Khe-Ni Ma

Family history and colorectal cancer: predictors of risk.

Introduction: While the association between family history of colorectal cancer in first-degree relatives and risk of developing colon cancer has been well defined, the association with rectal cancer is much less clear. The purpose of this study is to define rectal cancer risk associated with family history of colorectal cancer in first-degree relatives. We also evaluate diet and lifestyle factors associated with developing colorectal cancer among participants with a positive family history. Methods: Data were available from two population-based case–control studies of colon and rectal cancer. Participants were members of the Kaiser Permanente Medical Care Program (KPMCP) or residents of the state of Utah. Cases were first primary colon cancer diagnosed between 1991 and 1994 (n = 1308 cases and 1544 controls) or rectal cancer diagnosed between 1997 and 2001 (n = 952 cases and 1205 controls). Results: A family history of colorectal cancer in any first-degree relatives slightly increased risk of rectal cancer (OR: 1.37 95% CI: 1.02–1.85). Family history of colorectal cancer was associated with the greatest risk among those diagnosed at age 50 or younger (OR: 2.09 95% CI: 0.94–4.65 for rectal tumors; OR: 3.00 95% CI: 0.98–9.20 for distal colon tumors; and OR: 7.88 95% CI: 2.62–23.7 for proximal colon tumors). Factors significantly associated with cancer risk among those with a family history of colorectal cancer, included not having a sigmoidoscopy (OR: 2.81 95% CI: 1.86–4.24); a diet not Prudent, i.e. high in fruits, vegetables, whole grains, fish and poultry, (OR: 2.79 95% CI: 1.40–5.56); smoking cigarettes (OR: 1.68 95% CI: 1.12–2.53), and eating a Western diet, i.e. a diet high in meat, refined grains, high-fat foods, and fast foods, (OR: 2.15 95% CI: 1.06–4.35). Physical inactivity was not associated with increased cancer risk among those with a positive family history of colorectal cancer. Summary: These results confirm observations reported by others that a family history of colorectal cancer increases risk of cancer among those diagnosed at a younger age. Associations with family history are weakest for rectal cancer and strongest for proximal colonic tumors. Since several diet and lifestyle factors influence development of cancer among those with a family history of the disease, there appears to be practical approaches for individuals with a family history of colorectal cancer to reduce their cancer risk.

Dietary intake and microsatellite instability in colon tumors

Microsatellite instability (MSI) occurs in approximately 15% of colon tumors. Other than relatively rare mutations in mismatch repair genes, the causes of MSI are not generally known. The purpose of this study was to determine if dietary intake of nutrients previously reported as being associated with colon cancer relate specifically to the MSI disease pathway. Data from a population‐based case‐control study of adenocarcinoma of the colon were used to evaluate associations between dietary intake and MSI. Participants were between 30 and 79 years of age at time of diagnosis and included both men and women. Dietary intake data were obtained from a computerized diet history questionnaire. MSI was evaluated in several ways: by a panel of 10 tetranucleotide repeats, and by 2 mononucleotide repeats, BAT‐26 and TGFβRII. A total of 1,510 cases had valid study data and tumor DNA on which we were able to obtain MSI status. Cases with and without MSI were compared with dietary data reported by 2,410 population‐based controls to determine dietary associations that may be different for these 2 subsets of cases. We compared dietary intake for cases with and without MSI to further determine associations that are specific to the MSI disease pathway. When comparing MSI+ to MSI− tumors we observed that long‐term alcohol consumption, especially intake of liquor, increased the probability of having a tumor with MSI [odds ratio (OR) for MSI+ vs. MSI− tumors for alcohol 1.6, 95% confidence interval (CI) 1.0–2.5; OR for liquor 1.6, 95% CI 1.1–2.4]. The likelihood of having MSI in the tumor from the combined effects of high alcohol consumption and smoking cigarettes showed a 70% excess in risk from the additive model. There were some suggestions that high intakes of refined grain might also be associated with MSI+ tumors, although associations were less consistent. Risk estimates for most other dietary factors did not differ substantially by MSI status. Data from this large population‐based case‐control study of colon cancer indicate that alcohol consumption, especially consumption of liquor, may increase the odds of an MSI+ tumor. Most other dietary factors do not appear operate exclusively in the MSI+ disease pathway.

Lifestyle factors and Ki-ras mutations in colon cancer tumors

Heterogeneity in colon tumors implies that environmental, lifestyle, or genetic factors influence the type of mutations seen in tumors. In this study we evaluate the association between previously identified risk factors for colon cancer and Kirsten-ras (Ki-ras) mutations in tumors. The presence of Ki-ras mutations in codons 12 and 13 were determined in a population-based case-control study of colon cancer. Participants were between 30 and 79 years of age at time of diagnosis and include both men and women. Questionnaire data were used to obtain information on lifestyle factors. Valid study data and Ki-ras mutational status were available from 1428 cases of colon cancer, data from 2410 controls were available for comparative purposes. Participants with Ki-ras mutations were more likely to have proximal rather than distal tumors. Cigarette smoking, use of aspirin and/or NSAIDs, use of vitamin/mineral supplements, and consumption of caffeine were associated with both Ki-ras+ and Ki-ras- tumors; the associations were not confounded by dietary intake or other lifestyle factors. Among men, but not among women, those with low levels of physical activity were more likely to have a tumor with a Ki-ras mutation than one without a Ki-ras mutation. However, among women, those with a larger BMI were more likely to have a Ki-ras mutation in their tumor. Given the limited information available on what causes Ki-ras mutations, the information generated from this study indicates that these factors previously associated with colon cancer work through other disease pathways.

