for cells to stay organized and communicate with neighboring cells. This can possibly allow abnormal cells to grow unchecked. These mutations can also disrupt proper chromosome division during cell replication, leading to instability—a common feature in colorectal cancers that contributes to faster tumor growth.
WNT Signaling Pathway Disruption
A faulty APC protein may fail to regulate beta-catenin. When this happens, beta-catenin can build up in the cell, activating genes that drive excessive cell division. This uncontrolled growth can lead to the formation of polyps in the colon and rectum. If untreated, these polyps may increase the risk of developing colorectal cancer.
Recognizing the link between APC gene mutations and polyposis is essential, especially for identifying hereditary conditions that increase colorectal cancer risk. Let’s discuss polyposis in detail and how APC gene testing helps in early detection.
Polyposis and APC Gene Testing
Uncontrolled cell growth caused by faulty APC proteins can lead to the formation of polyps in the colon and rectum. These growths are more than just a warning sign — they play a key role in conditions like Familial Adenomatous Polyposis (FAP), which can significantly increase the risk of colorectal cancer if left untreated.
Understanding polyposis syndromes is important for recognising potential risks early. While they account for only about 1% of all colorectal cancer cases, certain types pose a higher threat.
These include Familial Adenomatous Polyposis (FAP) and MUTYH-associated polyposis (MAP). More recently, two additional syndromes have been identified — NTHL1-associated polyposis (NAP) and polymerase proofreading-associated polyposis (PPAP).
Here are the types of polyposis syndrome.
| Syndrome | Cause | Polyp Growth | Key Features |
| Familial Adenomatous Polyposis (FAP) | Autosomal dominant disorder caused by APC gene mutations | Hundreds to thousands of adenomatous polyps, significantly increasing colorectal cancer risk if untreated | Attenuated FAP (AFAP, a milder form of FAP) presents with fewer polyps (<100) and later onset; extracolonic signs may include desmoid tumors, osteomas, and CHRPE |
| MUTYH-Associated Polyposis (MAP) | Autosomal recessive disorder caused by biallelic MUTYH mutations | Typically fewer polyps than FAP but still carries a significant colorectal cancer risk | Requires mutations in both MUTYH gene copies; MUTYH mutations impair DNA base excision repair, increasing mutation risk |
| NTHL1-Associated Polyposis (NAP) & Polymerase Proofreading-Associated Polyposis (PPAP) | NAP: Biallelic NTHL1 mutations; PPAP: POLD1 or POLE mutations (autosomal dominant) | Rare conditions that may mimic FAP or MAP with multiple colorectal polyps | NTHL1 mutations affect base excision repair; POLD1/POLE mutations impair DNA polymerase proofreading, increasing mutation rates and cancer risk; identified via genetic testing |
APC gene testing plays a crucial role in identifying these risks. Early detection can guide healthcare providers in recommending preventive measures and improving long-term outcomes.
Benefits of APC Gene Testing for Polyposis
APC gene testing is an important step in managing conditions like Familial Adenomatous Polyposis (FAP) and related syndromes. Identifying mutations in the APC gene can provide crucial insights for diagnosis, risk assessment, and treatment planning.
For individuals with a family history of polyposis or colorectal cancer, this test can offer clarity about their genetic risk and guide preventive strategies. Understanding these benefits can help individuals and families make informed decisions about their health.
1. Confirming Diagnosis
APC gene testing is a valuable tool for confirming Familial Adenomatous Polyposis (FAP) in individuals with multiple polyps, particularly those with a family history of the condition. Identifying the exact APC mutation responsible helps healthcare providers establish a clear diagnosis and recommend appropriate next steps.
2. Risk Assessment
The test helps assess an individual’s risk of developing colorectal cancer and other associated conditions. It also provides insights into the likelihood of extracolonic manifestations, such as desmoid tumors, osteomas, thyroid cancer, and brain tumors. Understanding these risks allows healthcare providers to create tailored monitoring plans.
3. Family Screening and Prevention
APC gene testing is crucial in identifying family members who may carry the same mutation. This allows at-risk relatives to undergo early screening and adopt preventive strategies, such as regular colonoscopies or risk-reducing surgeries, to manage their health proactively.
4. Personalized Management
Knowing the specific APC mutation can help guide personalized care. For instance, some mutations are linked to a milder form of FAP (attenuated FAP), which may require different monitoring and treatment approaches. This information allows healthcare providers to tailor risk management strategies for better long-term outcomes.
5. Advancing Genetic Knowledge
APC gene testing can identify previously unknown mutations, expanding the understanding of how genetic changes influence polyposis conditions. Studying these mutations in different populations also helps uncover geo-ethnic variations, improving diagnostic accuracy and supporting more personalized treatment approaches.
6. Cost-Effective Screening
APC gene testing can support stepwise, cost-effective screening strategies in resource-limited settings. By identifying individuals at higher risk, healthcare providers can focus surveillance efforts more efficiently, reducing unnecessary procedures and improving overall care.
