Introduction
Background
Hereditary nonpolyposis colorectal cancer (HNPCC), an autosomal-dominant syndrome, accounts for 2-5% of all colorectal carcinomas. Colorectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) presents at an earlier age than in the general population and is characterized by an increased risk of other cancers, such as endometrial cancer and, to a lesser extent, cancers of the ovary, stomach, small intestine, hepatobiliary tract, pancreas, upper urinary tract, prostrate, brain, and skin.
Hereditary nonpolyposis colorectal cancer (HNPCC) is divided into Lynch syndrome I (familial colon cancer) and Lynch syndrome II (HNPCC associated with other cancers of the gastrointestinal [GI] or reproductive system). The increased cancer risk is due to inherited mutations that degrade the self-repair capability of DNA .
Lynch syndrome was named after Dr. Henry T. Lynch. In 1966, Dr. Lynch and colleagues described familial aggregation of colorectal cancer with stomach and endometrial tumors in 2 extended kindreds and named it cancer family syndrome. Authors later termed this constellation Lynch syndrome, and, more recently, this condition has been called hereditary nonpolyposis colorectal cancer (HNPCC).
Before molecular genetic diagnostics became available in the 1990s, a comprehensive family history was the only basis from which to estimate the familial risk of colorectal cancer.
For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Cancer Screening, Colon Cancer, and Rectal Cancer.
Pathophysiology
In hereditary nonpolyposis colorectal cancer (HNPCC), an inherited mutation in one of the DNA mismatch repair (MMR) genes appears to be a critical factor. MMR genes normally produce proteins that identify and correct sequence mismatches that may occur during DNA replication. In hereditary nonpolyposis colorectal cancer (HNPCC), a mutation that inactivates an MMR gene leads to the accumulation of cell mutations and greatly increases the likelihood of malignant transformation and cancer.
Researchers have identified 7 distinct MMR genes, including the following:
- hMLH1 on band 3p22
- hMSH2 and hMSH6 on band 2p16
- hPMS1 on band 3p32 and hPMS2 on band 7q22
Other mutations include hMSH3 on band 5q14.1 and EXO1 on band 1q43. Mutations of hMLH1 and hMSH2 account for nearly 70% of MMR mutations in hereditary nonpolyposis colorectal cancer (HNPCC); 10% involve hMSH6. The genes responsible for the remaining 20-25% of cases have not yet been discovered.
Table 1. Seven different genes are known to be associated with HNPCC, and all of them are involved with DNA mismatch repair. How often they have been identified:
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Table
| Mismatch Excision Repaired MMR | Chromosome Location | Frequency of HNPCC Cases |
| MSH2 | 2p16 | 45-50% |
| MLH1 | 3p22.3/A> | 20% |
| MSH6 | 2p16 | 10% |
| PMS2 | 7p22.1 | 1% |
| PMS1 | 2q32.2 | Rare |
| MSH3 | 5q14.1 | Rare |
| EXO1 | 1q43 | Rare |
| Other genes not yet discovered | | 20-25% |
| Mismatch Excision Repaired MMR | Chromosome Location | Frequency of HNPCC Cases |
| MSH2 | 2p16 | 45-50% |
| MLH1 | 3p22.3/A> | 20% |
| MSH6 | 2p16 | 10% |
| PMS2 | 7p22.1 | 1% |
| PMS1 | 2q32.2 | Rare |
| MSH3 | 5q14.1 | Rare |
| EXO1 | 1q43 | Rare |
| Other genes not yet discovered | | 20-25% |
Germline mutations are often inherited but may also arise spontaneously or de novo in a new generation. These patients are often identified only after they develop colon cancer early in life. Transmission is autosomal dominant (see Image 1 and below), meaning that 50% of the offspring of affected individuals inherit a mutant allele.
Example of an autosomal dominant pedigree.
Because phenotypic expression of hereditary nonpolyposis colorectal cancer (HNPCC) requires inactivation of both alleles, germline mutations of one allele must be accompanied by somatic inactivation of the wild-type allele. Inactivation may result from deletions, mutations, or splicing errors occurring anywhere throughout the gene. Mutations that lead to protein truncation account for most inactivating hMLH1 and hMSH2 mutations. Failure to correct replication errors results in genomic instability.
Despite the absence of polyposis, hereditary nonpolyposis colorectal cancer (HNPCC)-associated colorectal cancers are believed to arise from preexisting discrete proximal colonic adenomas. Affected individuals have a propensity to develop predominantly right-sided, flat adenomas at a young age. Patients with Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) develop adenomas at the same rate as individuals in the general population; however, the adenomas in those with Lynch syndrome or HNPCC are more likely to progress to cancer. Carcinogenesis progresses more rapidly in these patients (in 2-3 y) than in patients with sporadic adenomas (8-10 y).
