Genetic testing plays a significant role in the management of colon cancer, offering insights into both inherited predispositions and the specific characteristics of an existing tumor. Understanding the different types of genetic tests and their implications is important for individuals and their families.
Identifying Inherited Risk Through Genetic Testing
Germline testing identifies inherited mutations that increase an individual’s lifetime risk of developing colon cancer, helping pinpoint individuals and families with a hereditary predisposition. This allows for proactive management strategies.
Individuals who should consider this testing often have a strong family history of colon cancer, related cancers, or early-onset colon cancer. Other indicators include the presence of multiple polyps found during a colonoscopy. About 5% to 10% of colon cancer cases are linked to such inherited genetic changes. Testing typically involves a blood or saliva sample.
Inherited syndromes associated with increased colon cancer risk include Lynch Syndrome, the most common inherited form, caused by mutations in mismatch repair genes such as MLH1, MSH2, MSH6, PMS2, and sometimes the EPCAM gene. Familial Adenomatous Polyposis (FAP) is another significant syndrome, characterized by hundreds or thousands of polyps and caused by mutations in the APC gene. MUTYH-associated polyposis (MAP) results from mutations in the MUTYH gene. Less common syndromes include Peutz-Jeghers Syndrome (STK11 gene) and Juvenile Polyposis Syndrome (BMPR1A, SMAD4 genes).
Understanding Tumor Genetic Testing
Separate from inherited risk assessment, tumor genetic testing, also known as somatic testing or molecular profiling, analyzes the genetic makeup of cancer cells. Performed on tissue from a biopsy or surgical sample, its purpose is to understand the tumor’s unique characteristics, informing treatment decisions, predicting therapy response, and offering prognostic information.
Genetic alterations found in colon tumors include mutations in KRAS, NRAS, and BRAF genes. These mutations can influence the effectiveness of targeted therapies, such as epidermal growth factor receptor (EGFR) inhibitors. For instance, tumors with specific KRAS or NRAS mutations may not respond to EGFR inhibitors.
Microsatellite Instability (MSI) or Mismatch Repair (MMR) deficiency is an important marker; tumors with high MSI or MMR deficiency often respond well to immunotherapy. HER2 amplification, found in a small percentage of colon tumors, is a target for specific therapies.
Interpreting Results and Guiding Care
Genetic test results can be classified in several ways: a “positive” result indicates a pathogenic or likely pathogenic variant (a genetic change associated with disease risk). A “negative” result means no such variant was found. A “Variant of Uncertain Significance” (VUS) indicates a genetic change has been found, but there is insufficient information to determine if it is disease-causing. Clinical decisions based on a VUS are typically guided by personal and family history, rather than the VUS itself.
For inherited risk testing, a positive result leads to enhanced screening protocols for the individual and their family members. This involves earlier and more frequent colonoscopies, and sometimes consideration of risk-reducing surgeries. Family members can undergo cascade testing, allowing for personalized screening and prevention plans.
Tumor genetic test results directly influence treatment strategies. For example, the presence of MSI-high or MMR-deficient tumors can make individuals eligible for immunotherapies. The identification of HER2 amplification may guide the use of HER2-targeted therapies. Conversely, mutations, like those in KRAS or NRAS, may indicate that targeted therapies, such as EGFR inhibitors, are unlikely to be effective. Genetic counselors play an important role in explaining complex results, discussing implications for the patient and their family, and supporting informed decision-making regarding medical management.