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Colorectal cancer (Lynch syndrome)

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Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC) , was first identified nearly a century ago as familial clustering of cancers, particularly of the colon, small intestine, stomach, endometrium, upper urinary tract and sebaceous tumors of the skin.

There is no tendency to polyposis and hence the name HNPCC.


Lynch syndrome accounts for approximately 2% to 5% of all cases of CRC (colorectal cancer) (1,2,3).

  • it is the most common genetic syndrome associated with an increased susceptibility to CRC

Characteristics of Lynch syndrome

  • individuals with Lynch syndrome have a 60%-80% risk for CRC, as well as an increased risk for cancers, most notably endometrial cancer

    • endometrial cancer is the second most common malignancy in Lynch syndrome with a lifetime risk between 40% and 60%, often occurring before CRC in females

    • Lynch syndrome is also associated with an increased relative risk for cancer in the stomach, ovary, small bowel, pancreas, ureter, renal pelvis, biliary tract, and brain

    • one of the major characteristics (phenotype) of Lynch syndrome carriers is that cancer often develops at an earlier age than in the general population

      • for example, the average age of onset for CRC and endometrial cancer for individuals with Lynch syndrome is approximately 44 and 48 years, respectively, compared to 65 years for colorectal and 60 years for endometrial sporadic carcinomas in the general population

      • the incidence of synchronous (multiple primary cancers occurring simultaneously) and metachronous (multiple cancers occurring at intervals) CRCs occur in up to 50% of individuals with Lynch syndrome, compared to less than 20% risk in individuals with sporadic CRC

      • further, CRC in Lynch syndrome patients often occurs in the right or proximal colon in contrast to predominance of sigmoid/distal carcinomas in sporadic disease

      • pathologic features of Lynch syndrome-associated CRC often include tumor-infiltrating lymphocytes, Crohn's like reactions, signet ring cells, and mucinous adenocarcinoma. These pathologic features of Lynch syndrome are less typically found in sporadic CRC and often are red flags for Lynch syndrome

      • there is a controversial association between Lynch syndrome and breast cancer. Study evidence revealed 50% of breast cancers arising in Lynch syndrome mutation carriers had a loss of mismatch repair proteins (3)

Lynch syndrome is a genetic condition caused by germ line mutations or alterations in any one of the four genes known as mismatch repair (MMR) genes

  • MMR genes are essential to maintain the integrity of the DNA, checking for and correcting mistakes that if not repaired have the potential for tumor formation and cancer development
    • the four MMR genes implicated in the Lynch syndrome are MLH1, MSH2, MSH6, and PMS2

Lynch syndrome is transmitted in a mendelian autosomal-dominant (AD) pattern of inheritance whereby individuals with Lynch syndrome have a 50% chance of transmitting the genetic mutation to each of their offspring. Individuals with Lynch syndrome are born with a normal functioning gene (wild type allele) on one chromosome and a mutated gene on the other chromosome

  • despite the presence of a Lynch syndrome-associated gene mutation at birth (known as the 'first hit'), cancer does not arise unless there is a loss of function (or acquired somatic mutation) on the remaining chromosomal gene or allele (second hit)
    • this acquired mutation is likely because of gene/environment interaction and leads to a 'second hit' that disables the remaining wild-type allele. The second hit leads to the development of cancer due to the loss of the protective repair mechanisms of the MMR genes
    • the requirement for the second hit illustrates why some individuals with the genetic mutation might not develop Lynch syndrome-associated cancers

Individuals with a high risk of HNPCC should be offered annual or biannual colonoscopies from the age of 25 years (4).


Individuals with Lynch Syndrome have a high lifetime risk of developing CRC (15% - 80%), including a variety of other malignancies such as ovarian, pancreatic, gastric, biliary tract, urothelial (ureter, renal pelvis), sebaceous gland adenomas, keratoacanthomas, and brain cancers (5,6)

Criteria for Testing for Lynch syndrome

Amsterdam and Bethesda criteria are often used to help determine who might benefit from genetic counseling and testing for Lynch syndrome (7):

  • Amsterdam criteria
    • assesses risk of Lynch syndrome based on family history
    • people who have at least 3 relatives diagnosed with a type of cancer associated with Lynch syndrome and who meet all of the following criteria are at risk of Lynch syndrome:
      • (1) one relative is a first-degree relative (parent, sibling, or child) of the other 2 relatives;
      • (2) at least 2 successive generations are affected; and
      • (3) at least 1 relative had cancer diagnosed before age 50 years

  • Bethesda criteria
    • assesses risk of Lynch syndrome for people diagnosed with colorectal cancer
    • individuals are at risk if they
      • have been diagnosed with colorectal or uterine cancer and are younger than 50 years
      • have been diagnosed with a second colorectal cancer or another cancer associated with Lynch syndrome (endometrial, stomach, pancreas, small intestine, ovary, kidney, brain, ureters, or bile duct)
      • are younger than 60 years and have a cancer that is characteristic of Lynch syndrome when viewed under a microscope
      • have a first-degree relative (parent, sibling, or child) younger than 50 years who was diagnosed with colorectal cancer or another cancer associated with Lynch syndrome
      • have 2 or more first- or second-degree relatives (aunt, uncle, niece, nephew, or grandparent) with colorectal cancer or another Lynch syndrome–related cancer at any age


  1. Douglas JA et al. History and molecular genetics of Lynch syndrome in family G: a century later.JAMA. 2005 Nov 2;294(17):2195-202.
  2. Lynch HT, Lynch JF. What the physician needs to know about Lynch syndrome: an update. Oncology (Williston Park). 2005 Apr;19(4):455-63; discussion 463-4, 466, 469.
  3. Walsh MD et al. Lynch syndrome-associated breast cancers: clinicopathologic characteristics of a case series from the colon cancer family registry. Clin Cancer Res. 2010 Apr 1;16(7):2214-24. Epub 2010 Mar 9.
  4. Pulse (2005); 65(14):55-60.
  5. Nolano, A., Medugno, A., Trombetti, S., Liccardo, R., De Rosa, M., Izzo, P. and Duraturo, F., 2022. Hereditary Colorectal Cancer: State of the Art in Lynch Syndrome. Cancers, 15(1), 75.
  6. Lynch, H.T., Lynch, P.M., Lanspa, S.J., Snyder, C.L., Lynch, J.F. and Boland, C.R., 2009. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clinical genetics, 76(1), 1-18.
  7. Hornbuckle K, Fritz CDL. What Is Lynch Syndrome? JAMA. Published online June 01, 2024. doi:10.1001/jama.2024.8552

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