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Colon cancer exhibits the characteristics of familial clustering in >10-15% of cases. The most well-characterized hereditary colon cancer is Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC). Lynch syndrome is caused by germline mutations in the genes that encode mismatch repair (MMR) factors. It is the most common cause of hereditary colorectal cancer and accounts for 2-3% of colorectal cancer.
Tests generally appear in the order most useful for common clinical situations
| Test name: Mismatch Repair by Immunohistochemistry |
| ARUP #: 0049302 |
| Methodology: Qualitative Immunohistochemistry |
| Use: Preferred test to discriminate between Lynch syndrome and sporadic mutations in colorectal cancers Surrogate test for MSI by PCR May help guide subsequent mutation analysis |
| Limitations: 83% clinical sensitivity; 90% clinical specificity |
| Follow-up: If negative, but strong suspicion for Lynch syndrome exists, follow up testing with PCR |
| Test name: HNPCC/Lynch Syndrome, Microsatellite Instability by PCR |
| ARUP #: 0051740 |
| Methodology: Polymerase Chain Reaction/Fragment Analysis |
| Use: Discriminate between MSI and microsatellite-stable cancer |
| Limitations: 90% sensitivity for Lynch syndrome |
| Test name: HNPCC/Lynch Syndrome Deletion/Duplication |
| ARUP #: 2001728 |
| Methodology: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification |
| Use: Detect mutations and large deletions in MLH1, MSH2, MSH6 or PMS2 genes |
| Limitations: For PMS2 testing, suspected deletions or duplication in exons 12-15 require sequencing to exclude pseudogene copy number variants |
| Test name: HNPCC/Lynch Syndrome (MLH1) Sequencing and Deletion/Duplication |
| ARUP #: 0051650 |
| Methodology: Polymerase Chain Reaction/Sequencing/Multiplex Ligation Probe Amplification |
| Use: Identify mutations and large deletions in MLH1gene Present in ~45% of Lynch syndrome |
| Limitations: Rare diagnostic errors can occur due to primer and probe site mutations Breakpoints of large deletions/duplications will not be determined Regulatory region mutations, deep intronic mutations and mutations in genes other than MLH1 will not be detected |
| Test name: HNPCC/Lynch Syndrome (MSH2) Sequencing and Deletion/Duplication |
| ARUP #: 0051654 |
| Methodology: Polymerase Chain Reaction/Sequencing/Multiplex Ligation Probe Amplification |
| Use: Detect mutations and large deletions in MSH2 gene Present in ~45% of Lynch syndrome |
| Limitations: Rare diagnostic errors can occur due to primer and probe site mutations Breakpoints of large deletions/duplications will not be determined Regulatory region mutations, deep intronic mutations and mutations in genes other than MSH2 will not be detected |
| Test name: HNPCC/Lynch Syndrome (MSH6) Sequencing and Deletion/Duplication |
| ARUP #: 0051656 |
| Methodology: Polymerase Chain Reaction/Sequencing/Multiplex Ligation Probe Amplification |
| Use: Detect mutations and large deletions in MSH6 gene Present in ~10% of Lynch syndrome |
| Limitations: Rare diagnostic errors can occur due to primer and probe site mutations Breakpoints of large deletions/duplications will not be determined Regulatory region mutations, deep intronic mutations and mutations in genes other than MSH6 will not be detected |
| Test name: HNPCC/Lynch Syndrome (PMS2) Sequencing and Deletion/Duplication |
| ARUP #: 0051737 |
| Methodology: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification |
| Use: Detect mutations and large deletions in PMS2 gene Present in a small fraction of Lynch syndrome Suspected deletions or duplications in exons 12-15 require additional sequencing to exclude pseudogene copy number variants |
| Limitations: Rare diagnostic errors can occur due to primer and probe site mutations Breakpoints of large deletions/duplications will not be determined Regulatory region mutations, deep intronic mutations and mutations in genes other than PMS2 will not be detected PMS2 exons 3, 4, 12, 13, 14 or 15 are not evaluated for deletions/duplications |
| Test name: Mismatch Repair by Immunohistochemistry with Reflex to MLH1 Promoter Methylation |
| ARUP #: 2005270 |
| Methodology: Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction |
