Hereditary nonpolyposis colorectal cancer

Lynch syndrome
Micrograph showing tumor-infiltrating lymphocytes (in a colorectal cancer), a finding associated with MSI-H tumours, as may be seen in Lynch syndrome. H&E stain.
Classification and external resources
Specialty oncology
ICD-10 C18-C20
ICD-9-CM 153.0-154.1
OMIM 120435 609310 114400
DiseasesDB 5812
MeSH D003123

Lynch syndrome (HNPCC or hereditary nonpolyposis colorectal cancer) is an autosomal dominant genetic condition that has a high risk of colon cancer[1] as well as other cancers including endometrial cancer (second most common), ovary, stomach, small intestine, hepatobiliary tract, upper urinary tract, brain, and skin. The increased risk for these cancers is due to inherited mutations that impair DNA mismatch repair. It is a type of cancer syndrome.


Henry T. Lynch, Professor of Medicine at Creighton University Medical Center, characterized the syndrome in 1966.[2] In his earlier work, he described the disease entity as "cancer family syndrome." The term "Lynch syndrome" was coined in 1984 by other authors; Lynch named the condition HNPCC in 1985. Since then the two terms have been used interchangeably, until later advances in the understanding of the genetics of the disease led to the term HNPCC falling out of favour.[3]

Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair defect, and use the term "familial colorectal cancer type X" when the Amsterdam criteria are met but there is no known DNA mismatch repair defect.[4] The putative "type X" families appear to have a lower overall incidence of cancer and lower risk for non-colorectal cancers than families with documented DNA mismatch repair deficiency.[5] About 35% of patients meeting Amsterdam criteria do not have a DNA-mismatch-repair gene mutation.[6]

Complicating matters is the presence of an alternative set of criteria, known as the "Bethesda Guidelines."[7][8][9]


Three major groups of MSI-H (MSI, MicroSatellite Instability) cancers can be recognized by histopathological criteria:

In addition, HNPCC can be divided into Lynch syndrome I (familial colon cancer) and Lynch syndrome II (HNPCC associated with other cancers of the gastrointestinal tract or reproductive system).[10]

Signs and symptoms

Tumoral predisposition

Risk of colon cancer

Individuals with HNPCC have about an 80% lifetime risk for colon cancer. Two-thirds of these cancers occur in the proximal colon. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. Also, women with HNPCC have an 80% lifetime risk of endometrial cancer. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome.[12] In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal-type adenocarcinoma being the most commonly reported pathology. HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years-old; approximately 30% are diagnosed before age 40. Other HNPCC-related cancers have been reported with specific features: the urinary tract cancers are transitional carcinoma of the ureter and renal pelvis; small bowel cancers occur most commonly in the duodenum and jejunum; the central nervous system tumor most often seen is glioblastoma.


HNPCC is inherited in an autosomal dominant fashion.

The hallmark of HNPCC is defective DNA mismatch repair, which leads to microsatellite instability, also known as MSI-H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory.[13] Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...).[14]

HNPCC is known to be associated with mutations in genes involved in the DNA mismatch repair pathway.

OMIM name Genes implicated in HNPCC Frequency of mutations in HNPCC families Locus First publication
HNPCC1 (120435) MSH2 approximately 60% 2p22 Fishel 1993[15]
HNPCC2 (609310) MLH1 approximately 30% 3p21 Papadopoulos 1994[16]
HNPCC5 MSH6 7-10% 2p16 Miyaki 1997[17]
HNPCC4 PMS2 relatively infrequent 7p22 [18] Nicolaides 1994
HNPCC3 PMS1 case report[18] 2q31-q33 Nicolaides 1994
HNPCC6 TGFBR2 case report[19] 3p22
HNPCC7 MLH3 disputed[20] 14q24.3

Patients with MSH6 mutations are more likely to be Amsterdam criteria II-negative.[21] The presentation with MSH6 is slightly different than with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition.[22] In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it.[23]

Up to 39% of families with mutations in an HNPCC gene do not meet the Amsterdam criteria. Therefore, families found to have a deleterious mutation in an HNPCC gene should be considered to have HNPCC regardless of the extent of the family history. This also means that the Amsterdam criteria fail to identify many patients at risk for Lynch syndrome. Improving the criteria for screening is an active area of research, as detailed in the Screening Strategies section of this article.

