Genetic markers in colon cancer are specific alterations in a person’s DNA that influence the development, progression, and response to treatment of the disease. These markers provide a deeper understanding of colon cancer at a molecular level. Identifying them helps characterize each tumor’s unique biological profile, guiding more precise treatment approaches.
Hereditary Genetic Markers
Hereditary genetic markers are inherited mutations present in an individual’s germline cells, passed down through families and found in every cell. These mutations increase a person’s risk of developing colon cancer. Familial Adenomatous Polyposis (FAP) is one such syndrome, caused by inherited changes in the APC gene. When mutated, this gene leads to hundreds to thousands of polyps in the colon, with nearly all individuals developing colorectal cancer if untreated. A less severe form, attenuated FAP (AFAP), involves later onset and fewer polyps, typically between 0 and 100.
Lynch Syndrome, also known as Hereditary Nonpolyposis Colorectal Cancer (HNPCC), accounts for 2% to 4% of all colorectal cancers. It results from germline mutations in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2, or large deletions in the EPCAM gene. These genes correct errors during DNA replication; their malfunction leads to accumulated genetic mistakes and high microsatellite instability (MSI). Individuals with Lynch Syndrome face an increased lifetime risk of colorectal cancer, up to 80%, and an elevated risk of other cancers like endometrial, gastric, and ovarian cancers. Family history is a strong indicator, as affected individuals often have multiple family members diagnosed with colon cancer at earlier ages.
Acquired Genetic Markers
Acquired genetic markers, or somatic mutations, are DNA changes occurring within tumor cells during a person’s lifetime. These mutations are specific to cancer cells and influence tumor behavior and treatment response. The KRAS gene mutation, found in approximately 40-50% of colorectal cancer patients, can impact the effectiveness of certain targeted therapies, especially those blocking the epidermal growth factor receptor (EGFR).
The BRAF V600E mutation is present in about 8-12% of metastatic colorectal cancers. This mutation is associated with a poorer prognosis and can predict a reduced response to anti-EGFR therapies. Tumors with BRAF V600E mutations often metastasize to the peritoneum more frequently than to the lungs or liver and are commonly found in sporadic colorectal cancers with high microsatellite instability.
Microsatellite instability (MSI) status and Mismatch Repair (MMR) deficiency affect about 15% of colorectal adenocarcinomas. Tumors with high MSI (MSI-high) or deficient MMR (dMMR) often have many mutations and respond differently to treatments, including showing clinical benefit from immune checkpoint therapies. HER2 amplification, where there are too many copies of the HER2 gene, can also occur and may indicate responsiveness to HER2-targeted therapies. NTRK gene fusions, while less common, are also acquired mutations that can be targets for specific therapies.
Identification of Genetic Markers
Identifying genetic markers in colon cancer involves several specialized testing procedures. Tumor tissue biopsy analysis is a primary method, where a small tumor sample is extracted, typically during a colonoscopy or surgery. This tissue is then analyzed using techniques such as next-generation sequencing (NGS), which detects a wide range of mutations across many genes simultaneously. Polymerase Chain Reaction (PCR) can detect specific, known mutations with high sensitivity, and immunohistochemistry (IHC) detects the presence or absence of specific proteins, often indicating underlying genetic changes like MMR deficiency. These tests characterize the somatic mutations driving cancer growth.
Liquid biopsies offer a less invasive alternative, using blood tests to analyze circulating tumor DNA (ctDNA). ctDNA is fragmented DNA released from cancer cells into the bloodstream, carrying tumor-specific genetic alterations. These tests detect mutations without a tissue biopsy, providing assessment of the tumor’s genetic profile. Liquid biopsies are useful for monitoring disease progression, assessing treatment response, and detecting recurrence.
For hereditary genetic markers, germline genetic testing is performed, usually on a blood or saliva sample. This test looks for inherited mutations in genes like APC or MMR genes, which are present in all of an individual’s cells. These methods provide comprehensive genetic information to guide personalized patient care.
Impact on Patient Care
Identifying genetic markers transforms colon cancer patient care by enabling personalized treatment strategies. The presence of specific acquired mutations, such as KRAS or BRAF V600E, guides the selection of targeted therapies, predicting whether a patient will respond to certain drugs, like anti-EGFR agents. For example, patients with RAS mutations do not benefit from anti-EGFR therapies, while those without these mutations might. The status of Microsatellite Instability (MSI) or Mismatch Repair (MMR) deficiency can also direct the use of immunotherapies, which have shown benefit in MSI-high/dMMR tumors.
Genetic markers also play a role in predicting prognosis. For instance, BRAF V600E mutations are linked to a poorer prognosis in metastatic colon cancer. This information helps clinicians and patients make informed decisions about treatment intensity and type. For hereditary markers, identifying a germline mutation means the patient and their family members can undergo risk stratification and receive tailored screening recommendations. This might involve earlier and more frequent colonoscopies, or considering preventive surgeries in cases like FAP, to detect precancerous lesions or early-stage cancer.