Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

Primary Author: Samowitz, Wade S., MD.

  • Key Points
  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Lynch syndrome (formerly referred to as hereditary nonpolyposis colorectal cancer or HNPCC)

  • Universal screening of all colorectal cancer (CRC) specimens (NCCNASCO, AGA, 2015) and endometrial cancer specimens (ASCO, NCCN, 2015; ESMO, 2013) is recommended
  • LS is an autosomal dominant inherited cancer syndrome that predisposes to colorectal, endometrial, gastric, ovarian, upper urinary tract, and other cancers
  • The presence of mismatch repair (MMR) deficiency helps identify patients at risk for Lynch syndrome (LS); however, it also occurs in ~15% of sporadic colorectal cancers
    • Differentiating colorectal tumors with MMR deficiency due to a sporadic somatic event from colorectal tumors with MMR deficiency due to a LS germline mutation is important

Indications for Testing

  • All colorectal cancer (CRC) and/or endometrial tumors

Laboratory Testing

  • For additional information regarding testing strategies, refer to the following

Prognosis

  • Patients with MMR-deficient colorectal cancer have improved prognosis compared to patients without MMR deficiency
  • Refer to NCCN guidelines, Genetic/Familial High Risk Assessment (2015), ASCO (2015), ESMO (2013)
  • Refer to NCCN guidelines, Genetic/Familial High Risk Assessment (2015)

Colon cancer exhibits the characteristics of familial clustering in ~10-15% of cases. The most common cause of hereditary colon cancer is Lynch syndrome (LS – hereditary nonpolyposis colorectal cancer [HNPCC]). LS is caused by a germline mutation in one of the genes within the DNA mismatch repair system.

Epidemiology

  • Prevalence – 2-4% of colorectal cancer (CRC) (NCCN, 2015)
  • Age – mutation dependent (44-66 years mean)
    • >75% risk of developing CRC by 70 years
  • Sex – M:F, equal

Inheritance

  • Autosomal dominant with incomplete penetrance
  • Germline mutations in 1 of 4 DNA MMR genes
    • MLH1 50%
    • MSH2 40%
      • Small percentage of MSH2 inactivation is due to EPCAM deletions
        • Included with MSH2 testing
    • MSH6 – 7-10%
    • PMS2 <5%

Clinical Presentation

  • Early onset of proximal (right side) colorectal cancer – often <50 years
    • Multiple metachronous and synchronous tumors are common
  • Early-onset extra colonic tumors, including endometrial, ovarian, small bowel, brain, pancreatic, gastric, renal pelvis, ureter, hepatobiliary tract
    • Risk depends on mutation present
  • Penetrance variable; patients may present with tumors at older age
    • Especially true for MSH6 and PMS2
    • Universal screening will identify these tumors and patients will not be mistakenly classified as sporadic CRC
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Mismatch Repair by Immunohistochemistry with Reflex to BRAF Codon 600 Mutation and MLH1 Promoter Methylation 2002327
Method: Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction

Limitations 

~10% of individuals with LS will have IHC tests which show normal staining of the MMR proteins

Since the correlation of MSI with IHC is not 100%, direct testing of MSI by PCR may be helpful

Follow-up 

Definitive diagnosis of LS requires additional targeted MMR germline mutation studies

Mismatch Repair by Immunohistochemistry with Reflex to MLH1 Promoter Methylation 2005270
Method: Qualitative Immunohistochemistry/Qualitative Real-time Polymerase Chain Reaction

Limitations 

~10% of individuals with LS will have IHC tests which show normal staining of the MMR proteins

Since the correlation of MSI with IHC is not 100%, direct testing of MSI by PCR may be helpful

Mismatch Repair by Immunohistochemistry 0049302
Method: Qualitative Immunohistochemistry

Limitations 

~10% of individuals with LS will have IHC tests which show normal staining of the MMR proteins

Since the correlation of MSI with IHC is not 100%, direct testing of MSI by PCR may be helpful

Microsatellite Instability (MSI), HNPCC/Lynch Syndrome, by PCR 0051740
Method: Polymerase Chain Reaction/Fragment Analysis

Limitations 

15% of sporadic CRCs are also MSI-H

Preoperative chemoradiation of rectal cancer

  • May complicate IHC interpretation and/or decrease tumor mass
  • May make MSI testing difficult

Evaluation of pretreatment biopsies will avoid this limitation

HNPCC/Lynch Syndrome (MLH1) Sequencing and Deletion/Duplication 0051650
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the MLH1 gene will not be detected

