Colorectal (Colon) Cancer

Medical Experts

Contributor

Bayrak-Toydemir

Pinar Bayrak-Toydemir, MD, PhD, FACMG

Professor of Pathology (Clinical), University of Utah

Medical Director, Molecular Genetics and Genomics, ARUP Laboratories

Contributor

Matynia

Anna P. Matynia, MD

Associate Professor of Pathology (Clinical), University of Utah

Section Chief, Solid Tumor Molecular Oncology; Subspecialty Director, Solid Tumor Non-NGS Molecular Pathology, ARUP Laboratories

Contributor

Shaaban

Sherin Shaaban, MD, PhD, MSci, FACMG

Associate Professor (Clinical), University of Utah

Medical Director, Molecular Genetics and Pharmacogenomics, ARUP Laboratories

Colorectal cancer (CRC), also referred to as colon cancer, is a leading cause of cancer death. Although sporadic colon cancers are more common, hereditary colon cancers also occur, and the identification of these cancers influences screening recommendations for both patients and their family members. CRC screening relies on colonoscopy, laboratory testing, or a combination of the two. Molecular testing of cancer tissue, including evaluation for microsatellite instability (MSI), is recommended to inform prognosis, guide therapy, and determine the necessity of testing family members for Lynch syndrome. Monitoring of serum carcinoembryonic antigen (CEA) is recommended after the resection of most CRCs to detect recurrence.

Quick Answers for Clinicians

When is genetic testing for hereditary colorectal cancer syndromes recommended?

All patients newly diagnosed with colorectal cancer (CRC) should undergo universal screening for Lynch syndrome via evaluation of tumor tissue using immunohistochemistry (IHC) for mismatch repair (MMR) protein expression or microsatellite instability (MSI) testing. If tumor testing suggests Lynch syndrome, germline genetic testing is recommended to confirm the diagnosis. Germline genetic testing is recommended for individuals who have a known pathogenic or likely pathogenic variant in a cancer susceptibility gene within their family. However, genetic testing is generally not advised for individuals younger than 18 years unless the results would directly impact current medical management. Germline genetic testing is also recommended in those who meet clinical criteria for a hereditary cancer predisposition syndrome. Syndromes include Lynch syndrome, familial adenomatous polyposis (FAP), juvenile polyposis syndrome (JPS), Peutz-Jeghers syndrome (PJS), hereditary diffuse gastric cancer, Li-Fraumeni syndrome (LFS), and Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS). Individuals who previously tested negative using a limited genetic assay (e.g., a single-gene test, no deletion/duplication analysis) but meet clinical or tumor-based criteria for hereditary CRC syndromes should be offered more comprehensive testing, such as multigene panel testing.

Can blood tests be used for colorectal cancer screening?

According to guidelines from the National Comprehensive Cancer Network (NCCN), blood-based, cell-free DNA (bb-cfDNA) tests can be used to screen individuals at average risk; abnormal results should be followed by a diagnostic colonoscopy. The NCCN’s recommended screening interval for blood-based tests is every 3 years. There is currently one FDA-approved bb-cfDNA test available: the Shield test, which can be used in individuals 45 years and older with average CRC risk.

Indications for Testing

Laboratory testing for CRC is used to:

Screen individuals at average risk
Diagnose and inform prognosis in patients with suggestive signs and symptoms or a family history of CRC
Predict response to treatment
Monitor for recurrence

Laboratory Testing

Screening

Screening recommendations for CRC vary.^,^, Most guidelines recommend regular CRC screening for individuals 45-75 years of age.^, The U.S. Preventive Services Task Force (USPSTF) also has a B-grade recommendation for screening in individuals 45-49 years of age and a C-grade recommendation for selective screening in individuals 76-85 years of age. Screening may involve imaging (e.g., colonoscopy), laboratory testing, or a combination of techniques.

Laboratory Tests for CRC Screening in Persons at Average Risk
Test	Recommended Frequency	Description
Stool-Based Tests (Follow-Up With Visualization Is Required for Positive Test Results)
FIT	Yearly	More sensitive and specific than the guaiac fecal occult blood test Can be performed with a single specimen
FIT DNA (sDNA-FIT)	Every 1-3 yrs (every 3 yrs is suggested and approved by the FDA; every 1-3 yrs is suggested by the USPSTF)	Combines FIT with testing for altered DNA biomarkers in cells shed into the stool Greater single-test sensitivity than FIT alone
Blood-Based cfDNA Tests
Shield test	Every 3 yrs is recommended by the NCCN	For individuals ≥45 yrs at average risk A positive result should be followed by a diagnostic colonoscopy
cfDNA, cell-free DNA; FIT, fecal immunochemical test; NCCN, National Comprehensive Cancer Network; sDNA, stool DNA Sources: NCCN, 2025; FDA, 2025; Lopes, 2019; USPSTF, 2021

Diagnosis, Prognosis, and Therapy Selection

Initial Workup

The initial laboratory workup for patients with resectable, nonmetastatic CRC includes a CEA baseline measurement, CBC, and chemistry profile. These same laboratory tests are recommended for the initial workup of suspected metastatic adenocarcinoma, in addition to tumor molecular profiling, which is described in further detail in the following section. The need for germline genetic testing is often guided by an individual’s personal or family history of cancer, molecular features of the tumor, or clinical characteristics suggestive of hereditary cancer syndromes.

