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FeedbackLynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited cancer syndrome that predisposes an individual to colorectal, endometrial, gastric, ovarian, upper urinary tract, and other cancers. The risk of developing one of these cancers varies, depending on the associated gene. LS results from pathogenic variants of the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. In certain cases, a deletion of the EPCAM gene leads to MSH2 inactivation, and thus LS. Testing for LS includes screening for MMR deficiency in patients with colorectal cancer (CRC) or endometrial tumors, as well as diagnostic germline genetic testing in patients with a personal and/or family history suggestive of LS.
Quick Answers for Clinicians
Lynch syndrome (LS) often presents with early-onset colorectal cancer (CRC), in many cases before 50 years of age. Multiple tumors are common. Extracolonic tumors may also arise, depending on the specific causative pathogenic variant. Common extracolonic tumors include endometrial, prostate, ovarian, gastric, urinary tract, small bowel, hepatobiliary, brain/central nervous system, and pancreatic tumors, as well as sebaceous neoplasms.
Several organizations recommend universal screening for Lynch syndrome (LS) in all patients with colorectal cancer (CRC) - or endometrial cancer. Germline genetic testing is generally recommended for patients with an early cancer diagnosis, positive family history, and/or abnormal tumor testing results. The National Comprehensive Cancer Network (NCCN) has published specific criteria for LS screening (available at www.nccn.org).
In most situations, it is cost-effective to first test for microsatellite instability (MSI) by polymerase chain reaction (PCR) and/or mismatch repair (MMR) protein deficiency by immunohistochemistry (IHC), given that only 2-4% of colorectal cancer cases are Lynch syndrome (LS) associated. Both tests are sensitive and usually produce concordant results. If these tests reveal that a tumor has MSI or is MMR deficient, molecular germline genetic testing should be performed. However, if strong suspicion exists (eg, family history, cancer at a young age), it is reasonable to bypass MSI testing and proceed directly to molecular germline genetic testing.
BRAF V600E testing is not appropriate for follow-up testing of endometrial cancer specimens with MLH1 loss by immunohistochemistry (IHC); only MLH1 promoter methylation testing should be performed. In colorectal cancer (CRC) specimens with MLH1 loss by IHC, BRAF V600E and MLH1 promoter methylation testing can be performed to determine the likelihood of Lynch syndrome (LS). See Screening of Cancer Specimens and the Lynch Syndrome (HNPCC) Testing Algorithm for more information.
Indications for Testing
Laboratory testing for LS is used to:
- Screen for LS in all CRC specimens -
- Screen for LS in all endometrial tumors
- Diagnose LS in patients with a suggestive personal or family history of tumors and/or cancer
Laboratory Testing
Screening of Cancer Specimens
In most situations, it is most effective to first perform somatic testing, ie, to evaluate specimens from patients with suspected LS with immunohistochemistry (IHC) or polymerase chain reaction (PCR) testing for MMR protein deficiency or microsatellite instability (MSI). This eliminates the expense of full gene sequencing for the majority of tumors that lack MMR deficiency, given that only 2-4% of CRCs are LS associated. Both IHC and PCR tests are sensitive and usually produce concordant results. However, if strong suspicion exists (eg, family history, cancer at a young age), it is reasonable to proceed directly to germline genetic testing.
| Test | Characteristics | Test Interpretation | |
|---|---|---|---|
| IHC |
Involves staining of tumor tissue for protein expression of 4 MMR genes known to be mutated in LS (MLH1, MSH2, MSH6, and PMS2) Pattern of protein loss identified on IHC directs germline testing NOTE: Loss of MLH1 may be due to acquired hypermethylation in sporadic tumors or a germline mutation in LSa; see the Lynch Syndrome (HNPCC) Testing Algorithm for additional information |
IHC Result | Likely Gene Mutationa |
| MLH1, PMS2 loss | MLH1 or, rarely, PMS2 | ||
| MSH2, MSH6 loss | MSH2 or, rarely, MSH6 | ||
| MSH6 | MSH6 or MSH2 | ||
| PMS2 | PMS2 or MLH1 | ||
| MSI by PCR (panel of 5 or more mononucleotide microsatellites) |
Use to detect expansion or contraction of microsatellite repeats in the tumor Does not detect which specific MMR protein is deficient Patient tumor tissue is compared with normal tissue Highest sensitivity is achieved when PCR is combined with IHC Useful for MSI testing when IHC testing is negative despite high clinical suspicion of LS |
Determination of MSI | |
High (≥2 markers, or ≥30% of markers in an expanded panel, with instability):
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Low (1 marker, or <30% of markers in an expanded panel, with instability):
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Stable (no markers detected with instability):
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| BRAF V600E or MLH1 promoter methylation |
When MLH1 loss is identified using IHC, perform before LS mutation analysis Loss of MLH1 may be due to acquired hypermethylation in sporadic tumors or a germline mutation in LS NOTES: The BRAF V600E variant is uncommon in LS but common in sporadic CRC of the MSI pathway BRAF V600E testing is not appropriate for endometrial cancer; use only MLH1 promoter methylation testing Additional BRAF testing may be appropriate for sporadic CRC (see Colorectal Cancer topic) |
If BRAF V600E or MLH1 hypermethylation is positive:
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aRefer to Lynch Syndrome (HNPCC) Testing Algorithm. NCCN, National Comprehensive Cancer Network Sources: NCCN, 2020 ; Rubenstein, 2015 ; NCCN, 2020 ; Sepulveda, 2017 ; NCCN, 2021 ; Giardiello, 2014 |
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Diagnosis
Molecular germline genetic testing is the gold standard for the diagnosis of LS. Genetic testing can be used in patients with suggestive screening results or if strong suspicion exists based on personal and/or family history. Germline gene analysis can take the form of single gene testing or a multigene panel. Single gene testing may be considered when IHC results indicate that a specific LS gene should be targeted. Consider a multigene panel if strong suspicion exists for LS or other hereditary cancer syndromes due to a suggestive personal and/or family history.
