Lynch Syndrome

(Hereditary Non-polyposis Colorectal Cancer, HNPCC)

Lynch syndrome (LS) is the most common type of hereditary colorectal cancer. It is characterized by the development of colorectal cancer, endometrial cancer and various other cancers.

LS is caused by a mutation in one of the mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. The MMR-defect leads to instability at microsatellites of tumour-DNA (called microsatellite instability, MSI) which could be found in >90% of colorectal cancer associated with LS.

Currently, mainly clinical criteria (Bethesda criteria) are used to select patients with colorectal cancer for molecular genetic (MSI-analysis) and/or immunohistochemical analysis of the tumour. Those with evidence of MSI or loss of MMR protein expression are offered mutation analysis. 

Identification of LS families is important because it allows offering preventive measures to affected family members. Many studies have shown that colonoscopic surveillance leads to a substantial reduction of the risk of colorectal cancer and also reduction of the mortality associated with colorectal cancer. Besides, surveillance of endometrial cancer may lead to detection of premalignant lesions and early cancers. Knowledge on the effectiveness of surveillance for the other LS-associated cancer is limited.

The lifetime risk of developing one of these associated cancers (stomach, ureter, renal pelvis, small bowel, bile ducts and brain tumours) is relatively low (less than 15%). 

Characteristic Features of LS

  1. Autosomal dominant inheritance – in other words, offspring of an affected individual will have 50% chance of inheriting the condition;
  2. Associated cancers: cancer of colorectum, stomach, ovary, ureter/renal pelvis, brain, small bowel, hepatobiliary tract, skin (sebaceous adenoma);
  3. Development of cancer at an early age – the average age of colorectal cancer is about 40 years;
  4. Development of multiple cancers;
  5. Features of colorectal cancer: predilection for proximal colon, improved survival, multiple colorectal cancers, poorly differentiated cancers, tumour-infiltrating lymphocytes and Crohn’s-like lymphoid reaction;
  6. Features of adenoma: number varies from one to a few, high proportion with a villous growth pattern, high degree of dysplasia, rapid progression from adenoma to carcinoma;
  7. High frequency of microsatellite instability;
  8. Immunohistochemistry: loss of MLH1, MSH2, MSH6 and PMS2 protein expression.

Estimated Lifetime Risk of Various Cancer Development in LS

Cancer Percentage
Colorectal (men) 28-75%
Colorectal (women) 24-52%
Endometrial 27-71%
Ovarian 3-13%
Gastric 2-13%
Urinary tract 1-12%
Brain 1-4%
Bile duct / gallbladder 2%
Small bowel 4-7%

Clinical Criteria for LS – Amsterdam Criteria II

In contrast to polyposis syndromes, the absence of pathognomonic clinical features hampered the diagnosis of LS. The diagnosis of LS could only be suspected on the basis of personal and family history of cancer. One of the clinical criteria to facilitate recognition of this condition is the Amsterdam criteria which was first established in 1990 and then revised in 1999. This set of criteria allows international collaborative studies and promote the use of uniform terminology.

Amsterdam criteria II

  • There should be at least 3 relatives with colorectal cancer or with a LS-associated cancer: cancer of the endometrium, small bowel, ureter or renal pelvis;
  • One relative should be a first-degree relative of the other two;
  • At least two successive generations should be affected;
  • At least one tumour should be diagnosed before age 50;
  • FAP should be excluded in the CRC case, if any;
  • Tumours should be verified by histopathological examination.

Revised Bethesda Criteria

As mentioned before, the revised Bethesda criteria is a set of clinical criteria that facilitates selection of colorectal cancer patients for MSI analysis and/or immunohistochemical (IHC) staining of the tumour.

  • Colorectal cancer diagnosed in a patient <50 years of age;
  • Presence of synchronous, metachronous colorectal or other LS-related tumours regardless of age;
  • Colorectal cancer with MSI-H histology diagnosed in a patient <60 years of age;
  • Patient with colorectal cancer and a first-degree relative with a LS-related tumor, with one of the cancers diagnosed under age 50 years;
  • Patients with colorectal cancer with two or more first-degree or second-degree relatives with a LS-related tumour, regardless of age.

Our Clinical Research Results on LS

  1. Clinical Predictors of MSI & MMR Gene Mutation Analysis
    Relying solely on traditional (Amsterdam) clinical criteria will underestimate the incidence of LS in Hong Kong Chinese. In an earlier Registry report1, of the 27 patients with identifiable germline MMR gene mutation, only one patient’s family history satisfied the Amsterdam criteria.
    In one study on clinical predictors of MSI-H colorectal cancer2, we found that (1) young age at colorectal cancer diagnosis, (2) tumour located at the right colon; (3) increasing number of first-degree relatives with colorectal cancer; and (4) a personal history of metachronous cancer were independent predictors of MSI-H colorectal cancer in Hong Kong Chinese.
    In a subsequent study on clinical predictors of germline MMR gene mutation in young colorectal cancer patients in Hong Kong3, we found that the success rate of mutation detection increased with increasing strength of colorectal cancer family history.
    The above information facilitates the Registry in selecting suitable patients for LS genetic testing; and it also provides an estimate as to the success rate of such mutation detection.
  2. Founder Mutation
    In 2001 and 2004, the Registry have reported on the identification of two founder mutations, one on the MLH1 gene and another on the MSH2 gene which account for 11.1% and 33.3% of mutations detected in the respective genes in our cohort at that time4-5.
    Identification of these founder mutations has important implications in the design of mutation detection strategy in our Hong Kong Chinese.

Clinical Surveillance Protocol for Germline MMR Gene Mutation Carriers

 Cancer Type

Starting Age (year)

Interval (year)



25 Age 25-35: 2 years Colonoscopy
Age >35: 1 year
Gynaecological 25 Age 25-35: 3 years Vaginal examination, endometrial aspiration, pelvic ultrasound, serum ovarian tumour marker
Age >35: 2 years
Gastric (if positive family history) 25 Age 25-35: 3 years Upper endoscopy
Age >35: 2 years


For MMR gene mutation carriers, treatment is mainly by means of surveillance which should be lifelong once started. To promote maximal compliance with the recommended surveillance protocols, careful education and counseling about all the details of the disease are essential. Experience has shown that long-term surveillance of high-risk families cannot be adequately guaranteed by individual specialists. The establishment of regional registries ensures that surveillance protocol would be offered to members of families followed-up by different specialists. Hereditary cancer registries also have a role in the assessment of the results of long-term surveillance. This is important because the value of most suggested surveillance protocols is as yet unknown.


  1. Chan TL et al. Frequent microsatellite instability and mismatch repair gene mutations in young Chinese patients with colorectal cancer. J Natl Cancer Inst 1999; 91: 1221-1226.
  2. Ho JW et al. Distinct clinical features associated with microsatellite instability in colorectal cancers of young patients. Int J Cancer 2000; 89: 356-360.
  3. Ho JWC et al. Hereditary colorectal cancer syndromes in Hong Kong: a Registry’s perspective. Hereditary Cancer in Clinical Practice 2005; 3: 147-154.
  4. Chan TL et al. A novel germline 1.8-kb deletion of hMLH1 mimicking alternative splicing: a founder mutation in the Chinese population. Oncogene 2001; 20: 2976-2981.
  5. Chan TL et al. MSH2 c.1452-1455delAATG is a founder mutation and an important cause of hereditary nonpolyposis colorectal cancer in the southern Chinese population. Am J Hum Genet 2004; 74: 1035-1042.