Understanding these benefits is only part of the picture. Interpreting APC gene testing results correctly is just as important as it helps individuals and their healthcare providers make informed decisions about future care and preventive measures.
APC Gene Testing Results and Interpretation
APC gene testing results can vary, and each type of result offers different insights. Knowing what a positive, negative, or uncertain result means can help you understand your cancer risk, guide preventive actions, and support family health decisions.
1. Positive Result: APC Mutation Identified
A positive result confirms a mutation in the APC gene, which is linked to conditions such as:
- Familial Adenomatous Polyposis (FAP)
- Attenuated FAP (AFAP)
What This Means:
- Increased Cancer Risk: Confirms a higher risk for colorectal cancer and conditions like FAP. Individuals with a positive result should consult their healthcare provider for guidance on preventive measures, such as regular colonoscopies, lifestyle adjustments, or potential surgical options to reduce cancer risk.
- Benign Growths: Conditions such as CHRPE (a type of eye change), desmoid tumors, and osteomas may also develop.
- Family Screening: Relatives may need genetic testing to assess their risk.
- Treatment Planning: Your healthcare provider may recommend early screenings, preventive surgeries, or medication to reduce cancer risk.
2. Positive Result: MUTYH Mutation Identified
A positive result for a MUTYH gene mutation indicates MUTYH-Associated Polyposis (MAP). This condition generally presents with fewer polyps than FAP.
What This Means:
- Family members may also need testing to assess their risk.
- MAP is more common in individuals of Tamil ancestry due to the E466X mutation.
3. Negative Result: No APC or MUTYH Mutation Identified
A negative result does not rule out FAP or MAP entirely. Clinical features may still suggest these conditions in some cases despite no identified mutations.
Important Considerations:
- Additional genetic tests for conditions like NTHL1, POLD1, or POLE may be recommended in certain cases.
- Clinical evaluation remains crucial for those with strong FAP or MAP features.
While APC gene testing provides valuable insights, it is crucial to understand its limitations to avoid misconceptions and ensure accurate diagnosis and care.
Limitations of APC Gene Testing
APC gene testing provides valuable insights, but it has limitations that are important to understand. Some mutations may go undetected, and additional genetic factors can complicate diagnosis. These challenges highlight the need for advanced testing methods in some instances. Below are key limitations to consider.
Here are some limitations of APC Gene Testing.
1. Incomplete Mutation Detection
Approximately 10-20% of clinically diagnosed FAP cases may not show identifiable APC mutations, even with comprehensive genetic analysis. This suggests that some mutations may remain undetected using standard testing methods. In such cases, additional strategies may be necessary to improve diagnostic accuracy.
2. Other Gene Involvement
In some patients with suspected FAP, neither APC nor MUTYH mutations are identified. This indicates that other, less common genetic factors may be involved. These unidentified contributors highlight the complexity of FAP and the need for expanded genetic testing in some cases.
3. Detection Gaps
Standard APC point mutation tests may fail to identify large genomic rearrangements (LGRs) and structural changes within the gene. MLPA (Multiplex Ligation-dependent Probe Amplification) is important for detecting these mutations and improving overall accuracy.
| MLPA (Multiplex Ligation-dependent Probe Amplification) is a technique used to detect large gene deletions or duplications. It identifies changes in DNA copy numbers that standard tests may miss, improving mutation detection in conditions like FAP. |
4. Complex Genetic Architecture
Some FAP cases involve multiple genes or inheritance patterns that standard single-gene tests cannot detect. This complexity may require broader approaches, such as exome or genome sequencing, to identify underlying genetic contributors.
5. Testing Gaps in Newly Identified Genes
Specific genes like NTHL1, POLD1, and POLE have been linked to FAP in recent research. However, current evidence does not support routine testing for these genes in patients who are negative for both APC and MUTYH mutations. Studies suggest these genes have minimal diagnostic value in such cases.
6. Population Bias
Most APC gene research has been conducted in Caucasian populations. As a result, genetic variations specific to other ethnic groups, such as the codon 935 mutation identified in Indian populations, may go undetected without targeted testing strategies.
Expanding studies to include diverse populations is essential for improving diagnostic accuracy and ensuring appropriate care for all individuals.
APC gene testing is valuable for diagnosing and managing FAP, but its limitations in mutation detection, population diversity, and rare genetic contributors should be considered. Combining APC sequencing with MLPA and focusing on population-specific variations can improve outcomes.
Real-Life Scenario: APC Gene Testing and MUTYH Mutation Detection
A South Indian Tamil individual with Attenuated FAP (AFAP) underwent genetic testing. While no APC mutations were found, further analysis revealed a homozygous MUTYH mutation E466X (now E480X). This confirmed a diagnosis of MUTYH-Associated Polyposis (MAP).