HNPCC is inherited in an autosomal dominant manner. Most people with HNPCC inherit the condition from a parent. However, due to incomplete penetrance, variable age of cancer diagnosis, cancer risk reduction, or early death, not all patients with an HNPCC gene mutation have a parent who had cancer. Some patients develop HNPCC de-novo in a new generation, without inheriting the gene. These patients are often only identified after developing an early-life colon cancer. Parents with HNPCC have a 50% chance of passing the genetic mutation on to each child.


Genetic testing for mutations in DNA mismatch repair genes is expensive and time-consuming, so researchers have proposed techniques for identifying cancer patients who are most likely to be HNPCC carriers as ideal candidates for genetic testing. The Amsterdam Criteria (see below) are useful, but do not identify up to 30% of potential Lynch syndrome carriers. In colon cancer patients, pathologists can measure microsatellite instability in colon tumor specimens, which is a surrogate marker for DNA mismatch repair gene dysfunction. If there is microsatellite instability identified, there is a higher likelihood for a Lynch syndrome diagnosis. Recently, researchers combined microsatellite instability (MSI) profiling and immunohistochemistry testing for DNA mismatch repair gene expression and identified an extra 32% of Lynch syndrome carriers who would have been missed on MSI profiling alone. Currently, this combined immunohistochemistry and MSI profiling strategy is the most advanced way of identifying candidates for genetic testing for the Lynch syndrome.

Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer.

Amsterdam criteria

The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing:[24]

Amsterdam Criteria (all bullet points must be fulfilled):

Amsterdam Criteria II (all bullet points must be fulfilled):


The Amsterdam clinical criteria identifies candidates for genetic testing, and genetic testing can make a diagnosis of Lynch syndrome. Genetic testing is commercially available and consists of a blood test.


Surgery remains the front-line therapy for HNPCC. There is an ongoing controversy over the benefit of 5-fluorouracil-based adjuvant therapies for HNPCC-related colorectal tumours, particularly those in stages I and II.[25]


After reporting a null finding from their randomized controlled trial of aspirin (ASA) to prevent the colorectal neoplasia of Lynch Syndrome,[26] Burn and colleagues have recently reported new data, representing a longer follow-up period than reported in the initial NEJM paper. These new data demonstrate a reduced incidence in Lynch Syndrome patients who were exposed to at least four years of high-dose aspirin, with a satisfactory risk profile.[27] These results have been widely covered in the media; future studies will look at modifying (lowering) the dose (to reduce risk associated with the high dosage of ASA).


In the United States, about 160,000 new cases of colorectal cancer are diagnosed each year. Hereditary nonpolyposis colorectal cancer is responsible for approximately 2 percent to 7 percent of all diagnosed cases of colorectal cancer. The average age of diagnosis of cancer in patients with this syndrome is 44 years old, as compared to 64 years old in people without the syndrome.[28]

