Hereditary Nonpolyposis Colorectal Cancer (HNPCC)

ABSTRACT

• Colorectal cancer is a fairly common disease of Western populations with a typical onset at about age 70 years. The international epidemiology of this disease suggests that environmental factors, probably dietary, are the most important influences for the high prevalence of this disease in certain countries.¹ Woven into the epidemiologic fabric for colorectal cancer is an important influence of genetic factors. Individuals who have even one first-degree relative with colorectal neoplasia (i.e., either cancers or adenomatous polyps) have an increased risk for these tumors themselves, which will appear earlier in life.^2-4 The familial risk increases when there is more than one family member involved or cancers occur before age 50.^3,4

INTRODUCTION

The most readily distinguished form of familial risk is the autosomal dominant genetic disease familial adenomatous polyposis (FAP). This disease has a distinctive phenotypic syndrome characterized by a large number of precursor adenomatous polyps in the colon and occurs in about 1 in 10,000 births. This is completely unrelated to the more common autosomal dominant colon cancer syndrome termed hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC is due to an inactivating germ-line mutation in one of the DNA mismatch repair (MMR) genes (see below). This disease has no antecedent clinical phenotype until a cancer develops and was a controversial entity until the biologic basis of this disease was discovered in 1993.^5-8 Patients with HNPCC are at increased risk for cancers of the colon, endometrium, small intestine, ovary, stomach, urinary tract, brain, and some other, but not all, epithelial organs.^9-12 The mean age to develop colorectal cancer is in the early to mid-40's; however, many tumors occur in the 20's and even in teenagers. Although population-based surveys have not been completed, HNPCC may be the most common form of familial predisposition to cancer.^13-22 Now that the genetic basis of this disease has been elucidated, and the involvement of non-colonic cancers clearly demonstrated, it may be advised to refer to the disease as “Lynch syndrome” when a germ-line mutation in a DNA MMR gene has been identified in a family, and use “HNPCC” for familial clusters of colon cancer without an identifiable germ-line mutation,

FAMILY HISTORY AND COLORECTAL CANCER

The hereditary aspects of colon cancer are complex. The age-adjusted relative risk of developing colorectal cancer in individuals with one affected first-degree relative is 1.72 compared with those without such a family history. This risk rises to 2.75 when there are two or more affected first-degree relatives, and the relative risk increases as the family history occurs in younger relatives, reaching 5.37 when the affected siblings are between 30 and 44 years of age.³ Similarly, the relative risk for colorectal cancer is 1.78 for the first-degree relatives of patients with adenomatous polyps. The relative risk of cancer rises to 2.59 when the sibling is less than 60 years old and 3.25 ...