| Use: Distinguish between sporadic, microsatellite unstable non-colorectal cancer and Lynch-associated non-colorectal cancer |
| Limitations: Rare diagnostic errors can occur due to primer and probe site mutations Breakpoints of large deletions/duplications will not be determined Regulatory region mutations, deep intronic mutations and mutations in genes other than MLH1 will not be detected |
| Test name: CDX2 by Immunohistochemistry |
| ARUP #: 2003821 |
| Methodology: Immunohistochemistry |
| Use: Aid in histologic diagnosis of colorectal cancer Stained and returned to client pathologist; consultation available if needed |
| Test name: Carcinoembryonic Antigen, Monoclonal (CEA M) by Immunohistochemistry |
| ARUP #: 2003824 |
| Methodology: Immunohistochemistry |
| Use: Aid in histologic diagnosis of colorectal cancer Stained and returned to client pathologist; consultation available if needed |
| Test name: Cytokeratin 20 (CK 20) by Immunohistochemistry |
| ARUP #: 2003848 |
| Methodology: Immunohistochemistry |
| Use: Aid in histologic diagnosis of colorectal cancer Stained and returned to client pathologist; consultation available if needed |
| Test name: Muc-2 by Immunohistochemistry |
| ARUP #: 2004005 |
| Methodology: Immunohistochemistry |
| Use: Aid in histologic diagnosis of colorectal cancer Stained and returned to client pathologist; consultation available if needed |
| Test name: p16 by Immunohistochemistry |
| ARUP #: 2004064 |
| Methodology: Immunohistochemistry |
| Use: Prognostic stain Stained and returned to client pathologist; consultation available if needed |
| Test name: p21 (Waf1/Cip 1) by Immunohistochemistry |
| ARUP #: 2004067 |
| Methodology: Immunohistochemistry |
| Use: Prognostic stain Stained and returned to client pathologist; consultation available if needed |
| Test name: p27 (Kip1) by Immunohistochemistry |
| ARUP #: 2004070 |
| Methodology: Immunohistochemistry |
| Use: Prognostic stain Stained and returned to client pathologist; consultation available if needed |
| Test name: p53 Tissue Assay, Paraffin |
| ARUP #: 0049250 |
| Methodology: Immunohistochemistry |
| Use: Prognostic stain Stained and returned to client pathologist; if consultation required, contact anatomic pathology, surgical consult or hematopathology |
| Test name: BRAF Codon 600 Mutation Detection with Reflex to MLH1 Promoter Methylation |
| ARUP #: 0051750 |
| Methodology: Polymerase Chain Reaction/Pyrosequencing |
| Use: Detect the presence of the V600E mutation in colorectal cancers to differentiate Lynch syndrome from sporadic colorectal cancer V600E mutation accounts for ~90% of all BRAF mutations If no BRAF mutation is detected, MLH1 promoter methylation is evaluated; evaluation can also help determine whether further workup for Lynch syndrome is indicated Presence indicates colorectal cancer is sporadic and Lynch syndrome is not present |
| Limitations: Mutations other than BRAF V600E will not be detected Rare diagnostic errors may occur due to primer- or probe-site mutations Methylation at locations other than those covered by the primers and probes will not be detected <10% presence of a mutant allele may not be detected |
| Test name: BRAF codon 600 Mutation Detection by Pyrosequencing |
| ARUP #: 2002498 |
| Methodology: Polymerase Chain Reaction/Pyrosequencing |
| Use: Detect the presence of the V600E mutation in colorectal cancers Presence indicates colorectal cancer is sporadic and Lynch syndrome is not present |
| Test name: Familial Mutation, Targeted Sequencing |
| ARUP #: 2001961 |
| Methodology: Polymerase Chain Reaction/Sequencing |
| Use: Evaluate family members for a known family mutation in an MMR gene |
| Test name: Familial Adenomatous Polyposis Panel: APC Sequencing, APC Deletion/Duplication, and MYH 2 Mutations |
| ARUP #: 2004915 |
| Methodology: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification |
| Comments: Differential diagnosis of Lynch syndrome |
| Test name: Carcinoembryonic Antigen |
| ARUP #: 0080080 |
| Methodology: Quantitative Electrochemiluminescent Immunoassay |
| Comments: |
| Test name: Circulating Tumor Cell Count (Cell Search™) |
| ARUP #: 0093399 |
| Methodology: Immunomagnetic Separation/Immunofluorescence Staining/Computer Assisted Analysis |
| Comments: |