The E480X mutation has been reported in Tamil families, suggesting it may be a founder mutation in this population. Despite having only 40 polyps, the individual developed colorectal cancer (CRC), showing that MAP can present with a lower polyp count yet still carries significant cancer risk.
The confirmed diagnosis guided management decisions, including the following:
- Regular colonoscopic surveillance
- Potential prophylactic colectomy
- Screening for extracolonic risks linked to MAP
Since MAP follows an autosomal recessive pattern, family screening was advised to identify at-risk relatives. This case shows how targeted genetic testing improves diagnosis and ensures personalized care.
This case highlights the importance of precise genetic testing in identifying mutations and guiding care. Beyond DNA analysis, RNA sequencing offers additional insights, especially when assessing complex APC gene mutations.
RNA Sequencing in APC Gene Mutation Analysis
RNA sequencing offers valuable insights that complement DNA testing, particularly when results are unclear or when rare APC gene variants are suspected. It helps detect functional changes that may not be obvious through standard genetic testing alone.
This can improve diagnostic accuracy, especially in patients with suspected FAP or related conditions who present with atypical genetic findings.
1. Investigating Splice Site Mutations
Splice site mutations can disrupt standard mRNA processing, potentially leading to exon skipping, intron retention, or premature stop codons. While DNA sequencing methods like Sanger sequencing can identify these mutations, RNA sequencing provides additional insights by analyzing the resulting RNA transcripts.
| NoteSplice site mutations are genetic changes that affect the regions of a gene responsible for guiding proper mRNA splicing. Splicing is the process where non-coding regions (introns) are removed, and coding regions (exons) are joined to form a mature mRNA strand.When splice site mutations occur, this process can go wrong, leading to issues such as:Exon skipping: An exon is mistakenly left out during splicing, potentially removing essential coding information.Intron retention: An intron that should be removed is mistakenly kept in the final mRNA, which can interfere with normal protein production.Premature stop codons: Splicing errors may introduce a stop signal earlier than expected, resulting in a shortened, often non-functional protein. |
For example, if a patient presents with clinical features of Familial Adenomatous Polyposis (FAP) but has ambiguous DNA sequencing results, RNA sequencing can help confirm whether splicing errors are occurring. This is particularly important for identifying mutations that affect splicing regulatory regions, which standard DNA-based tests may not easily detect.
2. Validating Novel Variants
Determining their pathogenicity can be challenging when novel variants are identified through DNA sequencing. RNA sequencing helps assess their impact by examining changes in transcript levels, splicing patterns, and overall gene expression.
For instance, a newly discovered APC variant may appear benign in DNA sequencing. However, RNA sequencing may reveal that this variant leads to exon skipping or reduced transcript levels, confirming its pathogenic nature. This approach is especially useful in cases where a patient’s symptoms align with FAP, but conventional genetic testing fails to confirm a clear mutation.
RNA sequencing can be useful for investigating APC gene mutations, especially when standard genetic tests yield inconclusive results. It provides crucial insights into splicing errors, novel variant effects, and complex transcript patterns. Integrating RNA sequencing into genetic testing strategies can improve diagnostic accuracy and guide appropriate management for patients with suspected FAP or related conditions.
Winding Up!
APC gene testing is vital for detecting conditions like familial adenomatous polyposis (FAP), which significantly increases the risk of colorectal cancer. Early detection of mutations allows individuals to take preventive measures, such as screenings and medical interventions. RNA sequencing provides valuable insights into gene expression, helping researchers better understand conditions like FAP and refine care strategies.
Biostate AI offers affordable RNA sequencing services starting at $80 per sample. It specializes in mRNA, lncRNA, miRNA, and piRNA sequencing from various sample types, including FFPE tissue and blood.
Our services are designed for smaller sample sizes (starting at 30 samples) and deliver high-quality results for genetic mutation and gene expression research, including studies on the APC gene.
Contact us to learn how our RNA sequencing can support your research, and get your quote today!
FAQs
1. How is APC gene testing performed?
APC gene testing is usually done using a blood sample, though saliva or cheek swabs may also be used. The sample is sent to a lab, where DNA is analyzed for mutations in the APC gene that could increase the risk of colorectal cancer, especially in people with a family history of the disease.
2. What is the cost of APC gene testing, and does insurance cover it?
APC gene testing costs $750 if the mutation is unknown and $500 if the mutation is known. Insurance coverage may depend on your policy and the reason for testing, so it’s recommended to check with your healthcare provider and insurance company for details.
3. Can APC gene mutations be inherited from both parents?
Yes, APC gene mutations follow an autosomal dominant inheritance pattern, meaning inheriting just one copy of the mutated gene from either parent can increase the risk for conditions like familial adenomatous polyposis (FAP). In rare cases, inheriting the mutation from both parents can raise the risk.
The New England Journal of Medicine: 96.2
PubMed: J Natl Cancer Inst.: 10.5
PubMed: Cancer Metastasis Rev: 7.7