Colorectal Cancer Risk Assessment Research Articles

Association of matrix metalloproteinase‐2 and ‐9 promoter polymorphisms with colorectal cancer in Chinese

Matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) play an important role in cancer initiation, invasion, and metastasis. The aim of this study was to investigate whether common genetic variants in these two key MMPs are associated with the development and progression of colorectal cancer in a Chinese population. We detected the MMP-2-790T/G, -955A/C, -1575G/A, and MMP-9-1562 C/T polymorphisms in 126 colorectal cancer patients and matched normal controls by PCR-denaturing high-performance liquid chromatography (DHPLC) or PCR-restriction fragment length polymorphism (RFLP), respectively. We found that the G/G genotype in the MMP-2-1575G/A polymorphism was significantly increased in colorectal cancer patients than in the controls (odds ratio (OR), 1.96; 95% CI, 1.06-3.64). Colorectal cancers with G/G genotype were more common with serosa/adventitia layer involvement than those with G/A+A/A genotypes (P<0.05). However, no significant differences were observed in distribution of the MMP-2-790T/G, -955A/C, and MMP-9-1562 C/T polymorphisms or haplotype of MMP-2 SNPs between patients and controls. Our results suggest that the presence of -1575G allele in the MMP-2 promoter region may be of significance in the assessment of colorectal cancer risk and invasive potential.

Racial and Gender Disparities in Hereditary Colorectal Cancer Risk Assessment: The Role of Family History

In this study, we aimed to examine racial/ethnic and gender differences in self-reported family cancer history knowledge in patients at high risk for hereditary colon cancer syndromes. We performed retrospective analysis of all referrals to the University of Chicago High Risk Colon Cancer Clinic between 1995 and 2003. We found hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis in 17% and 9% of Whites, respectively, and 6% and 0% of Blacks, respectively. Unknown paternal history was found in 6.5% of Whites and 18.9% of Blacks (23% men, 11% women). Blacks and men had significantly decreased rates of paternal history cancer knowledge.

Polymorphism of CD14 gene but not the mutation of TLR4 gene is associated with colorectal cancer in Chinese patients

Toll-like receptor 4 and CD14 are components of the lipopolysaccharide receptor complex. Our study aimed to investigate an association between TLR4 Asp299Gly and CD14-260 polymorphisms in Chinese patients with colorectal cancer. By a method of polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP), we genotyped TLR4 Asp299Gly and CD14-260 polymorphisms in 110 unrelated patients with colorectal cancer and 160 healthy controls from the Chinese Han population. We found significant differences in CD14 genotypes between healthy controls and patients with colorectal cancer. The frequency of the C/C genotype in healthy controls (15.6%) was significantly lower than in the group of colorectal cancer patients (32%). The frequency of the C/T genotype in healthy controls (48.1%) was significantly higher than that in the group of colorectal cancer patients (31%). No TLR4 Asp299Gly mutation was detected in any patients or healthy controls in the Chinese Han population. These findings indicated that the polymorphism of CD14 but not TLR4 Asp299Gly mutation was associated with Chinese patients with colorectal cancer, and the CD14 gene may contribute to the predisposition to colorectal cancer. Screening for the CD14 C-260T genotype is likely to be a useful tool for risk assessment or prognostication for colorectal cancer in the Chinese Han population.

MGMT Promoter Methylation and Field Defect in Sporadic Colorectal Cancer

Sporadic colorectal cancers often arise from a region of cells characterized by a "field defect" that has not been well defined molecularly. DNA methylation has been proposed as a candidate mediator of this field defect. The DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is frequently methylated in colorectal cancer. We hypothesized that MGMT methylation could be one of the mediators of field cancerization in the colon mucosa. We studied MGMT promoter methylation by three different bisulfite-based techniques in tumor, adjacent mucosa, and non-adjacent mucosa from 95 colorectal cancer patients and in colon mucosa from 33 subjects with no evidence of cancer. Statistical tests were two-sided. MGMT promoter methylation was present in 46% of the tumors. Patients whose cancer had MGMT promoter methylation also had substantial MGMT promoter methylation in apparently normal adjacent mucosa. This methylation was seen with a quantitative assay in 50% (22/44; 95% confidence interval [CI] = 34% to 65%) of normal samples with MGMT promoter methylation in the adjacent tumors, 6% (3/51; 95% CI = 1% to 16%) of samples without MGMT methylation in adjacent tumors, and 12% (4/33; 95% CI = 3% to 28%) of control samples (P < .001 for comparison between each of the latter two groups and the first group). MGMT methylation was detected with a more sensitive assay in 94%, 34%, and 27% of these samples, respectively (P < .001). In grossly normal colonic mucosa of colon cancer patients, methylation was detected 10 cm away from the tumor in 10 of 13 cases. Tumors with MGMT promoter methylation had a higher rate of G-to-A mutation in the KRAS oncogene than tumors without MGMT promoter methylation (10/42 versus 3/46, P = .03). Using a sensitive mutant allele-specific amplification assay for KRAS mutations, we also found KRAS mutations in 12% (3/25; 95% CI = 2.5% to 31%) of colorectal mucosas with detectable MGMT methylation and 3% (2/64; 95% CI = 0.4% to 11%) of colorectal mucosas without MGMT methylation (P = .13). Some colorectal cancers arise from a field defect defined by epigenetic inactivation of MGMT. Detection of this abnormality may ultimately be useful in risk assessment for colorectal cancer.

