Hereditary Colorectal Cancer 

  • Author: Juan Carlos Munoz, MD; Chief Editor: Julian Katz, MD   more...
 
Updated: Oct 31, 2011
 

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.

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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, identified with the frequencies below. (Open Table in a new window)

Mismatch Excision Repaired MMRChromosome LocationFrequency of HNPCC Cases
MSH22p1645-50%
MLH13p22.3/A>20%
MSH62p1610%
PMS27p22.11%
PMS12q32.2Rare
MSH35q14.1Rare
EXO11q43Rare
Other genes not yet discovered20-25%

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 below), meaning that 50% of the offspring of affected individuals inherit a mutant allele.

Example of an autosomal dominant pedigree. 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.

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Epidemiology

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 9-12% 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 lifetime risk is around 13% (higher in Asians). 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: The lifetime risk is 4-10%. This principally affects the upper urinary tract (ureters and renal pelvis).
  • Adenocarcinoma of the small bowel cancers: The lifetime risk is 1-3%. These occur most commonly in the duodenum and jejunum.
  • Glioblastoma: The lifetime risk is 1-4%. 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).

Table 2. Incidence of different types of cancers between individuals with Lynch syndrome and those in the general population. (Open Table in a new window)

Type of CancerGeneral Population Risk (by age 70 y)Lynch Syndrome Risk (by age 70 y)
Endometrial1.5%30-40%
Ovarian1%9-12%
Upper Urinary TractLess than 1%4-10%
StomachLess than 1%13% (higher in Asians)
Small BowelLess than 1%1-3%
BrainLess than 1%1-4%
Biliary TractLess 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).

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Contributor Information and Disclosures
Author

Juan Carlos Munoz, MD  Associate Professor of Medicine and Director of the Endoscopy Unit, Division of Gastroenterology, University of Florida College of Medicine at Jacksonville

Juan Carlos Munoz, MD is a member of the following medical societies: American College of Physicians, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Coauthor(s)

Louis R Lambiase, MD, MHA  Professor of Medicine, University of Tennessee College of Medicine Chattanooga; Chief, Division of Gastroenterology, University of Tennessee Chattanooga Unit; Assistant Dean for Clinical Affairs, University of Tennessee College of Medicine Chattanooga

Louis R Lambiase, MD, MHA is a member of the following medical societies: American Gastroenterological Association, American Pancreatic Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Simmy Bank, MD  Chair, Professor, Department of Internal Medicine, Division of Gastroenterology, Long Island Jewish Hospital, Albert Einstein College of Medicine

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

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Example of an autosomal dominant pedigree.
Diagnostic approach for patients with colorectal tumors.
Table 1. Seven different genes are known to be associated with HNPCC, and all of them are involved with DNA mismatch repair, identified with the frequencies below.
Mismatch Excision Repaired MMRChromosome LocationFrequency of HNPCC Cases
MSH22p1645-50%
MLH13p22.3/A>20%
MSH62p1610%
PMS27p22.11%
PMS12q32.2Rare
MSH35q14.1Rare
EXO11q43Rare
Other genes not yet discovered20-25%
Table 2. Incidence of different types of cancers between individuals with Lynch syndrome and those in the general population.
Type of CancerGeneral Population Risk (by age 70 y)Lynch Syndrome Risk (by age 70 y)
Endometrial1.5%30-40%
Ovarian1%9-12%
Upper Urinary TractLess than 1%4-10%
StomachLess than 1%13% (higher in Asians)
Small BowelLess than 1%1-3%
BrainLess than 1%1-4%
Biliary TractLess than 1%1-5%
Table 3. IHC staining findings.
MMR MutationsProtein Staining
MLH1MSH2MSH6PMS2
MLH1-++-
MSH2+--+
MSH6++-+
PMS2+++-
Table 4. Netherlands surveillance protocol for carriers of an MMR-gene mutation.
SurveillanceMLH1, MSH2, MSH6 (males)MSHG (females)
ColonColonoscopy, every 1-2 years, starting at age 20-25 yearsColonoscopy, every 1-2 years, starting at age 30 years
EndometriumUltrasonography and CA-125, every 1-2 years, starting at age 30-35 yearsUltrasonography and CA-125, every 1-2 years, starting at age 30-35 years; consider hysterectomy after age 50 years
Upper Urinary TractUrine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a familyUrine cytology analysis, every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family
StomachGastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a familyGastroscopy every 1-2 years, starting at age 30-35 years, if it occurs 2 or more times in a family
Table 5. Dukes classification.
StageTumorNodeMetastasisDukes
Stage 1T1N0M0Dukes A
T2N0M0
Stage IIT3N0M0Dukes B
T4N0M0
Stage IIIAny TN1M0Dukes C
Any TN2, N3Mo
Stage IVAny TAny NM1Dukes D
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