See also


  1. Kastrinos F, Mukherjee B, Tayob N, Wang F, Sparr J, Raymond VM, Bandipalliam P, Stoffel EM, Gruber SB, Syngal S (Oct 2009). "Risk of pancreatic cancer in families with Lynch syndrome". JAMA. 302 (16): 1790–5. doi:10.1001/jama.2009.1529. PMID 19861671.
  2. Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ (Feb 1966). "Hereditary factors in cancer. Study of two large midwestern kindreds". Archives of Internal Medicine. 117 (2): 206–12. doi:10.1001/archinte.117.2.206. PMID 5901552.
  3. Bellizzi AM, Frankel WL (Nov 2009). "Colorectal cancer due to deficiency in DNA mismatch repair function: a review". Advances in Anatomic Pathology. 16 (6): 405–17. doi:10.1097/PAP.0b013e3181bb6bdc. PMID 19851131.
  4. Lindor NM (Oct 2009). "Familial colorectal cancer type X: the other half of hereditary nonpolyposis colon cancer syndrome". Surgical Oncology Clinics of North America. 18 (4): 637–45. doi:10.1016/j.soc.2009.07.003. PMC 3454516Freely accessible. PMID 19793571.
  5. Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D (Apr 2005). "Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X". JAMA. 293 (16): 1979–85. doi:10.1001/jama.293.16.1979. PMC 2933042Freely accessible. PMID 15855431.
  6. Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, du Sart D, Tucker K, Kirk J (Jan 2001). "Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds". American Journal of Human Genetics. 68 (1): 118–127. doi:10.1086/316942. PMC 1234904Freely accessible. PMID 11112663.
  7. Gologan A, Krasinskas A, Hunt J, Thull DL, Farkas L, Sepulveda AR (Nov 2005). "Performance of the revised Bethesda guidelines for identification of colorectal carcinomas with a high level of microsatellite instability". Archives of Pathology & Laboratory Medicine. 129 (11): 1390–7. doi:10.1043/1543-2165(2005)129[1390:POTRBG]2.0.CO;2. PMID 16253017.
  8. Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Rüschoff J, Fishel R, Lindor NM, Burgart LJ, Hamelin R, Hamilton SR, Hiatt RA, Jass J, Lindblom A, Lynch HT, Peltomaki P, Ramsey SD, Rodriguez-Bigas MA, Vasen HF, Hawk ET, Barrett JC, Freedman AN, Srivastava S (Feb 2004). "Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability". Journal of the National Cancer Institute. 96 (4): 261–8. doi:10.1093/jnci/djh034. PMC 2933058Freely accessible. PMID 14970275.
  9. Lipton LR, Johnson V, Cummings C, Fisher S, Risby P, Eftekhar Sadat AT, Cranston T, Izatt L, Sasieni P, Hodgson SV, Thomas HJ, Tomlinson IP (Dec 2004). "Refining the Amsterdam Criteria and Bethesda Guidelines: testing algorithms for the prediction of mismatch repair mutation status in the familial cancer clinic". Journal of Clinical Oncology. 22 (24): 4934–43. doi:10.1200/JCO.2004.11.084. PMID 15611508.
  10. Hereditary Colorectal Cancer > Background. From Medscape. By Juan Carlos Munoz and Louis R Lambiase. Updated: Oct 31, 2011
  11. Lee SE, Kang SY, Cho J, Lee B, Chang DK, Woo H, Kim JW, Park HY, Do IG, Kim YE, Kushima R, Lauwers GY, Park CK, Kim KM (Jun 2014). "Pyloric gland adenoma in Lynch syndrome". The American Journal of Surgical Pathology. 38 (6): 784–92. doi:10.1097/PAS.0000000000000185. PMC 4014525Freely accessible. PMID 24518125.
  12. Hoffman, Barbara L. (2012). Williams Gynecology: Chapter 33, Endometrial Cancer (2nd ed.). New York: McGraw-Hill Medical. ISBN 978-0071716727.
  13. Pathology of Hereditary Nonpolyposis Colorectal Cancer - JASS 910 (1): 62 - Annals of the New York Academy of Sciences
  14. Oki E, Oda S, Maehara Y, Sugimachi K (Mar 1999). "Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair". Oncogene. 18 (12): 2143–7. doi:10.1038/sj.onc.1202583. PMID 10321739.
