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The Hereditary Nonpolyposis Colorectal Cancer Syndrome: Genetics and Clinical Implications[dhelix]

Daniel C. Chung, MD; and Anil K. Rustgi, MD
[+] Article, Author, and Disclosure Information

From Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; and University of Pennsylvania Medical School, Philadelphia, Pennsylvania.

Acknowledgment: The authors thank Jonathan Terdiman for sharing his photoµgraphs of MSH2/MLH1 immunohistochemistry.

Grant Support: Elsevier Research Award/American Digestive Health Foundation, NIH R01 CA92594 (Dr. Chung) and National Colon Cancer Research Alliance/Entertainment Industry Foundation, Irving Hansen Foundation, NIH DK56645 (Dr. Rustgi).

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Daniel C. Chung, MD, Gastrointestinal Unit, GI Cancer Genetics Service, GRJ 825, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02 114; e-mail, dchung@partners.org.

Current Author Addresses: Dr. Chung: Gastrointestinal Unit, GI Cancer Genetics Service, GRJ 825, Massachusetts General Hospital, 50 Blossom Street, Boston, MA 02114.

Dr. Rustgi: Division of Gastroenterology, Abramson Family Cancer Research Institute and Cancer Center, University of Pennsylvania Medical School, 415 Curie Boulevard, Philadelphia, PA 19104.

Ann Intern Med. 2003;138(7):560-570. doi:10.7326/0003-4819-138-7-200304010-00012
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Basic studies of DNA replication and repair have provided surprising and pivotal insights into a novel pathway of tumorigenesis. Defects in the DNA mismatch repair process dramatically increase the risk for specific types of cancer because of instability in microsatellite DNA sequences. A germline mutation in either the hMSH2 or hMLH1 mismatch repair gene results in the hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch, syndrome. The lifetime risk for colon cancer is 80% in affected persons, and an aggressive cancer surveillance program is essential not only for these individuals but also for at-risk family members. The diagnosis of HNPCC can be made by fulfillment of the Amsterdam clinical criteria or through genetic testing for germline mutations in hMSH2 or hMLH1. Genetic testing is particularly useful in families with atypical clinical features and also for cancer risk assessment within an established HNPCC kindred. Microsatellite instability (MSI) of DNA is a hallmark feature of HNPCC-associated tumors, and as many as 15% of cases of sporadic colorectal cancer also display MSI. The biological behavior of colorectal tumors with MSI is distinctive; the most intriguing feature is their favorable natural history. The study of HNPCC has provided an example of the powerful interplay between molecular genetics and clinical care.


Grahic Jump Location
Figure 1.
Events at the replication fork.

After primers anneal to the individual strands, synthesis of new complementary DNA proceeds in a 5′ to 3′ direction. This occurs on both strands and at both replication forks. Therefore, replication proceeds bi-directionally. Synthesis of DNA is continuous along the leading strand but discontinuous along the lagging strand because of opposing directions of movement of the replication fork and DNA elongation. A, B, and C represent sequential time points.

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Grahic Jump Location
Figure 2.
Slippage during DNA replication.MSSMSI

The DNA polymerase enzyme adds complementary deoxynucleotide bases to the growing strand. Slippage may occur when microsatellite DNA sequences are encountered. In this example, there are six copies of a CA dinucleotide repeat. Because of slippage, an additional CA repeat is inserted, resulting in a mismatched loop of DNA. With an intact DNA mismatch repair system, the error is corrected and DNA microsatellite stability ( ) is observed. However, when the DNA mismatch repair system is mutated, the error is not corrected and microsatellite instability ( ) results.

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Figure 3.
Components of the DNA mismatch repair system.

The DNA mismatch repair system can correct either single base-pair mismatches or larger loops of mismatched DNA. hMSH2 serves as the “scout” that recognizes mismatched DNA. It forms a complex with either hMSH6 or hMSH3, depending on the number of mismatched nucleotides. A second heterodimeric complex (hMLH1/hPMS1) is then recruited to excise the mispaired nucleotides. hMutSα = hMSH2/hMSH6; hMutSβ = hMSH2/hMSH3; hMutLα = hMLH1/hPMS1. bp = base pair.

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Figure 4.
The conversion technique.MSH2MSH2

Human blood mononuclear cells are fused with mouse cells. Several outcomes are possible. Often, one of the two human chromosomes is lost in the fused heterokaryon. These can be identified through the use of polymorphic markers for a specific chromosome. These specific populations are then amplified, and their DNA is analyzed for mutations in a specific DNA mismatch repair gene. In this manner, only one allele is analyzed at a time. = wild type; * = mutant.

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Figure 5.
Immunohistochemical staining for MSH2 and MLH1 protein.ACDFA.B.C.D.E.F.

Representative images using specific antiserum for MSH2 protein (Calbiochem, La Jolla, California) and MLH1 protein (Pharmingen, San Diego, California) in two cases of colon cancer from individuals with the hereditary nonpolyposis colorectal cancer syndrome demonstrating loss of MLH1 staining in case 1 ( – ) and loss of MSH2 staining in case 2 ( – ). Positive staining for MLH1 in a normal colon. Absent staining for MLH1 in a cancerous colon. Positive staining for MSH2 in a cancerous colon. Positive staining for MSH2 in a normal colon. Positive staining for MLH1 in a cancerous colon. Absent staining for MSH2 in colon cancer. Bar = 100 µm. Slides provided by Jonathan Terdiman, with permission.

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Figure 6.
Overall strategy for genetic testing of an affected proband from a suspected hereditary nonpolyposis colorectal cancer kindred.MSIIHCasterisk†

If the Amsterdam criteria are fulfilled, then genetic testing of an affected family member should proceed. Consideration can also be given to directly testing persons who fulfill Bethesda criteria 1 through 3. At-risk relatives should be tested only after a pathogenic mutation is identified within the family. Persons with negative results on microsatellite instability ( ) or immunohistochemistry ( ) testing still require clinical cancer screening as dictated by their personal and family medical histories ( ). Inconclusive results are defined as no mutation or missense mutation ( ). MSI-H = high level of MSI (MSI-H phenotype); MSI-L = low level of MSI (MSI-L phenotype); MSS = microsatellite stable.

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Summary for Patients

Mutations in DNA Mismatch Repair Genes

The summary below is from the full report titled “The Hereditary Nonpolyposis Colorectal Cancer Syndrome: Genetics and Clinical Implications.” It is in the 1 April 2003 issue of Annals of Internal Medicine (volume 138, pages 560-570). The authors are D.C. Chung and A.K. Rustgi.


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