Inherited Polyposis Syndromes: Molecular Mechanisms, Clinicopathology, and Genetic Testing

The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.

Genetic Testing for Inherited Colon Cancer

The genes associated with each of the inherited syndromes of colon cancer have now been identified, and genetic testing is available for diagnosis. These syndromes include familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz-Jeghers syndrome, juvenile polyposis syndrome, and, possibly, Cowden's syndrome. Clinical genetic testing approaches have been developed for each of these syndromes and are now a part of accepted clinical care. Disease-causing mutations can be found in the majority of families affected with one of the inherited syndromes, and, most importantly, once a mutation is found in an index case of the family, relatives can be tested for the presence or absence of that mutation with near 100% accuracy. Cancer screening and management in syndrome families is then based on the results of genetic testing. For the physician to order and properly interpret genetic tests, a basic understanding of the types of mutations that lead to inherited disease and the methods for detecting them is vital. These issues will be presented. Additional clinical issues somewhat unique to genetic testing include genetic counseling and informed consent for genetic testing, both of which will also be reviewed. Often the most difficult aspect of genetic testing is deciding which patients and families should undergo the testing. Furthermore, this issue is quite specific for each of the syndromes. Thus, following presentation of general principles of selection for genetic testing, a detailed approach for identifying persons who should undergo testing for each of the individual syndromes will be given, together with relevant descriptions of the syndromes. Finally, the ongoing work to discover new and possibly more common but less penetrant colon cancer susceptibility genes that cause common familial colon cancer will be presented.

A Novel Educational Strategy to Enhance Internal Medicine Residents' Familial Colorectal Cancer Knowledge and Risk Assessment Skills

Internal medicine residents are deficient in their knowledge about familial colorectal cancer (CRC) and thus unable to comply with appropriate screening guidelines. The objective of this study was to evaluate the effectiveness of a mixed educational program that incorporates both a didactic lecture (DL) and interactive, case-based seminar (ICBS), plus distribution of a personal digital assistant (PDA)-based risk assessment tool. Internal medicine resident continuity care teams were randomly assigned to an intervention (9 teams; 43 residents) or control (11 teams; 39 residents) arm. Both groups participated in a DL addressing the current status of CRC screening for average, moderate, and high-risk groups. Intervention teams also participated in a 1-h pre-clinic ICBS that included vignettes about patients at moderate or high risk of CRC because of family history, following which they received the risk assessment tool by e-mail. Knowledge and clinical risk assessment skills were evaluated using pre/posttests, patient exit interviews, and chart audits. Baseline test scores were similar for both groups (intervention, 51%vs control, 54%; p= 0.35). Immediate post-ICBS scores (intervention group only) significantly increased to 82% (p < 0.001). Six-month post-ICBS scores declined for the intervention group but remained significantly higher than 6-month control group scores (63%vs 56%, p= 0.002), which were unchanged from baseline. No significant differences were observed with respect to family history-taking or documentation skills. A mixed educational program that incorporates both a DL and ICBS is more effective that the DL alone for increasing knowledge about familial CRC risk but may have limited influence on clinical risk assessment skills.

A high degree of aneuploidy, loss of p53 gene, and low soluble p53 protein serum levels are detected in ulcerative colitis patients.

The causes for the increased risk of colorectal cancer associated with ulcerative colitis have not been fully defined. Colonic tissue of ulcerative colitis patients was examined for changes in chromosome-17-centromere copy number, loss of the p53 gene, and alterations in serum levels of the 53-kDa protein. This study was performed under the assumption that these molecular events correlate with ulcerative colitis status and duration. Ulcerative colitis patients (n = 42) and healthy controls (n = 37) participated in the study. All participants were histopathologically and medically diagnosed. The stage of ulcerative colitis patients was stratified according to increasing risk factors for the development of colorectal cancer: left-sided colitis, pancolitis, sclerosing cholangitis, and dysplasia-associated lesions or masses. Changes in centromere number of chromosome 17 alone or in association with changes in copy number of the p53 gene were analyzed in colon tissue biopsies by fluorescence in situ hybridization. Serum p53 level was determined in blood samples by immunoprecipitation followed by separation using high-pressure liquid chromatography. Changes in chromosome 17 and p53 copy number and lower levels of serum p53 protein in ulcerative colitis patients directly correlated with colorectal cancer risk factors. All values significantly differed from controls. Significant direct correlations were obtained for ulcerative colitis disease duration, levels of p53 in the serum, and extent of aneuploidy. We demonstrate that in the colonic mucosa of ulcerative colitis patients, high levels of genomic instability, changes in p53 gene copy number, and lower levels of p53 in the serum directly correlate with the extent of disease duration and increased risk factors for colorectal cancer. Any of the measurements described herein can provide an acceptable prognostic tool in the assessment of colorectal cancer risk in ulcerative colitis patients.