HNPCC/Lynch Syndrome (MSH2) Sequencing and Deletion/Duplication 0051654
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the MSH2 gene will not be detected

HNPCC/Lynch Syndrome (MSH6) Sequencing and Deletion/Duplication 0051656
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the MSH6 gene will not be detected

HNPCC/Lynch Syndrome (PMS2) Sequencing and Deletion/Duplication 0051737
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Limitations 

Gene sequencing may identify mutations of unknown clinical significance

Rare false negatives can occur due to primer- and probe-site mutations

Breakpoints of large deletions/duplications will not be determined

Deep intronic mutations or promoter mutations of the PMS2 gene will not be detected

BRAF Codon 600 Mutation Detection with Reflex to MLH1 Promoter Methylation 0051750
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations 

Mutations other than BRAF V600E will not be detected

Rare false negatives may occur due to primer- and probe-site mutations

BRAF Codon 600 Mutation Detection by Pyrosequencing 2002498
Method: Polymerase Chain Reaction/Pyrosequencing

Limitations 

Limit of detection

  • MassARRAY and pyrosequencing − 10% mutant alleles
  • NGS – 5% mutant alleles

MassARRAY and pyrosequencing – oncogenic mutations outside of codon 600 will not be detected

HNPCC/Lynch Syndrome Deletion/Duplication 2001728
Method: Polymerase Chain Reaction/Multiplex Ligation-dependent Probe Amplification

Guidelines

Balmana J, Balaguer F, Cervantes A, Arnold D, ESMO Guidelines Working Group. Familial risk-colorectal cancer: ESMO Clinical Practice Guidelines. Ann Oncol. 2013; 24 Suppl 6: vi73-80. PubMed

Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genet Med. 2009; 11(1): 35-41. PubMed

Giardiello FM, Allen JI, Axilbund JE, Boland R, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK, US Multi-Society Task Force on Colorectal Cancer. 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): 502-26. PubMed

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL, Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015; 17(1): 70-87. PubMed

Ladabaum U, Ford JM, Martel M, Barkun AN. American Gastroenterological Association Technical Review on the Diagnosis and Management of Lynch Syndrome Gastroenterology. 2015; 149(3): 783-813.e20. PubMed

NCCN Clinical Practice Guidelines in Oncology, Colorectal Cancer Screening. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

NCCN Clinical Practice Guidelines in Oncology, Genetic/Familial High-Risk Assessment: Colorectal. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jan 2016]

NCCN Clinical Practice Guidelines in Oncology, Uterine Neoplasms. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jul 2015]

Protocol for the Examination of Specimens from Patients with Neuroendocrine Tumors (Carcinoid Tumors) of the Colon and Rectum. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Accessed: Sep 2015]

Rubenstein JH, Enns R, Heidelbaugh J, Barkun A, Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome Gastroenterology. 2015; 149(3): 777-82; quiz e16-7. PubMed

Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, Lu KH, Roach N, Limburg PJ, American Society of Clinical Oncology, European Society of Clinical Oncology. Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 2015; 33(2): 209-17. PubMed

Vasen HF, Möslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin J, Møller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007; 44(6): 353-62. PubMed

General References

Bedeir A, Krasinskas AM. Molecular diagnostics of colorectal cancer. Arch Pathol Lab Med. 2011; 135(5): 578-87. PubMed

Bodo S, Colas C, Buhard O, Collura A, Tinat J, Lavoine N, Guilloux A, Chalastanis A, Lafitte P, Coulet F, Buisine M, Ilencikova D, Ruiz-Ponte C, Kinzel M, Grandjouan S, Brems H, Lejeune S, Blanché H, Wang Q, Caron O, Cabaret O, Svrcek M, Vidaud D, Parfait B, Verloes A, Knappe UJ, Soubrier F, Mortemousque I, Leis A, Auclair-Perrossier J, Frébourg T, Fléjou J, Entz-Werle N, Leclerc J, Malka D, Cohen-Haguenauer O, Goldberg Y, Gerdes A, Fedhila F, Mathieu-Dramard M, Hamelin R, Wafaa B, Gauthier-Villars M, Bourdeaut F, Sheridan E, Vasen H, Brugières L, Wimmer K, Muleris M, Duval A, European Consortium “Care for CMMRD”. Diagnosis of Constitutional Mismatch Repair-Deficiency Syndrome Based on Microsatellite Instability and Lymphocyte Tolerance to Methylating Agents Gastroenterology. 2015; 149(4): 1017-29.e3. PubMed

