Genetic testing for colon cancer serves two distinct purposes: identifying inherited risk and guiding treatment for an existing tumor. The first type, germline testing, uses blood or saliva to determine if an individual inherited a gene mutation that increases their lifetime cancer risk. The second type, somatic testing, analyzes the tumor tissue itself to identify specific genetic changes the cancer acquired. Both forms of testing are standard practice in personalized cancer care, moving away from a one-size-fits-all approach. Understanding the difference between germline testing for prevention and somatic testing for treatment is important for patients and their families.
Identifying Inherited Risk Factors
Inherited risk testing, known as germline testing, analyzes DNA from healthy cells, typically sourced from a blood or saliva sample. This testing looks for gene changes passed down through generations that predispose a person to cancer. While most colon cancers are sporadic, approximately 5% to 10% are hereditary, caused by these inherited mutations.
The two most common hereditary colon cancer syndromes are Lynch Syndrome and Familial Adenomatous Polyposis (FAP). Lynch Syndrome, the most frequent, is caused by mutations in mismatch repair (MMR) genes, such as MLH1, MSH2, MSH6, or PMS2, which fix errors in DNA replication. Carriers of Lynch Syndrome have a lifetime risk of colorectal cancer that can reach 70% to 80%, depending on the specific gene involved.
FAP, while less common, presents a near 100% lifetime risk of colon cancer if left untreated. It is caused by a mutation in the APC gene and is characterized by the development of hundreds to thousands of precancerous polyps, often starting in adolescence. Testing for these inherited syndromes is recommended for individuals with a strong family history of colon or related cancers, or those diagnosed with colon cancer at a young age. This information implements heightened surveillance protocols long before cancer develops.
Analyzing Cancer Tissue for Treatment
The second type of genetic analysis, called somatic testing, is performed exclusively on the tumor tissue after a cancer diagnosis. These tests identify mutations the cancer acquired as it grew, which inform treatment decisions. Analyzing the tumor’s genetic profile is foundational to modern personalized oncology, helping doctors predict how the cancer will respond to specific medications.
One area of focus is the analysis of the RAS genes (KRAS and NRAS) and the BRAF gene, which are involved in cell growth signaling pathways. Mutations in these genes predict resistance to certain targeted therapies, specifically anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies. For example, if a tumor has a KRAS mutation, a doctor knows an anti-EGFR drug will likely be ineffective, allowing them to choose a different chemotherapy regimen.
Another crucial analysis involves looking for Microsatellite Instability (MSI) or Mismatch Repair (MMR) deficiency. Tumors that are MSI-High or MMR-deficient have a high number of DNA errors, making them highly responsive to immunotherapy drugs called immune checkpoint inhibitors. Universal testing for RAS, BRAF, and MSI/MMR status is recommended for all patients with metastatic colon cancer to ensure the most effective, tailored treatment plan is chosen.
Understanding Test Results and Surveillance
Genetic testing results for inherited risk fall into three categories: positive, negative, or a Variant of Uncertain Significance (VUS). A positive result means a pathogenic mutation, such as one associated with Lynch Syndrome or FAP, was found, confirming an increased cancer risk. A negative result means no known pathogenic mutation was identified, though a person may still have a family history risk requiring earlier screening than the general population.
A VUS result indicates a change in the gene was found, but current scientific knowledge cannot determine if that change is harmful or harmless. VUS results are often reclassified over time as more data is collected, but they do not change immediate surveillance recommendations. For individuals who test positive for an inherited syndrome, surveillance protocols are intensified to prevent cancer or catch it at the earliest stage.
For example, a person with an APC mutation (FAP) may need to start colonoscopies as early as age 10 to 12, with repeated procedures every one to two years. Carriers of Lynch Syndrome mutations begin colonoscopies at age 20 to 25, with a required repeat interval of every one to two years. This early and frequent monitoring is designed to locate and remove precancerous polyps before they become invasive cancer.