Screening for colorectal cancer

PREVIEWThe importance of screening for colorectal cancer has been established, but the decision about which test to use for each patient may seem less clear. In this article, Dr Wineman discusses assessment of colorectal cancer risk and the advantages and disadvantages of the fecal occult blood test, flexible sigmoidoscopy, double-contrast barium enema, and colonoscopy. Potential screening methods that could make regular colon examination more acceptable to patients also are presented.

Risk assessment and screening for colorectal cancer.

Risk assessment and screening for colorectal cancer.

Colon cancer screening strategies

Screening has been shown to reduce morbidity and mortality related to colorectal cancer. However, the optimal strategy for population screening for colorectal cancer has been a topic of heated debate. Recent studies have challenged the efficacy and cost-effectiveness of current population screening practices. Novel approaches to improve the assessment of an individual's colorectal cancer risk and advances in technology are changing our approach to colorectal screening. This review covers current guidelines for screening for colorectal cancer, recent advances in cancer risk assessment, and the role of endoscopy, virtual colonoscopy, and fecal DNA testing in colorectal cancer screening.

Colon cancer screening strategies

Screening has been shown to reduce morbidity and mortality related to colorectal cancer. However, the optimal strategy for population screening for colorectal cancer has been a topic of heated debate. Recent studies have challenged the efficacy and cost-effectiveness of current population screening practices. Novel approaches to improve the assessment of an individual's colorectal cancer risk and advances in technology are changing our approach to colorectal screening. This review covers current guidelines for screening for colorectal cancer, recent advances in cancer risk assessment, and the role of endoscopy, virtual colonoscopy, and fecal DNA testing in colorectal cancer screening.

Authors’ Response: Acromegaly and Colorectal Cancer—Risk Assessment Should Be Based on Population-Based Studiesd

Authors’ Response: Acromegaly and Colorectal Cancer—Risk Assessment Should Be Based on Population-Based Studies<i>d</i>

Response to genetic counseling and testing for the APC I1307K mutation.

The APC I1307K gene mutation is associated with increased colorectal cancer (CRC) risk in Ashkenazi Jews. Factors predicting acceptance of this and other hereditary colon cancer mutation tests in a clinical setting are unknown. We analyzed sex, age, family history, personal history, and gene test results of patients at increased risk for cancer who sought cancer risk counseling at the Johns Hopkins (JH) CRC Risk Assessment Clinic (n = 91), and those submitting samples to the JH Pathology Molecular Diagnostic Laboratory (n = 256) for APC I1307K testing. Of patients seen at the JH Clinic, 77/91 (84.6%) elected APC I1307K testing after pretest counseling (acceptors). There were no statistically significant differences in demographic characteristics between acceptors and decliners. In comparison, only 8 of 57 (14.0%) patients offered HNPCC testing proceeded with testing (P < 0.001). Of 256 individuals tested at the JH laboratory, most were male (61.3%) and most had a personal or family history of colorectal cancer or polyps. Test positivity correlated with increasing risk of colorectal cancer. Acceptance of testing for the APC I1307K mutation is high, with more men than women pursuing counseling and testing. The reported association between the APC I1307K mutation and colon cancer risk was supported by a correlation in these data between personal or family history of CRC or polyps and a gene mutation.

A computerized colorectal cancer prevention registry and risk assessment tool

A computerized colorectal cancer prevention registry and risk assessment tool

Assessment of Colorectal Cancer Risk in Patients With Ulcerative Colitis: Experience From a Private Practice

The cumulative risk of developing colon cancer in patients with ulcerative colitis has been stated to increase 10%-20% for every decade of duration of disease after 10 yr. We reviewed the clinical course of 673 patients with inflammatory bowel disease restricted to the colon who were seen by the authors since 1955. A subset of 258 patients with a diagnosis of ulcerative colitis established before 1970 and followed by the authors was studied by both the classical life table and a generalized approach to estimate the risk of colorectal carcinoma. Only nine instances of colorectal carcinoma occurred. Using the former method and eliminating 3 patients referred with known colorectal carcinoma, the actuarial risk for developing this complication for all patients, regardless of extent of disease, was computed to be only 6.6% at 26 yr and 11.4% at 32 yr following the onset of ulcerative colitis. The cumulative probability of colorectal carcinoma among patients with universal colitis at 26 yr was 19.7% by the generalized method and 11.6% using the standard life table. The generalized approach consistently gave higher risk estimates due to a smaller number of patients in the denominator of the risk calculation. Using an alternative method, we calculated cancer risk from the date first seen for patients with universal extent and a history of greater than or equal to 10 yr of disease (means = 17.4 yr). The magnitude of the resulting colorectal carcinoma risk was even less than previously reported in hospitalized patients. This method is more suited for colorectal carcinoma risk assessment of a large series of ulcerative colitis patients seen in private practice and the results should modify the fear of cancer development in these patients.