Synchronous colorectal tumors (primary tumors diagnosed within 6 mo of each other) and metachronous colorectal tumors (primary tumors occurring more than 6 mo apart) are more common in persons with hereditary nonpolyposis colorectal cancer (HNPCC). An individual with an HNPCC mutation who does not undergo a partial or total colectomy after the first mass is diagnosed as malignant has an estimated 30-40% risk of developing a metachronous tumor within 10 years and a 50% risk within 15 years. In the general population, the risk is 3% in 10 years and 5% within 15 years.
Mortality/Morbidity
Although not everyone who inherits the gene for hereditary nonpolyposis colorectal cancer (HNPCC) develops colorectal cancer, individuals with Lynch syndrome have a 70-80% lifetime risk of developing colon cancer. Of these cancers, two thirds occur in the proximal colon (proximal to the splenic flexure). In approximately 45% of affected individuals, multiple synchronous and metachronous colorectal may occur within 10 years of resection.
Other cancers associated with hereditary nonpolyposis colorectal cancer (HNPCC) include the following:
- Endometrial cancer: The lifetime risk is 30-40% by age 70 years. The average age at diagnosis is 46 years. Half of patients with both colon and endometrial cancer present with endometrial cancer first.
- Ovarian cancer: The lifetime risk is 9% by age 70 years. The average age at diagnosis is 42.5 years. Approximately 30% of these tumors present before age 40 years.
- Gastric cancer: The mean age at diagnosis of gastric cancer is 56 years; intestinal-type adenocarcinoma is the most commonly reported pathology, especially in Asian countries such as Japan, Korea, and China.
- Transitional cell carcinoma: This principally affects the upper urinary tract (ureters and renal pelvis).
- Adenocarcinoma of the small bowel cancers: These occur most commonly in the duodenum and jejunum.
- Glioblastoma: Also known as Turcot syndrome, this is a variant of hereditary nonpolyposis colorectal cancer (HNPCC) (see below).
- Malignancies of the larynx, breast, prostate, liver, biliary tree, pancreas, and the hematopoietic system are more common in patients with hereditary nonpolyposis colorectal cancer (HNPCC).
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Table
| Type of Cancer | General Population Risk (by age 70 y) | Lynch Syndrome Risk (by age 70 y) |
| Endometrial | 1.5% | 40-50% |
| Ovarian | 1% | 9-12% |
| Upper Urinary Tract | Less than 1% | 4-10% |
| Stomach | Less than 1% | 13% (higher in Asians) |
| Small Bowel | Less than 1% | 1-3% |
| Brain | Less than 1% | 1-4% |
| Biliary Tract | Less than 1% | 1-5% |
| Type of Cancer | General Population Risk (by age 70 y) | Lynch Syndrome Risk (by age 70 y) |
| Endometrial | 1.5% | 40-50% |
| Ovarian | 1% | 9-12% |
| Upper Urinary Tract | Less than 1% | 4-10% |
| Stomach | Less than 1% | 13% (higher in Asians) |
| Small Bowel | Less than 1% | 1-3% |
| Brain | Less than 1% | 1-4% |
| Biliary Tract | Less than 1% | 1-5% |
Turcot syndrome
Formerly considered a separate disorder from familial adenomatosis polyposis (FAP), Turcot syndrome is clinically characterized by both multiple colorectal adenomas and primary brain tumor. In 1995, Hamilton et al demonstrated that this association may result from at least 2 distinct types of germline defects: a mutation in the APC gene (which represents two thirds of cases and is responsible for FAP) and a mutation in MMR gene PMS2 or MLH1 (which represents one third of cases).1 Medulloblastoma is most common with APC mutations, whereas glioblastoma is most common with MMR gene mutations.
Muir-Torre syndrome
A mutation in MSH2 and MHL causes Muir-Torre syndrome, which is considered a variant of hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome. Muir-Torre syndrome accounts for much less than 1% of all hereditary colorectal cancer cases and is characterized by the typical features of HNPCC, sebaceous gland tumors, and keratoacanthomas.
Age
Colorectal cancer in persons with hereditary nonpolyposis colorectal cancer (HNPCC) occurs at an earlier age than in the general population. In persons with hereditary nonpolyposis colorectal cancer (HNPCC), the average age of polyp onset is in the late second decade and early third decade of life. The average age of colorectal cancer onset is 44 years in members of families that meet the Amsterdam criteria compared with age 60-65 years in the general population (see History, Guidelines).
