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HNPCC

Monday 29 September 2003

Definition: Lynch syndrome (HNPCC or Hereditary nonpolyposis colorectal cancer ) is an autosomal dominant genetic condition which has a high risk of colon cancer as well as other cancers including endometrium, 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 (MMR system of DNA reparation).

Hereditary nonpolyposis colorectal cancer (HNPCC) accounts for approximately 2% of all colorectal cancer (CRC) cases and is the most common hereditary CRC syndrome.

Nosology

Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair defect (MMR system), and use the term "Familial colorectal cancer type X" when the Amsterdam criteria are met but there is no known DNA mismatch repair defect.

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. About 35% of patients meeting Amsterdam criteria do not have a DNA-mismatch-repair gene mutation.

Complicating matters is the presence of an alternative set of criteria, known as the "Bethesda Guidelines".

Epidemiology

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.

Transmission

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 to pass the gene on to each child.

Synopsis

- tumoral predisposition

  • colorectal adenocarcinoma
  • gastric carcinomas
  • endometrial carcinoma (15823135)
  • cutaneous tumors

- cerebral tumors

  • astrocytomas
  • gangliogliomas

MSI-H cancers

Three major groups of MSI-H cancers can be recognized by histopathological criteria:

- (1) right-sided poorly differentiated cancers
- (2) right-sided mucinous cancers
- (3) adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)

DNA mismatch repair proteins

MLH1 MLH3 MSH2 MSH6 PMS1 PMS2 TGFBR2

Pathology

HNPCC syndromes and mismatch repair deficiency (MMR deficiency)

Disease MIM Gene MIM. Loc. Frequency in HNPCC
HNPCC1 MIM.120435 MSH2 MIM.609309 2p22-p21 60%
HNPCC2 MIM.609310 MLH1 MIM.120436 3p21.3 30%
HNPCC3 MIM.600258 PMS1 MIM.600258 2q31-q33 7-10%
HNPCC4 MIM.600259 PMS2 MIM.600259 7p22 rare
HNPCC5 MIM.600678 MSH6 MIM.600678 2p16 < 5%
HNPCC6 MIM.190182 TGFBR2 MIM.190182 3p22 rare
HNPCC7 MIM.604395 MLH3 MIM.604395 14q24.3 rare

MSH2 and MLH1 mutations are found in approximately two-thirds of the Amsterdam-criteria-positive families and in much lower percentages of the Amsterdam-criteria-negative families.

In one series, 92% Amsterdam-criteria-positive families and 70% of the Amsterdam-criteria-negative families, a mutation was detected in one of three MMR genes: MSH2, MLH1, MSH6. 27% of the mutations were genomic rearrangements. (12658575)

- MSH6-associated HNPCC

Patients with MSH6 mutations are more likely to be Amsterdam criteria II-negative. The presentation with MSH6 is slightly different than with MLH1 and MSH2, and the term "MSH6 syndrome" has been used to describe this condition.

Guidelines: Amsterdam Criteria

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.

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

Amsterdam Criteria I:

- Three or more family members with a confirmed diagnosis of colorectal cancer, one of whom is a first degree (parent, child, sibling) relative of the other two
- Two successive affected generations
- One or more colon cancers diagnosed under age 50 years
- Familial adenomatous polyposis (FAP) has been excluded

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 or more of the HNPCC-related cancers diagnosed under age 50 years
- Familial adenomatous polyposis (FAP) has been excluded

In one study, the Bethesda guidelines were more sensitive than the Amsterdam Criteria in detecting it.

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.

BRA-V600E Immunohistochemistry

- BRAFV600E Immunohistochemistry Facilitates Universal Screening of Colorectal Cancers for Lynch Syndrome. (23797718)

  • BRAFV600E mutation in microsatellite-unstable (MSI) colorectal carcinomas (CRCs) virtually excludes Lynch syndrome (LS).
  • In microsatellite-stable (MSS) CRCs it predicts poor prognosis.
  • BRAF IHC is highly concordant with 2 commonly used PCR-based BRAFV600E assays.
  • It performed well in identifying MLH1 mutation carriers from the ACCFR and identified all cases of proven LS.
  • Reflex BRAFV600E and MMR IHC are simple cheap tests that facilitate universal LS screening and identify the poor prognosis of the BRAFV600E-mutant MSS CRC phenotype.

History

Henry T. Lynch (professor of medicine at Creighton University Medical Center), characterized the syndrome in 1966. In his earlier work, he described the disease entity as "cancer family syndrome."

The term "Lynch syndrome" was coined in 1984 by other authors, and Lynch himself coined the term HNPCC in 1985. Since then, the two terms were used interchangeably, until more recent advances in the understanding of the genetics of the disease lead to the term HNPCC falling out of favour.

Management

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.

After reporting a null finding from their randomized controlled trial of aspirin (ASA) to prevent against the colorectal neoplasia of Lynch Syndrome, Burn and colleagues have recently reported new data, representing a longer follow-up period than reported in the initial NEJM paper. These new data demonstrates a reduced incidence in Lynch Syndrome patients who were exposed to at least four years of high-dose aspirin, with a satisfactory risk profile.

Colorectal cancer risk

2 loci are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance.

- SNP rs16892766 at 8q23.3
- SNP rs3802842 at 11q23.1

See also

- microsatellite instability

Reviews

- Umar A, Risinger JI, Hawk ET, Barrett JC. Testing guidelines for hereditary non-polyposis colorectal cancer. Nat Rev Cancer. 2004 Feb;4(2):153-8. PMID: 14964310

- Lynch HT, de la Chapelle A. Hereditary colorectal cancer. N Engl J Med. 2003 Mar 6;348(10):919-32. PMID: 12621137

References

- BRAFV600E Immunohistochemistry Facilitates Universal Screening of Colorectal Cancers for Lynch Syndrome. Toon CW, Walsh MD, Chou A, Capper D, Clarkson A, Sioson L, Clarke S, Mead S, Walters RJ, Clendenning M, Rosty C, Young JP, Win AK, Hopper JL, Crook A, von Deimling A, Jenkins MA, Buchanan DD, Gill AJ. Am J Surg Pathol. 2013 Jun 20. PMID: 23797718

- Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel. Shia J, Tang LH, Vakiani E, Guillem JG, Stadler ZK, Soslow RA, Katabi N, Weiser MR, Paty PB, Temple LK, Nash GM, Wong WD, Offit K, Klimstra DS. Am J Surg Pathol. 2009 Nov;33(11):1639-45.PMID: 19701074