Case study of Hereditary Nonpolyposis Cancer Syndrome:

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Disease etiology and incidence:

At least 50% of individuals in western populations develop a colorectal tumor by the age of 70 years, and approximately 10% of these individuals eventually develop colorectal cancer. HNPCC is genetically heterogenous autosomal dominant cancer predisposition syndrome that is often caused by mutations in DNA mismatch repair genes. HNPCC has a prevalence of 2 to 5 per 1000 and accounts for approximately 3% to 8% of colorectal cancer.


In most colorectal cancers, including familial adenomatous polyposis, the tumor karyotype becomes progressively more aneuploidy. Approximately 13% to 15% of colorectal cancer donot have such chromosomal instability but have insertion or deletion mutations in repetitive sequences (microsatellite instability). Microsatellite instability occurs in 85%to 90% of HNPCC tumors. Consistent with this observation, approximately 70% of HNPCC families with carcinomas exhibiting microsatellite instability have germline mutations in one of six DNA mismatch repair genes: MSH2, MSH6, MLH1, MLH3, PMS1, or PMS2.

DNA mismatch repair induces DNA replication errors by 1000-fold. Errors of DNA synthesis cause mispairing and deform the DNA double helix. A complex of mismatch repair proteins recruits other enzymes to effect repair. By use of the process of long patch excision, this complex excises the errant fragment of the newly synthesized DNA strand and then resynthesizes it.

Both alleles of a DNA mismatch repair gene must lose function to cause microsatellite instability. The high frequency of somatic loss of function in the second allele defines HNPCC as a autosomal disease with approximately 80% penetrance. This somatic loss of function can occur by loss of heterozygosity, intragenic mutation, or hypermethylation.

In HNPCC, an increasing number of microsatellite loci mutate during the progression from adenoma to carcinoma. Inactivation of genes containing microsatellite sequences could play key roles in tumor progression. For example, microsatellite instability induces frameshift mutations in the transforming growth factor receptor 2gene (TGFBR2). Mutations within TGFBR2 cause the loss of TGFBR2 expression, and because the TGFB system inhibits the growth of colonic epithelial cells, its loss allows escape from growth control. In support of the role of TGFBR2 in HNPCC, one affected family without mutations in a DNA mismatch repair gene had germline mutation in TGFBR2. TGFBR2 mutations can occur in early HNPCC lesions and may contribute to the growth of adenomas.


Although patients with HNPCC develop polyps similar in number to those of the general population, they develop them at younger ages. Their median age at diagnosis with a colorectal adenocarcinoma in younger than 50 years, that is, 10 to 15 years younger than the general population. Patients with HNPCC and a defined germline mutations have 80% lifetime risk for development of colorectal cancer. 60% to 70% of adenomas and carcinomas in HNPCC occur between the splenic flexure and ileocecal junction. By way of contrast, most sporadic colorectal cancers occur in the descending colon and sigmoid. Carcinomas in HNPCC are less likely to have chromosomal instability and behave aggressively than sporadic colon cancer; sporadic cancers and the carcinomas in familial adenomatous polyposis are more likely to be aneuploidy and more aggressive. For this reason, patients with HNPCC have better prognosis when it is adjusted for stage and age than do patients with familial adenomatous polyposis or colorectal tumors with chromosome instability.

In addition to colorectal cancer, HNPCC-associated cancers include cancer of the stomach, small bowel, pancreas, kidney, endometrium, and ovaries; cancers of the lung and breast are not associated with HNPCC. Patients with HNPCC and a defined germline mutation have a more than 90% lifetime risk for development of colorectal cancer or one of these associated cancers or both.


Family history defines HNPCC; patients do not have distinguishing physical features. The minimal criteria for considering HNPCC are the occurrence of colorectal cancers or another HNPCC-associated tumor in three numbers of a family, at least two of whom are first-degree relatives, across two or more generations, and the development of colorectal cancer in at least one affected individual before the age of 50years. In patients without a family history but with early onset colorectal cancer, DNA analysis of the tumor to detect microsatellite instability and immunohistochemistry for the MLH1 and MSH2 proteins are now used to screen for HNPCC. Early recognition of HNPCC is necessary for effective intervention; surveillance colonoscopy of the proximal colon beginning at the age of 25 years increases life span expectancy by 15.6 years. In families with known germline mutations, identification of the DNA mismatch repair gene mutation can focus surveillance on those patients carrying the mutation, but in HNPCC families without an identified germline mutation, the absence of a mutation does not negate the need for frequent surveillance.


The empirical western general population risk for the development of colorectal cancer is 5% to 6%. This risk is markedly modified by family history. Patients with first-degree relative with colorectal cancer have a 1.7 relative risk; this relative risk increases to 2.75 if two or more first-degree relatives had colorectal cancer. If an affected first-degree relative developed colorectal cancer before 44 years of age, the relative risk increases to more than 5.

In contrast, a patient with a DNA mismatch repair gene germline mutation has a 50% risk of having a child carrying a germline mutation. Each child carrying such a mutation has a life time cancer risk of approximately 90%, assuming the 80% penetrance of HNPCC is responsible for a cancer risk. Prenatal diagnosis is highly controversial and not routine but is theoretically possible if the germline mutation has been identified in the parent. Because of incomplete penetrance and variation in expressivity, the severity and onset of HNPCC and the occurrence of associated cancers cannot be predicted.


A 38-year- old banker and mother of three children, was referred to the cancer genetics clinic by her physician for counseling regarding her family history of cancer. Her father, brother, nephew, niece, paternal uncle and paternal grandfather all developed colorectal cancer. She did not have a medical history or surgical problems. The findings from her physical examination were normal. The geneticist explained to him that her family history was suggestive of hereditary nonpolyposis colon cancer (HNPCC) and that the most efficient and effective way to determine the genetic cause of HNPCC in her family was through molecular testing of a living affected family family member. After some discussion with her niece, the only surviving affected family member, is her and her niece, returned to the clinic for testing. Testing of an archived tumor sample from the niece’s resected colon identified microsatellite instability; subsequent sequencing of DNA from a blood sample obtained from the niece revealed a germline mutation in MLH1. She did not carry any mutation; therefore the geneticist counseled that her risk and her children’s risk for development of cancer were similar to that of the general population. Her unaffected brother was found to carry the mutations and continued to have an annual screening colonoscopy.