Hereditary nonpolyposis colorectal cancer
|Micrograph showing tumor-infiltrating lymphocytes (in a colorectal cancer), a finding associated with MSI-H tumours, as may be seen in Lynch syndrome. H&E stain.|
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that has a high risk of colon cancer as well as other cancers including endometrial cancer (second most common), 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. It is a type of cancer syndrome.
Signs and symptoms
- Colorectal cancer
- Endometrial carcinoma
- Digestive adenoma: gastric adenoma, pyloric gland adenoma, duodenal adenoma, intestinal adenoma
- Ovarian serous cystadenocarcinoma
Risk of cancer
Individuals with HNPCC have about an 80% lifetime risk for colon cancer. Two-thirds of these cancers occur in the proximal colon. The mean age of colorectal cancer diagnosis is 44 for members of families that meet the Amsterdam criteria. Also, women with HNPCC have an 80% lifetime risk of endometrial cancer. The average age of diagnosis of endometrial cancer is about 46 years. Among women with HNPCC who have both colon and endometrial cancer, about half present first with endometrial cancer, making endometrial cancer the most common sentinel cancer in Lynch syndrome. In HNPCC, the mean age of diagnosis of gastric cancer is 56 years of age with intestinal-type adenocarcinoma being the most commonly reported pathology. HNPCC-associated ovarian cancers have an average age of diagnosis of 42.5 years-old; approximately 30% are diagnosed before age 40. Other HNPCC-related cancers have been reported with specific features: the urinary tract cancers are transitional carcinoma of the ureter and renal pelvis; small bowel cancers occur most commonly in the duodenum and jejunum; the central nervous system tumor most often seen is glioblastoma.
A large follow up study (3119 patients; average follow up 24 years) has found significant variation in the cancer rates depending on the mutation involved. Up to the age of 75 years the risks of colorectal cancer, endometrial cancer, ovarian cancer, upper gastrointestinal (gastric, duodenal, bile duct or pancreatic), urinary tract cancers, prostate cancer and brain tumours were as follows: for MLH1 mutations the risk was - 46%, 43%, 10%, 21%, 8%, 17% and 1% respectively: for MSH2 mutations the risks were 57%, 17%, 10%, 25%, 32%, and 5% respectively: for MSH6 mutations the risks were 15%, 46%, 13%, 7%, 11%, 18% and 1% respectively.
|Gene||Ovarian cancer risk||Endometrial cancer risk|
|PMS2||6% (combined risk)||15%|
HNPCC is inherited in an autosomal dominant fashion. The hallmark of HNPCC is defective DNA mismatch repair, which leads to microsatellite instability, also known as MSI-H (the H is "high"). MSI is identifiable in cancer specimens in the pathology laboratory. Most cases result in changes in the lengths of dinucleotide repeats of the nucleobases cytosine and adenine (sequence: CACACACACA...).
However, as in cancer resulting from autosomal dominant germline tumor suppressor gene mutations, such as familial adenomatous polyposis, for malignancy to develop in HNPCC a second deleterious mismatch-repair gene mutation at the same locus in the homologous chromosome is required to occur at the cellular, or somatic, level.
|OMIM name||Genes implicated in HNPCC||Frequency of mutations in HNPCC families||Locus||First publication|
|HNPCC1 (120435)||MSH2/EPCAM||approximately 60%||2p22||Fishel 1993|
|HNPCC2 (609310)||MLH1||approximately 30%||3p21||Papadopoulos 1994|
|HNPCC4||PMS2||relatively infrequent||7p22||Nicolaides 1994|
|HNPCC3||PMS1||case report||2q31-q33||Nicolaides 1994|
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. 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.
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 of passing the genetic mutation on to each child.
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.
Three major groups of MSI-H (microsatellite instability – MSI) cancers can be recognized by histopathological criteria:
- right-sided poorly differentiated cancers
- right-sided mucinous cancers
- adenocarcinomas in any location showing any measurable level of intraepithelial lymphocyte (TIL)
After reporting a null finding from their randomized controlled trial of aspirin (acetylsalicylic acid – ASA) to prevent the colorectal neoplasia of Lynch syndrome, Burn and colleagues have reported new data, representing a longer follow-up period than reported in the initial NEJM paper. These new data demonstrate a reduced incidence in Lynch syndrome patients who were exposed to at least four years of high-dose aspirin, with a satisfactory risk profile. These results have been widely covered in the media; future studies will look at modifying (lowering) the dose (to reduce risk associated with the high dosage of ASA).
Genetic testing for mutations in DNA mismatch repair genes is expensive and time-consuming, so researchers have proposed techniques for identifying cancer patients who are most likely to be HNPCC carriers as ideal candidates for genetic testing. The Amsterdam Criteria (see below) are useful, but do not identify up to 30% of potential Lynch syndrome carriers. In colon cancer patients, pathologists can measure microsatellite instability in colon tumor specimens, which is a surrogate marker for DNA mismatch repair gene dysfunction. If there is microsatellite instability identified, there is a higher likelihood for a Lynch syndrome diagnosis. Recently, researchers combined microsatellite instability (MSI) profiling and immunohistochemistry testing for DNA mismatch repair gene expression and identified an extra 32% of Lynch syndrome carriers who would have been missed on MSI profiling alone. Currently, this combined immunohistochemistry and MSI profiling strategy is the most advanced way of identifying candidates for genetic testing for Lynch syndrome.
Genetic counseling and genetic testing are recommended for families that meet the Amsterdam criteria, preferably before the onset of colon cancer.
The following are the Amsterdam criteria in identifying high-risk candidates for molecular genetic testing:
Amsterdam Criteria (all bullet points must be fulfilled):
- 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 (all bullet points must be fulfilled):
- 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
Prophylactic hysterectomy and salpingo-oophorectomy (removal of the uterus, Fallopian tubes, and ovaries to prevent cancer from developing) can be performed before ovarian or endometrial cancer develops.
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.
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.
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; Lynch named the condition HNPCC in 1985. Since then the two terms have been used interchangeably, until later advances in the understanding of the genetics of the disease led to the term HNPCC falling out of favour.
Other sources reserve the term "Lynch syndrome" when there is a known DNA mismatch repair defect, 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.
There are a number of non-profit organisations providing information and support, including Lynch Syndrome International, Lynch Syndrome UK and Bowel Cancer UK. In the US, National Lynch Syndrome Awareness Day is March 22.
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