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Lynch syndrome

Last updated: March 24, 2021

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Lynch syndrome, or hereditary nonpolyposis colon cancer (HNPCC), is a familial cancer syndrome caused by an autosomal dominant mutation in DNA mismatch repair (MMR) genes. Affected individuals develop a small number of adenomas that can rapidly progress to colorectal cancer (CRC), resulting in a considerably earlier symptom onset compared to sporadic colorectal cancer. Individuals with Lynch syndrome are also at increased risk of developing other forms of cancer, especially endometrial, gastric, and ovarian cancer. Individuals are asymptomatic until they present with symptoms of advanced cancer. To identify those at high risk for Lynch syndrome, individuals are assessed according to the Amsterdam II criteria. Subsequent genetic analysis with detection of MMR mutations confirms the diagnosis. Treatment of CRC consists of surgical colectomy and immunotherapy. Preventative screening for colorectal cancer and associated tumors is recommended in individuals with family members known to have a Lynch syndrome gene mutation; it should occur every 1–2 years, starting at 20–25 years of age, or 2–5 years before the earliest recorded case of a tumor in the family.

References:[1]

Epidemiological data refers to the US, unless otherwise specified.

References:[2]

  • Patients are usually asymptomatic until CRC develops (see colorectal cancer).
  • Lynch syndrome-associated CRC usually affects the right (proximal) colon.
  • Possibly extracolonic symptoms of associated cancers (see “Epidemiology” section above)

References:[2]

References:[3]

Lynch syndrome should be suspected if there is a positive family history based on the Amsterdam II criteria. Genetic testing confirms the diagnosis.

Family history

The Amsterdam II criteria are used to identify individuals who are likely to be mutation carriers for Lynch syndrome.

Amsterdam II criteria

Presence of at least three relatives with a Lynch syndrome-associated cancer; all the following criteria should be present:

  • One should be a first-degree relative of the other two
  • At least two consecutive generations affected
  • At least one relative with a diagnosis before 50 years of age
  • Exclude cases of familial adenomatous polyposis.
  • Verify tumors with pathological examination.

3-2-1 rule: (3 affected family members, 2 generations, 1 relative under 50 years of age).

The Revised Bethesda guidelines are used to identify individuals with colorectal cancer who should undergo tumor testing for microsatellite instability.

Revised Bethesda guidelines

Individuals should be tested for MSI in the following situations:

  • Colorectal cancer diagnosed in patients < 50 years
  • Presence of synchronous, metachronous colorectal, or other Lynch syndrome-associated tumors, regardless of age
  • Colorectal cancer with MSI-H-like histology diagnosed in patients > 60 years
  • Colorectal cancer in ≥ 1 first-degree relative(s) with a Lynch syndrome-related tumor, with one of the cancers being diagnosed under age 50
  • Colorectal cancer in ≥ 2 first-degree or second-degree relatives with Lynch syndrome-related tumors, regardless of age

Genetic testing

Colorectal cancer

Lynch syndrome typically manifests with colorectal cancer of the proximal colon, with only a few adenomatous polyps, in contrast to familial adenomatous polyposis, in which hundreds of adenomatous polyps are present.

References:[2][4]

References:[7]

  • Genetic counseling
    • Genetic testing is generally not recommended for at-risk individuals < 18 years of age.
    • Genetic screening should be initiated 10 years before the earliest manifestation of the condition in the family.
  • Cancer screening: for Lynch syndrome patients with a confirmed mutation or who meet Amsterdam criteria
  • Total colectomy: not generally recommended in patients with normal endoscopy

References:[2][7]

  1. Aarnio M, Mecklin JP, Aaltonen LA, Nyström-Lahti M, Järvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome.. Int J Cancer. 1995; 64 (6): p.430-3.
  2. Win AK, Lindor NM. Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-clinical-manifestations-and-diagnosis?source=search_result&search=lynch%20syndrome&selectedTitle=1%E2%88%BC84.Last updated: January 19, 2016. Accessed: February 10, 2017.
  3. Vasen H, Watson P, Mecklin J, Lynch H. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative Group on HNPCC☆. Gastroenterology. 1999; 116 (6): p.1453-1456. doi: 10.1016/s0016-5085(99)70510-x . | Open in Read by QxMD
  4. Giardiello FM et al. Guidelines on Genetic Evaluation and Management of Lynch Syndrome: A Consensus Statement by the US Multi-Society Task Force on Colorectal Cancer. Am J Gastroenterol. 2014; 109 (8): p.1159-1179. doi: 10.1038/ajg.2014.186 . | Open in Read by QxMD
  5. Bonis PAL, Ahnen DJ, Axell L. Lynch syndrome (hereditary nonpolyposis colorectal cancer): Screening and management. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/lynch-syndrome-hereditary-nonpolyposis-colorectal-cancer-screening-and-management?source=search_result&search=lynch%20syndrome&selectedTitle=2%E2%88%BC84#H20526201.Last updated: May 12, 2016. Accessed: February 10, 2017.
  6. Overman MJ et al. Durable Clinical Benefit With Nivolumab Plus Ipilimumab in DNA Mismatch Repair–Deficient/Microsatellite Instability–High Metastatic Colorectal Cancer. Journal of Clinical Oncology. 2018; 36 (8): p.773-779. doi: 10.1200/jco.2017.76.9901 . | Open in Read by QxMD
  7. Salman P et al.. Evidence of response to pembrolizumab in a patient with Lynch syndrome-related metastatic colon cancer. OncoTargets and Therapy. 2018; Volume 11 : p.7295-7300. doi: 10.2147/ott.s167645 . | Open in Read by QxMD
  8. Ponti G, Manfredini M, Tomasi A, Pellacani G. Muir–Torre Syndrome and founder mismatch repair gene mutations: A long gone historical genetic challenge. Gene. 2016; 589 (2): p.127-132. doi: 10.1016/j.gene.2015.06.078 . | Open in Read by QxMD
  9. Munoz JC. Hereditary Colorectal Cancer. In: BS Anand, Hereditary Colorectal Cancer. New York, NY: WebMD. http://emedicine.medscape.com/article/188613. Updated: April 7, 2015. Accessed: February 10, 2017.