WESTERN DIET, FAMILY HISTORY OF COLORECTAL CANCER, NAT2, GSTM-1 AND RISK OF COLON CANCER

Objective: In this study we examine the combined effects of Western diet, age at diagnosis, and genetic susceptibility.Methods: We use data collected as part of an incident case–control study of colon cancer. Family history of colorectal cancer, N-acetyltransferase (NAT2), and gluathione-S-transferase (GSTM-1) are studied with Western diet and age at diagnosis.Results: A significant interaction between age at time of diagnosis, Western dietary pattern, and family history of colorectal cancer (p for interaction = 0.03) was detected. Those with a family history of colorectal cancer who ate a predominantly Western diet were at increased risk of colon cancer (OR 14.0, 95% CI 3.9–50.1 for ≤55 years; OR 7.7, 95% CI 2.0–29.1 for 56–66 years; OR 1.6, 95% CI 0.8–3.2 for ≥67 years) compared to those without a family history of colorectal cancer and low levels of a Western diet. Associations with the Western diet were stronger than individual components of the dietary pattern. Neither NAT2 nor GSTM-1 showed significant interaction with Western diet.Conclusion: The extent to which diet comprising a Western dietary pattern influences risk of colon cancer is dependent on age. This dietary pattern also appears to modulate the colon cancer risk associated with a family history of colon cancer.

GSTM-1 and NAT2 and genetic alterations in colon tumors

Objective: Phase II metabolizing enzymes such as glutathione S-transferases and N-acetyltransferase are involved in the detoxification of carcinogens. Genetic variants of genes coding for these enzymes have been evaluated as to their association with colon cancer, both as independent risk factors and as effect modifiers for associations with diet and cigarette smoking. In this study, we evaluate associations between the GSTM-1 genotype and the NAT2-imputed phenotype and acquired mutations in tumors Methods: Data is taken from a set of 1836 cases and 1958 controls with colon cancer who were part of a large case–control study of colon cancer and whose tumors were previously analyzed for Ki-ras, p53, and microsatellite instability (MSI). We also evaluate the modifying effects of these genetic variants with diet and cigarette smoking, factors previously identified as being associated with specific tumor alterations. Results: Neither GSTM-1 nor the NAT2-imputed phenotype was independently associated with Ki-ras, p53, or MSI. Cigarette smoking significantly increased the risk of tumors involving the MSI pathway. Additionally, cigarette smoking doubled the risk of p53 transversion mutations among those who were GSTM-1 present. Cases were slightly more likely to have a p53 mutation if they frequently consumed red meat and had the imputed NAT2 intermediate/rapid phenotype relative to slow phenotype/infrequent consumers of red meat (OR 2.0, 95% CI 1.3–3.0 for intermediate/rapid). Conclusions: These data provide support that diet and cigarette smoking may be associated with specific disease pathways, although GSTM-1 and NAT2 do not independently appear to alter susceptibility to these diet and lifestyle factors.

Associations among Body Mass Index, Waist Circumference, and Health Indicators in American Indian and Alaska Native Adults:

Purpose. Little is known about obesity-related health issues among American Indian and Alaska Native (AIAN) populations. Approach. A large cohort of AIAN people was assembled to evaluate factors associated with health. Setting. The study was conducted in Alaska and on the Navajo Nation. Participants. A total of 11,293 AIAN people were included. Methods. We present data for body mass index (BMI, kg/m2) and waist circumference (cm) to evaluate obesity-related health factors. Results. Overall, 32.4% of the population were overweight (BMI 25-29.9 kg/m2), 47.1% were obese (BMI ≥ 30 kg/m2), and 21.4% were very obese (BMI, ≥ 35 kg/m2). A waist circumference greater than 102 cm for men and greater than 88 cm for women was observed for 41.7% of men and 78.3% of women. Obese people were more likely to perceive their health as fair/poor than nonobese participants (prevalence ratio [PR], 1.91; 95% CI, 1.71-2.14). Participants younger than 30 years were three times more likely to perceive their health as being fair or poor when their BMI results were 35 or greater compared with those whose BMI results were less than 25 kg/m2. A larger BMI was associated with having multiple medical conditions, fewer hours of vigorous activity, and more hours of television watching. Conclusions. Given the high rates of obesity in AIAN populations and the association of obesity with other health conditions, it is important to reduce obesity among AIAN people.