Race
Lynch syndrome has no known racial proclivity; however, ethnic-specific mutations have been observed in Finnish and Swedish populations. Colorectal cancer rates in the Ashkenazi Jewish population are disproportionately high, possibly the highest of any ethnic group worldwide. Although neither HNPCC nor classic FAP are more common in Ashkenazim than in the general population, both have a connection to individuals of Ashkenazi Jewish heritage.
A specific mutation in the MSH2 gene, G1906K, is found in 2-3% of all colorectal cancers in Ashkenazi Jews younger than 60 years. One third of Ashkenazi Jewish individuals who meet criteria for genetic testing of HNPCC have this mutation. This mutation is rarely found in the general population but is more common in young Ashkenazi Jews with colorectal cancer. In individuals in whom colorectal cancer is diagnosed at age 40 years or younger, 7% have been found to carry this mutation. Conversely, the mutation is found in less than 1% of Ashkenazim persons in whom colorectal cancer is diagnosed after age 60 years.
Contrary to American and European reports, gastric cancer may be more common than endometrial cancer in the Asian (Japanese, Korean, Chinese) population.
Sex
Hereditary nonpolyposis colorectal cancer (HNPCC) is commonly diagnosed in both men and women; however, uterine and ovarian cancer are more common in women with HNPCC.
Frequency
United States
The incidence of hereditary nonpolyposis colorectal cancer (HNPCC) in the United States is 2-5%, or 7500 new occurrences of HNPCC annually.
International
Large geographic differences are observed in the occurrence of hereditary nonpolyposis colorectal cancer (HNPCC).
Clinical
History
Making the diagnosis of Lynch syndrome is usually a 3-stage process, including review of family cancer history, tumor testing, and genetic testing .
A considerable number of patients diagnosed with colorectal cancer have a family history of this disease; however, most patients do not have any of the known colorectal cancer syndromes. When a diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) or other familial colon cancer syndrome is considered, a pedigree should be drawn of each patient.
When a pedigree is analyzed, the family's size is an important consideration. For instance, a small family with 2 cases of colorectal cancer among first-degree relatives is more likely to indicate hereditary nonpolyposis colorectal cancer (HNPCC) than a large family with 2 cases of similar diagnosis. Patients must be asked about colorectal cancer or polyps in family members and about other associated neoplasms (see Table 2).
The following history findings should raise suspicion for hereditary nonpolyposis colorectal cancer (HNPCC):
- Multiple cases of colorectal cancer or numerous adenomatous polyps diagnosed in different generations
- People younger than 50 years affected
- The combination of syndrome-related tumors in other organs
- Synchronous or metachronous tumors in one person
Significant suspicion for hereditary nonpolyposis colorectal cancer (HNPCC) should prompt further evaluation of the patient and his or her family.
Guidelines
In 1990, following a conference in Amsterdam, the International Collaborative Group (ICG) first proposed clinical criteria to identify patients at risk of developing hereditary nonpolyposis colorectal cancer (HNPCC). These criteria, now known as the ICG or Amsterdam I criteria are predicated on an accurate family history of colorectal cancer that includes the number of affected relatives, degree of closeness, and age at diagnosis.
Amsterdam Criteria I
- Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first-degree relative (parent, child sibling) of the other two
- Two successive affected generations (one of the patients is a first-degree family member of the other patients)
- One or more colon cancers diagnosed younger than 50 years
- FAP has been excluded.
In 1999, the Amsterdam I criteria were revised to include extracolonic cancers, known as Amsterdam II criteria.
Amsterdam Criteria II
- Three or more family members with HNPCC-related cancers,* one of whom is a first-degree relative of the other two
- Two successive affected generations (one of the patients is a first-degree family member of the other patients)
- One or more of the HNPCC-related cancers diagnosed younger than 50 years
- FAP has been excluded.
* Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome).
Less stringent guidelines, such as the modified Bethesda criteria were established in 1997. These guidelines, for appropriate microsatellite instability (MSI) testing on colorectal tumor specimens, were used to identify families likely to have an MMR gene mutation.
- Colorectal cancer diagnosed in a patient who is younger than 50 years
- Presence of the synchronous or metachronous colorectal cancer or other HNPCC-associated tumors,* regardless of age
- Colorectal cancer with the MSI-H,† histology, diagnosed in a patient who is younger than 60 years
- Colorectal cancer diagnosed in one or more first-degree relatives with an HNPCC-related tumor,*with one of the cancers diagnosed in a patient younger than 50 years
- Colorectal cancer diagnosed in 2 or more first- or second-degree relatives with HNPCC-related tumors, regardless of age
* MSI-H in tumors refers to changes that are equal or greater than 2 of the 5 National Cancer Institute (NCI)-recommended panels.
† Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome).
The Bethesda criteria may be more sensitive than either form of the Amsterdam criteria in identifying families with hereditary nonpolyposis colorectal cancer (HNPCC), but they are not diagnostic of HNPCC, because MSI also occurs in 15% of sporadic tumors. These patients should undergo a DNA test for confirmation (see Image 2 and below).
Diagnostic approach for patients with colorectal tumors.
Criteria for referral to genetic counseling have also been developed, as follows. Endoscopic surveillance should be performed if genetic testing is refused, unavailable, or offers no information.
- Adenomatous polyps in patients younger than 40 years
- Greater than 10 or greater than 100 adenomatous polyps in the classic FAP
- Multiple colorectal carcinomas or other HNPCC-related tumors,* in one individual
- Colorectal cancer or endometrial cancer diagnosed in a patient younger than 50 years
- Two first-degree relatives with colorectal carcinoma or HNPCC-related tumor,* independent of age of diagnosis
* Colorectal carcinoma, endometrial carcinoma, and other related cancers: small bowel, transitional cell carcinoma of the upper urinary tract, stomach, ovarian, brain (Turcot syndrome) and sebaceous gland adenomas or keratoacanthomas (Muir-Torre syndrome).
Physical
Despite the term hereditary nonpolyposis, people with HNPCC actually do have polyps. However, these individuals tend to have less than 100; the number is usually much higher in other forms of inherited colorectal cancers.
Polyp formation starts in the late second and early third decade of life. Although these cancers are often asymptomatic in their early stages, the following signs and symptoms may develop as the cancer advances:
- Changes in bowel habits (eg, constipation or diarrhea that persists for longer than several days)
- Visible or no blood in stool (positive fecal occult blood test)
- Black, tarry stool (may represent bleeding above the rectum)
- Iron deficiency without an identifiable cause
- Abdominal pain, cramps, or frequent feeling of distention (or bloating) in the abdominal or bowel region
- Fatigue or weakness
- Decline in appetite
- Unexplained weight loss
Causes
See Pathophysiology.
More on Hereditary Colorectal Cancer |
 Overview: Hereditary Colorectal Cancer |
| Differential Diagnoses & Workup: Hereditary Colorectal Cancer |
| Treatment & Medication: Hereditary Colorectal Cancer |
| Follow-up: Hereditary Colorectal Cancer |
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Further Reading
Related eMedicine Topics
- Colon, Adenocarcinoma [in the Radiology section]
- Colorectal Tumors [in the Pediatrics: General Medicine section]
- Rectal Cancer [in the Oncology section]
American Cancer Society
National Home Office
250 Williams St NW
Atlanta, GA 30303-1002
Phone: 404-320-3333
Website: http://www.cancer.org/
In addition to offering information, the ACS has a number of educational programs and informational materials. Call the American Cancer Society for local chapters of the American Cancer Society.
National Cancer Institute
NCI Public Inquiries Office
6116 Executive Boulevard
Room 3036A
Bethesda, MD 20892-8322
Phone: 1-800-4-CANCER (1-800-422-6237)
TTY: 1-800-332-8615
Website: http://www.cancer.gov/
The NCI has help line open during working hours and offers free information on all aspects of cancer. The following site lists clinical trials (http://www.cancer.gov/clinicaltrials/).
Keywords
hereditary colorectal cancer, hereditary nonpolyposis colorectal cancer, HNPCC, hereditary colorectal neoplasms, cancer familial syndrome, Lynch syndrome, Lynch criteria type I, Lynch criteria type II, Amsterdam criteria I, Amsterdam criteria II, Bethesda criteria, international collaborative group, ICG, colonic neoplasia, colorectal cancer, rectal bleeding, Turcot syndrome, HNPCC variant, Muir-Torre syndrome, metachronous, synchronous, germline,
microsatellite instability, MSI, MSI testing, immunohistochemistry, IHC, mismatch repair gene, MMR, endoscopic polypectomy, colectomy, rectal resection, subtotal colectomy with ileoanal anastomosis, total colectomy with ileorectal anastomosis, total proctocolectomy with ileostomy, cancer family syndrome, familial adenomatosis polyposis, FAP, endometrial cancer, glioblastoma, ovarian cancer, adenoma, prophylactic subtotal colectomy, prophylactic hysterectomy and bilateral salpingo-oophorectomy, chemoprevention
