Family History of Colorectal Adenomatous Polyps and Increased Risk for Colorectal Cancer

The concept of the adenoma-adenocarcinoma sequence in colorectal cancer implies that adenomatous polyps (adenomas) and adenocarcinomas share etiologic risk factors [1]. An important risk factor for colorectal cancer is family history. Common inheritance of colorectal cancers and adenomatous polyps has been documented in studies of Utah kindreds [2, 3]. Family members of patients with adenomas or cancers should therefore be at higher risk for colorectal cancer than other persons. The risk for colorectal cancer among first-degree relatives of patients with colorectal cancer has been well established, but the risk among first-degree relatives of patients with colorectal adenomas has not been clearly established. Many studies found that persons with a family history of colorectal cancer had an elevated risk for adenomas [4-10], although some failed to demonstrate this association [11, 12]. The only previous study of colorectal cancer among relatives of patients with adenomas that used a cohort analysis was part of the National Polyp Study. The risk for colorectal cancer among parents and siblings of patients with newly diagnosed adenomas participating in the National Polyp Study was found to be nearly 80% higher than the risk among asymptomatic healthy spouses of these patients [13]. We examined whether the risk for colorectal cancer is higher in first-degree relatives of patients with newly diagnosed adenomas than in relatives of endoscopically normal (no previous or newly diagnosed adenoma) controls from the same colonoscopy clinics. Characterization of this risk would provide guidance about whether and when screening should be offered to family members of patients with newly diagnosed adenomas. Methods Patients Details of the study procedures and eligibility are described in detail elsewhere [14]. Briefly, the study sample consisted of patients who came to three large colonoscopy practices in New York City between April 1986 and March 1988. Eligible men and women were between 35 and 84 years of age; resided in New York, New Jersey, or Connecticut; spoke English or Spanish; and had undergone colonoscopic examination to at least the splenic flexure (>90% extended to the cecum). Persons who had had cancer, had known familial polyposis coli, or had inflammatory bowel disease were excluded. The colonoscopists completed data sheets indicating the reason for colonoscopy and the clinical findings at the time of colonoscopy. The study pathologist (Dr. Cecilia Fenoglio-Preiser, University of Cincinnati Medical School) reviewed the slides of all suspected neoplastic lesions. A total of 2988 patients were evaluated, 2443 of whom (81.8%) met the eligibility criteria and were invited to participate in the study by a letter signed by their colonoscopists. Of those who were invited, 2001 (81.9%) agreed to participate in the study. The study participants were interviewed by telephone or by mail questionnaire. Among other data, detailed information on history of colorectal cancer in first-degree relatives (parents, siblings, and children) was collected. Data collectors were blinded to the patients' casecontrol status. No attempt was made to validate self-reported family history of colorectal cancer by direct interview of family members or by review of medical records. Of 2001 patients who participated in the study, 303 had newly diagnosed adenoma, and 509 were endoscopically normal controls (no previous or newly diagnosed adenoma). These 812 patients were the baseline case and control groups (probands), respectively, for our study. Participants who did not provide complete information (such as age, cancer history, or vital status) on their first-degree relatives were excluded. Of the probands who provided adequate family history information, 272 were case-patients in whom colorectal adenomas at index colonoscopy were diagnosed for the first time and 462 controls had no history of adenomas and were normal at the index colonoscopy. Patients who had colonoscopy solely because of a family history of colorectal cancer (28 patients with adenoma and 100 controls) were excluded from this analysis. Therefore, our study describes the results for 244 patients with adenomas, 362 controls, and 3727 of their first-degree relatives. Statistical Analysis The primary analysis involved a comparison of case-patients who had newly diagnosed adenomas with controls by using a reconstructed cohort design: that is, we assessed the incidence of the outcome among family members assuming that casecontrol status was the exposure of interest [15]. Many studies examining family history have used this type of cohort analysis [13, 16, 17] because it is less susceptible to the bias in regular casecontrol analyses that results from the differential age distribution of family members and family size between case and control groups [18]. The Cox proportional-hazards regression model was used to compare the incidence