Lay Summary: Testing for the colon cancer gene and its role and appropriate use is described.
Hereditary nonpolyposis colorectal cancer (HNPCC) usually occurs in patients younger than age 45 and can result in the development of cancers in a variety of tissues, such as the colon, rectum, endometrium, stomach, ovaries, brain, and skin. A major genetic characteristic of HNPCC tumors is microsatellite instability (MSI). Microsatellites are short repeated sequences of DNA, and MSI results when mutations in genes that are responsible for repairing damaged DNA cause microsatellites to become longer or shorter. Cancers that exhibit MSI account for about 15% of all colorectal cancers. Myriad Genetic’s Colaris test is an MSI test.
Because HNPCC results from inherited mutations, it is possible that family members of patients with HNPCC also have the genetic characteristics that put them at an increased risk for cancers associated with a particular mutation. The Amsterdam criteria were the first diagnostic guidelines to be developed, and the aim of these was to determine whether a family should be classified as having HNPCC. All of the following criteria had to be met to diagnose HNPCC: at least three members of the family should have colorectal cancer and at least one should be a first-degree relative of the other two; at least two generations of the family should have colorectal cancer; and one of the cases of colorectal cancer should have been diagnosed before the individual was age 50 years.
Revised Amsterdam Criteria
In response to criticism that the Amsterdam criteria were too stringent, the revised Amsterdam criteria (Amsterdam II criteria) were developed in 1998 to include extracolonic HNPCC-associated cancers — colorectal cancer or cancer of the endometrium, small bowel, ureter, or renal pelvis — that are also quite common in HNPCC. This revision prevents some individuals and families from being left out of the classification. The original Amsterdam criteria were also modified so that very small families can be considered as having HNPCC. These families must have two diagnosed colorectal cancers in first-degree relatives, which involve at least two generations. One of these individuals must have been diagnosed by the age of 55. The presence of a third relative with an unusual early-onset neoplasm or endometrial cancer is considered sufficient to classify the family as meeting the Amsterdam II criteria.
The need for a set of guidelines for genetic diagnosis of HNPCC became obvious in the mid-1990s. The use of the Amsterdam criteria was achieving their original purpose; however, their limited sensitivity hampered decisions of choosing which patients should undergo genetic testing. The Bethesda guidelines (or criteria) were therefore developed with a different objective to the Amsterdam criteria — they mainly aid in the decision process for whether individuals with cancer in families that do not fulfill Amsterdam criteria should undergo genetic testing. The Bethesda guidelines include additional criteria such as pathological evaluation of the Amsterdam-criteria-positive individuals (BOX 3), which allows less stringent criteria. Individuals with two HNPCC-related cancers — including synchronous (two or more tumours are present at the same time) and metachronous (first tumour is followed by a second one at a later date) cancers — or associated extracolonic cancers, or individuals with colorectal cancer and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal adenoma are considered to fulfill the Bethesda criteria. Alternatively, individuals are considered to fulfill the Bethesda guidelines if one of the cancers is diagnosed by 45 years and the adenoma is diagnosed by 40 years; if colorectal cancer or endometrial cancer is diagnosed by 45 years; if right-sided colorectal cancer with an undifferentiated pattern (solid/cribiform) on histopathology is diagnosed by 45 years; or if signet-ring-cell-type colorectal cancer is diagnosed by 45 years.
Revised Bethesda Guidelines
Although the Bethesda guidelines are considered to be a useful tool for making decisions about whether genetic testing and/or MSI testing of the tumours from individuals with HNPCC should be performed, data that has been accumulated over the past five years on both genetics and IHC characterization indicate that these criteria should be updated. An international group of HNPCC researchers and clinicians unanimously decided to revise these guidelines. In the revised Bethesda guidelines, changes were undertaken for several reasons: to identify patients who were at risk for hereditary cancer, to include a complete spectrum of colonic and extracolonic cancers, and to identify MSH2 and MLH1 germline-mutation carriers in patients with cancers who might or might not fulfill the Amsterdam II criteria. First, the Amsterdam and then the Amsterdam II criteria can be used to assess cases that can be subjected to the revised Bethesda guidelines. Next, cancers from these cases can be analysed for MSI or the absence of MSH2 or MLH1 — by IHC — based on the availability of either test or the cost effectiveness in a particular situation. The final decision is whether genetic testing of the main HNPCC genes, MSH2 and MLH1, should be performed. If individuals are found to have disease-related mutations, they are confirmed as having HNPCC.
It was decided that individuals who meet one of the following criteria fulfilled the revised Bethesda guidelines and should be recommended to undergo genetic testing. Those diagnosed with colorectal cancer before the age of 50 years; who had synchronous or metachronous colorectal or other HNPCC-associated tumours, regardless of age; who had MSI-H under the age of 60 years; who had one or more first-degree relatives with colorectal cancer or other HNPCC-related tumour, with one of the cancers diagnosed by the age of 50 years (including adenoma by the age of 40 years); or who had colorectal cancer with two or more relatives with colorectal cancer or other HNPCC-related tumours, regardless of age.
Although Bethesda criteria differ in their original purpose to the Amsterdam criteria, several studies show that the Bethesda criteria are the most sensitive (94%), followed by the Amsterdam II criteria (72%) and then the Amsterdam criteria (61%). Now, with further refinements in the Bethesda guidelines (revised Bethesda guidelines), it is hoped that the clinical-research community will accept these new guidelines to make decisions in patients with familial cancer and to decide whether determination of precise gene mutation in MMR genes should be performed.
In summary, the revised criteria suggest that tumors from patients with colorectal cancer should be tested for MSI and subsequent genetic testing to confirm a mutation in one of the genes responsible for HNPCC in the following situations:
1. The patient is younger than age 50.
2. The patient has multiple HNPCC-associated tumors in the colon or in other areas known to be caused by the same mutations, either at the same time or occurring over a period of time.
3. A patient younger than age 60 has colorectal cancer that has microscopic characteristics that are often indicative of MSI.
4. A patient has one or more first-degree relatives who had an HNPCC-related tumor at age 50 or younger.
5. A patient has two or more first- or second-degree relatives who had HNPCC-related tumors at any age.
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Cancer Risks Are Lower in Lynch Syndrome Families with MSH6 Mutations
JWatch Gastroenterology. 2011;2011(624):1.