  15. Fishel R, Lescoe MK, Rao MR, Copeland NG, Jenkins NA, Garber J, Kane M, Kolodner R (Dec 1993). "The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer". Cell. 75 (5): 1027–38. doi:10.1016/0092-8674(93)90546-3. PMID 8252616.
  16. Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM, Adams MD (Mar 1994). "Mutation of a mutL homolog in hereditary colon cancer". Science. 263 (5153): 1625–9. doi:10.1126/science.8128251. PMID 8128251.
  17. Miyaki M, Konishi M, Tanaka K, Kikuchi-Yanoshita R, Muraoka M, Yasuno M, Igari T, Koike M, Chiba M, Mori T (Nov 1997). "Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer". Nature Genetics. 17 (3): 271–2. doi:10.1038/ng1197-271. PMID 9354786.
  18. 1 2 Nicolaides NC, Papadopoulos N, Liu B, Wei YF, Carter KC, Ruben SM, Rosen CA, Haseltine WA, Fleischmann RD, Fraser CM (Sep 1994). "Mutations of two PMS homologues in hereditary nonpolyposis colon cancer". Nature. 371 (6492): 75–80. doi:10.1038/371075a0. PMID 8072530.
  19. Lu SL, Kawabata M, Imamura T, Akiyama Y, Nomizu T, Miyazono K, Yuasa Y (May 1998). "HNPCC associated with germline mutation in the TGF-beta type II receptor gene". Nature Genetics. 19 (1): 17–8. doi:10.1038/ng0598-17. PMID 9590282.
  20. Ou J, Rasmussen M, Westers H, Andersen SD, Jager PO, Kooi KA, Niessen RC, Eggen BJ, Nielsen FC, Kleibeuker JH, Sijmons RH, Rasmussen LJ, Hofstra RM (Apr 2009). "Biochemical characterization of MLH3 missense mutations does not reveal an apparent role of MLH3 in Lynch syndrome". Genes, Chromosomes & Cancer. 48 (4): 340–50. doi:10.1002/gcc.20644. PMID 19156873.
  21. Ramsoekh D, Wagner A, van Leerdam ME, Dinjens WN, Steyerberg EW, Halley DJ, Kuipers EJ, Dooijes D (Nov 2008). "A high incidence of MSH6 mutations in Amsterdam criteria II-negative families tested in a diagnostic setting". Gut. 57 (11): 1539–44. doi:10.1136/gut.2008.156695. PMID 18625694.
  22. Suchy J, Lubinski J (2008). "MSH6 syndrome". Hereditary Cancer in Clinical Practice. 6 (2): 103–4. doi:10.1186/1897-4287-6-2-103. PMC 2735474Freely accessible. PMID 19804606.
  23. Goldberg Y, Porat RM, Kedar I, Shochat C, Galinsky D, Hamburger T, Hubert A, Strul H, Kariiv R, Ben-Avi L, Savion M, Pikarsky E, Abeliovich D, Bercovich D, Lerer I, Peretz T (Jun 2010). "An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC". Familial Cancer. 9 (2): 141–50. doi:10.1007/s10689-009-9298-9. PMID 19851887.
  24. Vasen HF, Watson P, Mecklin JP, Lynch HT (Jun 1999). "New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC". Gastroenterology. 116 (6): 1453–6. doi:10.1016/S0016-5085(99)70510-X. PMID 10348829.
  25. Boland CR, Koi M, Chang DK, Carethers JM (2007). "The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside". Familial Cancer. 7 (1): 41–52. doi:10.1007/s10689-007-9145-9. PMID 17636426.
  26. Burn J, Bishop DT, Mecklin JP, Macrae F, Möslein G, Olschwang S, Bisgaard ML, Ramesar R, Eccles D, Maher ER, Bertario L, Jarvinen HJ, Lindblom A, Evans DG, Lubinski J, Morrison PJ, Ho JW, Vasen HF, Side L, Thomas HJ, Scott RJ, Dunlop M, Barker G, Elliott F, Jass JR, Fodde R, Lynch HT, Mathers JC (Dec 2008). "Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome". The New England Journal of Medicine. 359 (24): 2567–78. doi:10.1056/NEJMoa0801297. PMID 19073976.
  27. "Aspirin Confers Long-Term Protective Effect in Lynch Syndrome Patients". Retrieved 2009-11-07.
  28. Cancer Information, Research, and Treatment for all Types of Cancer | OncoLink
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