Testing for Somatic Variants

Tumor molecular profiling can inform treatment decisions and, in some cases, the need for germline genetic testing. Testing of formalin-fixed, paraffin-embedded tissue is preferred, but a blood-based assay may be acceptable in certain clinical situations. For suspected or proven metastatic adenocarcinoma, testing for KRAS/NRAS and BRAF mutations, HER2 amplifications, and MSI or mismatch repair (MMR) deficiency is recommended. The use of next generation sequencing (NGS) panels rather than single gene assays can result in the detection of rare and actionable mutations such as NTRK and RET fusions. More details about testing for specific variants are provided in the following sections.

RAS and BRAF Mutation Testing

BRAF testing and extended RAS gene testing (KRAS and NRAS) are recommended in all patients with CRC who have been diagnosed with metastatic disease because BRAF, KRAS, and NRAS variants are associated with resistance to anti-epidermal growth factor receptor (anti-EGFR) therapy. BRAF testing is also indicated in screening for Lynch syndrome because the presence of the BRAF V600E variant in a tumor with MLH1/PMS2 loss by immunohistochemistry (IHC) suggests that CRC is likely sporadic (e.g., unrelated to Lynch syndrome).

HER2 Amplifications

Testing for HER2 amplification is useful in treatment planning and is recommended in patients with metastatic CRC, unless there is a known BRAF or RAS variant. HER2 amplification can be detected by IHC, fluorescence in situ hybridization (FISH), or NGS testing; an NGS panel may be particularly useful to detect HER2 amplification in conjunction with other biomarkers.

Microsatellite Instability and Mismatch Repair

Testing for MSI via polymerase chain reaction (PCR) or testing for MMR protein status via IHC is recommended in all patients with a history of CRC to evaluate for Lynch syndrome risk. Refer to the ARUP Consult Lynch Syndrome topic for more information.

MSI testing is also useful for treatment planning in stage II disease. Both MSI and MMR testing are useful for prognosis and to guide treatment selection in stage IV disease.

Other Molecular Alterations

Testing for NTRK fusions, which are very rare, may be considered in metastatic MMR-deficient CRC tumors that are wild type for BRAF, KRAS, and NRAS. Tumors with NTRK fusions may be sensitive to NTRK inhibitors. Testing for other rare and actionable mutations such as POLE/POLD1 and RET fusions may also be considered as part of broad molecular profiling. For stage II-III resectable, nonmetastatic CRC, testing for PIK3CA may be considered.

Testing for Germline Variants

Germline genetic testing for hereditary CRC syndromes should be based on clinical presentation and family history, and this testing should be performed in conjunction with genetic consultation. A hereditary cancer multigene panel, single gene testing, or familial mutation testing may be appropriate if a hereditary cancer syndrome is suspected.

Pharmacogenetic Testing

In addition to the somatic testing for MSI/MMR and BRAF, HER2, and RAS variants discussed previously, clinicians may choose to order testing for certain germline variants that have therapeutic implications.

UGT1A1

Genetic variants that result in decreased UGT1A1 expression are associated with an increased risk of toxicity with irinotecan treatment. Testing for clinically significant UGT1A1 variants should be considered before irinotecan treatment. For additional information on UGT1A1 testing, refer to the ARUP Consult Germline Pharmacogenetics topic.

DPYD

Certain DPYD gene variants are associated with life-threatening toxicity as a result of treatment with fluoropyrimidine. Testing for DPYD variants is recommended before fluoropyrimidine treatment. For additional information on pharmacogenetic testing, refer to the ARUP Consult Germline Pharmacogenetics - PGx topic.

Monitoring

Careful long-term monitoring that includes a combination of colonoscopy, clinical assessment, and laboratory testing is recommended following CRC treatment to assess for complications or recurrence.

Serum CEA should be monitored regularly after surgery. A serial increase in CEA from a preoperative baseline suggests recurrence and requires further examination (e.g., imaging and clinical assessment). For stage II, III, and IV tumors, CEA should be measured every 3-6 months for 2 years, and then every 6 months for an additional 5 years after surgery.