Boland R, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology. 2010; 138(6): 2073-2087.e3. PubMed

Djordjevic B, Broaddus RR. Role of the clinical pathology laboratory in the evaluation of endometrial carcinomas for Lynch syndrome. Semin Diagn Pathol. 2014; 31(3): 195-204. PubMed

Durno CA, Sherman PM, Aronson M, Malkin D, Hawkins C, Bakry D, Bouffet E, Gallinger S, Pollett A, Campbell B, Tabori U, International BMMRD Consortium. Phenotypic and genotypic characterisation of biallelic mismatch repair deficiency (BMMR-D) syndrome Eur J Cancer. 2015; 51(8): 977-83. PubMed

Geiersbach KB, Samowitz WS. Microsatellite instability and colorectal cancer. Arch Pathol Lab Med. 2011; 135(10): 1269-77. PubMed

Jasperson KW, Tuohy TM, Neklason DW, Burt RW. Hereditary and familial colon cancer. Gastroenterology. 2010; 138(6): 2044-58. PubMed

Legolvan MP, Taliano RJ, Resnick MB. Application of molecular techniques in the diagnosis, prognosis and management of patients with colorectal cancer: a practical approach. Hum Pathol. 2012; 43(8): 1157-68. PubMed

Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009; 76(1): 1-18. PubMed

Rybak C, Hall MJ. Interpretation of genetic testing for lynch syndrome in patients with putative familial colorectal cancer. J Natl Compr Canc Netw. 2011; 9(11): 1311-20. PubMed

Senter L. Genetic testing by cancer site: colon (nonpolyposis syndromes). Cancer J. 2012; 18(4): 334-7. PubMed

Sharma SG, Gulley ML. BRAF mutation testing in colorectal cancer. Arch Pathol Lab Med. 2010; 134(8): 1225-8. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Chadwick BE. Beyond cytomorphology: expanding the diagnostic potential for biliary cytology. Diagn Cytopathol. 2012; 40(6): 536-41. PubMed

Hegde M, Ferber M, Mao R, Samowitz W, Ganguly A, Working Group of the American College of Medical Genetics and Genomics (ACMG) Laboratory Quality Assurance Committee. ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014; 16(1): 101-16. PubMed

Panarelli NC, Vaughn CP, Samowitz WS, Yantiss RK. Sporadic microsatellite instability-high colon cancers rarely display immunohistochemical evidence of Wnt signaling activation Am J Surg Pathol. 2015; 39(3): 313-7. PubMed

Patil DT, Bronner MP, Portier BP, Fraser CR, Plesec TP, Liu X. A five-marker panel in a multiplex PCR accurately detects microsatellite instability-high colorectal tumors without control DNA. Diagn Mol Pathol. 2012; 21(3): 127-33. PubMed

Samowitz WS. Evaluation of colorectal cancers for Lynch syndrome: practical molecular diagnostics for surgical pathologists Mod Pathol. 2015; 28 Suppl 1: S109-13. PubMed

Slattery ML, Wolff RK, Curtin K, Fitzpatrick F, Herrick J, Potter JD, Caan BJ, Samowitz WS. Colon tumor mutations and epigenetic changes associated with genetic polymorphism: insight into disease pathways. Mutat Res. 2009; 660(1-2): 12-21. PubMed

Szankasi P, Reading S, Vaughn CP, Prchal JT, Bahler DW, Kelley TW. A quantitative allele-specific PCR test for the BRAF V600E mutation using a single heterozygous control plasmid for quantitation: a model for qPCR testing without standard curves. J Mol Diagn. 2013; 15(2): 248-54. PubMed

Tomsic J, Senter L, Liyanarachchi S, Clendenning M, Vaughn CP, Jenkins MA, Hopper JL, Young J, Samowitz W, de la Chapelle A. Recurrent and founder mutations in the PMS2 gene. Clin Genet. 2013; 83(3): 238-43. PubMed

Vaughn CP, Baker CL, Samowitz WS, Swensen JJ. The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. Genes Chromosomes Cancer. 2013; 52(1): 107-12. PubMed

Walter AW, Ennis S, Best H, Vaughn CP, Swensen JJ, Openshaw A, Gripp KW. Constitutional mismatch repair deficiency presenting in childhood as three simultaneous malignancies. Pediatr Blood Cancer. 2013; 60(11): E135-6. PubMed

Medical Reviewers

Last Update: September 2016