The diagnosis of LS is established by identification of a pathogenic variant in one of the MMR genes (MLH1, MSH2, MSH6, or PMS2) or an EPCAM deletion. Both sequencing and deletion/duplication analysis are necessary to identify all detectable pathogenic variants in MMR genes. If a pathogenic sequencing variant in an LS gene has already been identified in the family, targeted testing for the familial variant may be available (see ARUP test code 2001961).
Prognosis
Patients with MMR-deficient CRC have an improved prognosis compared with stage-matched patients without MMR deficiency.
ARUP Laboratory Tests
Preferred screening test for LS in individuals with CRC
Do not use in endometrial cancer
Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction
First-line screening test for LS
Qualitative Immunohistochemistry
Screening test for LS
Capillary Electrophoresis
Recommended reflex test to differentiate between LS and sporadic CRC in tumors showing loss of MLH1
Polymerase Chain Reaction/Pyrosequencing
Used within LS reflex testing pathway (for CRC specimens only)
Polymerase Chain Reaction/Pyrosequencing
Preferred reflex screening test for LS in non-CRC tumors (eg, endometrial carcinoma)
Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction
Recommended test to distinguish between LS and sporadic non-CRC tumors with loss of MLH1
Real-Time Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer
Recommended test to confirm a diagnosis of hereditary gastrointestinal (GI) cancer in individuals with a personal or family history of GI cancer and/or polyposis
Includes analysis of 5 LS genes (MLH1, MSH2, MSH6, PMS2, and EPCAM)
For additional test information, refer to the Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome Test Fact Sheet
Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray/Sequencing/Multiplex Ligation-dependent Probe Amplification
Useful when a pathogenic familial variant identifiable by sequencing is known
Polymerase Chain Reaction/Sequencing
Use to detect germline MLH1 variants
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Use to detect germline MSH2 variants and EPCAM deletion
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Use to detect germline MSH6 variants
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Use to detect germline PMS2 variants
Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification
Order if negative germline sequencing studies have been performed previously at another laboratory or if there is a known familial deletion or duplication
Multiplex Ligation-dependent Probe Amplification
Medical Experts
Bayrak-Toydemir
Matynia
Wiley
References
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GeneReviews - Lynch Syndrome
Idos G, Valle L. Lynch syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last revision: Feb 2021; Accessed: Feb 2021]
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NCCN - Genetic/Familial High-Risk Assessment: Colorectal - Colorectal, Lynch Vernsion 1.2020
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, Genetic/familial high-risk assessment: colorectal, Version 1.2020. [Updated: Jul 2020; Accessed: Feb 2021]
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Rubenstein JH, Enns R, Heidelbaugh J, et al. American Gastroenterological Association Institute guideline on the diagnosis and management of Lynch syndrome. Gastroenterology. 2015;149(3):777-782; quiz e16-17.
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Balmana J, Balaguer F, Cervantes A, et al. Familial risk-colorectal cancer: ESMO clinical practice guidelines. Ann Oncol. 2013;24: Suppl 6 vi73-vi80.
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National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, colorectal cancer screening, Version 2.2020. [Updated: Jun 2020; Accessed: Feb 2021]
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Sepulveda AR, Hamilton SR, Allegra CJ, et al. Molecular biomarkers for the evaluation of colorectal cancer: guideline from the American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017;35(13):1453-1486.
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National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, colon cancer, Version 2.2021. [Updated: Jan 2021; Accessed: Feb 2021]
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Giardiello FM, Allen JI, Axilbund JE, et al. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology. 2014;147(2):502-526.
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NCCN - Uterine Neoplasms - Lynch Syndrome
National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology, uterine neoplasms, Version 1.2021. [Updated: Oct 2020; Accessed: Feb 2021]
CAP - Primary Carcinoma of the Colon and Rectum
College of American Pathologists (CAP). Protocol for the examination of specimens from patients with primary carcinoma of the colon and rectum. [Posted: Feb 2020; Accessed: Mar 2021]