of colorectal cancer among first-degree relatives of patients with adenoma and controls. These analyses were initially adjusted for sex and race of the family members. Because age of the family members (age at diagnosis for relatives who developed cancer and current age or age at death for other relatives) served as the time variable in the Cox model, any differences in the age distribution of family members between cases and controls were also accounted for in these analyses. Because diagnostic procedures for colorectal cancer have changed over time, year of birth was included in the model to control for the effect of these changes. Furthermore, because familial risk may depend on the specific relationship between the proband and the relative [18], the type of relationship was also included in the models used to analyze all relatives together. However, adjustment for year of birth and type of relationship did not substantially change the effect estimates. To further adjust for proband and family characteristics, separate terms (keeping values the same for all members of a family) for the proband's age, years of education, smoking status, body mass index, and family membership were also included in the Cox model. None of these variables except age of the proband confounded the effect estimates substantially. Thus, the results adjusted for family members' sex and race and probands' age only are presented. The proportional hazards model assumption was examined by plotting the logarithm of the negative logarithm of the estimated product-limit survival function against the logarithm of time and was found to be satisfactory. The risk for other cancers was also examined as a negative control. Results Characteristics of the study groups are shown in Table 1. Patients with adenomas were more likely than those who had never had adenomas to be male, older, and white. Patients with adenomas were less likely to have had colonoscopy done for gastrointestinal symptoms (gastrointestinal bleeding, abdominal pain, and changes in bowel habits) [19] but were more likely to have had it done for other reasons (general screening; nonspecific gastrointestinal symptoms except abdominal pain, changes in bowel habits, or gastrointestinal bleeding; unexplained weight loss; and other nonspecific symptoms). Table 1. Characteristics of Patients with Newly Diagnosed Adenoma and Endoscopically Normal Controls First-degree relatives of patients with newly diagnosed adenoma, estimated from the Cox model, had a relative risk for colorectal cancer of 1.74 (95% CI, 1.24 to 2.45) compared with relatives of controls (Table 2). No increased risk was found for other cancers among family members of patients with newly diagnosed adenoma. No heterogeneity was found in the relative risks calculated for probands with one adenoma compared with multiple adenomas, right-sided compared with left-sided adenomas, or small ( 5 mm) compared with large (>5 mm) adenomas (results not shown). Table 2. Relative Risk for Colorectal and Other Cancer in First-Degree Relatives of Patients with Newly Diagnosed Adenoma Compared with Endoscopically Normal Controls The effect of age at diagnosis of adenoma in probands on the risk for colorectal cancer among their family members is shown in Table 3. The risk for colorectal cancer among family members was inversely associated with the age at which adenomas were diagnosed in probands. Compared with family members of probands who were older than 60 years of age when adenoma was diagnosed, family members of probands who were 50 years of age or younger at diagnosis had more than four times the risk for colorectal cancer. Table 3. Relative Risk for Colorectal Cancer in First-Degree Relatives of Patients with Newly Diagnosed Adenoma by Age at Diagnosis of Adenoma Because very few members of the offspring generation had colorectal cancer, the risk among children could not be examined separately. The risk for colorectal cancer was similar among parents (Table 4) and siblings (Table 5). For family members of patients with adenomas, we examined the effect of having an affected family member on the risk for colorectal cancer. Among parents, the risk was nearly three times higher if they had affected siblings (Table 4). Similarly, among siblings, the risk was more than five times higher if they had affected parents (Table 5). Table 4. Relative Risk for Colorectal Cancer in Parents of Patients with Adenoma by History of Colorectal Cancer in Siblings Table 5. Relative Risk for Colorectal Cancer in Siblings of Patients with Adenoma by History of Colorectal Cancer in Parents Discussion We found an elevated risk for colorectal cancer among first-degree relatives of patients with colorectal adenomas. This relative risk (1.74) is similar to that reported by Winawer and colleagues (1.78) [13] for family members of patients with newly diagnosed adenomas but is somewhat lower than the estimates in previous studies that used a casecontrol comparison [4-8]. It has been shown that the relative