HNPCC

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
  • sebaceous tumors (Muir-Torre syndrome)

 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